Childhood Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Hodgkin Lymphoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 2013 and 2019, the 5-year overall survival rate was 98% for patients younger than 20 years with Hodgkin lymphoma.[2]

Overview of Childhood Hodgkin Lymphoma

Childhood Hodgkin lymphoma is one of the few pediatric malignancies that shares aspects of its biology and natural history with an adult cancer. When initial treatment approaches for children were modeled after those used for adults, substantial morbidities resulted from unacceptably high radiation doses. As a result, strategies using chemotherapy and lower-dose radiation were developed. Presently, treatment approaches for pediatric and adult patients are merging, focusing on improving outcomes while reducing late effects in both populations.

Approximately 90% to 95% of children and adolescents with Hodgkin lymphoma can be cured, prompting increased attention to therapy that lessens long-term morbidity. Contemporary treatment programs use a risk-based and response-adapted approach in which patients receive multiagent chemotherapy, with or without low-dose involved-field or involved-site radiation therapy. Prognostic factors used to determine chemotherapy intensity include cancer stage, presence or absence of B symptoms (fever, weight loss, and night sweats), bulky disease, extranodal involvement, and/or erythrocyte sedimentation rate.

Epidemiology

Hodgkin lymphoma accounts for 6.5% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age related and is highest among adolescents aged 15 to 19 years (31.2 cases per 1 million per year). Children aged 10 to 14 years, 5 to 9 years, and 0 to 4 years have approximately threefold, tenfold, and 30-fold lower rates of Hodgkin lymphoma, respectively, than do adolescents.[2] In low-income countries, the incidence rate is similar in young adults but much higher in children.[3]

Hodgkin lymphoma has the following unique epidemiological features:

• Bimodal age distribution. Bimodal age distribution differs geographically and ethnically. In industrialized countries, the early peak occurs in the middle-to-late 20s and the second peak after age 50 years. In low-income countries, the early peak occurs before adolescence.[4]
• Male-to-female ratio. This ratio varies markedly by age. In children younger than 10 years, the incidence of Hodgkin lymphoma is threefold higher in males than in females. In children aged 10 to 14 years, the incidence is approximately 1.2-fold higher in males than in females. In adolescents aged 15 to 19 years, the incidence is similar for males and females.[2]
• Age cohorts. Hodgkin lymphoma can be segregated into the following three age cohorts because of the variation in etiologies and histological subtypes (see Table 1):
  • Children: More males than females are affected in the youngest age cohort, especially in children younger than 10 years.

    Individuals aged 14 years and younger have a higher prevalence of the non-classical nodular lymphocyte-predominant disease (NLPHL) and Epstein-Barr virus (EBV)–associated mixed-cellularity disease. EBV-associated Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status.[4]

    Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[5,6]

  • Adolescents and young adults: Hodgkin lymphoma in individuals aged 15 to 34 years is associated with a higher socioeconomic status in industrialized countries, increased sibship size, and earlier birth order.[7] The lower risk of Hodgkin lymphoma observed in young adults with multiple older, but not younger, siblings, is consistent with the hypothesis that early exposure to viral infection (which the siblings bring home from school, for example) may play a role in the pathogenesis of the disease.[5]

    Nodular-sclerosing Hodgkin lymphoma is the most common subtype, followed by mixed cellularity.

  • Older adults: Hodgkin lymphoma also occurs in individuals aged 55 to 74 years, who have a higher risk of lymphocyte-depleted Hodgkin lymphoma. The treatment of older adults is not discussed in this summary. For more information, see Hodgkin Lymphoma Treatment.
• Family history. A family history of Hodgkin lymphoma in siblings or parents has been associated with an increased risk of this disease.[8,9] In a population-based study that evaluated risk of familial classical Hodgkin lymphoma (i.e., not including NLPHL) by relationship, histology, age, and sex, the cumulative risk of Hodgkin lymphoma was 0.6%, a 3.3-fold increased risk compared with the general population.[10] The risk in siblings was significantly higher than the risk in parents and/or offspring. The risk in sisters was higher than the risk in brothers or siblings of opposite sex. The lifetime risk of Hodgkin lymphoma was higher when first-degree relatives were diagnosed before age 30 years.
• Genetic susceptibility. A study of twins affected by Hodgkin lymphoma showed that monozygotic twins, but not dizygotic twins, have a greatly increased risk of Hodgkin lymphoma (standardized incidence ratio of approximately 100). This finding supports the idea that genetic susceptibility underlies Hodgkin lymphoma.[11] A meta-analysis of genome-wide association studies identified 18 risk loci for Hodgkin lymphoma, further validating the major role of genetic susceptibility. Genes putatively associated with the risk loci affected three general biological processes: germinal center reaction, T-cell differentiation and function, and constitutive nuclear factor kappa-light-chain-enhancer of activated B cells activation.[12]

  A comprehensive whole genome sequencing effort was conducted in 234 individuals with and without Hodgkin lymphoma, selected from 36 pedigrees that had two or more affected first-degree relatives.[13] Using linkage and a tiered variant prioritization algorithm, 44 Hodgkin lymphoma pathogenic risk variants were identified (33 coding variants and 11 noncoding variants). A recurrent coding variant was seen in KDR, and a 5' untranslated region variant was seen in KLHDC8B—both of which have previously been identified. Two new noncoding variants were seen in PAX5 (intron 5) and GATA3 (intron 3). In addition, multiple unrelated families harbored novel loss of function variants in POLR1E and stop-gain variants in IRF7 and EEF2KMT. These findings validated previous studies and identified additional germline pathogenic variants associated with an increased risk of Hodgkin lymphoma.

Table 1. Epidemiology of Hodgkin Lymphoma (HL) Across the Age Spectrum^a

Variables		Childhood HL	AYA HL	Adult HL	Older Adult HL
Age Range		≤14 y	15–34 y	≥35 y	≥55 y
Prevalence of HL		10%–12%	50%		35%
Sex (Male-to-Female Ratio)		2–3:1	1:1–1.3:1		1.2:1–1:1.1
Histology:
	Nodular sclerosing	40%–45%	65%–80%		35%–40%
	Mixed cellularity	30%–45%	10%–25%		35%–50%
	NLPHL	8%–20%	2%–8%		7%–10%
EBV Associated		27%–54%	20%–25%	34%–40%	50%–56%
Advanced Stage		30%–35%	40%		55%
B Symptoms		25%	30%–40%		50%
Relative Survival: Rates at 5 Years		94% (age <20 y)	90% (age <50 y)		65% (age >50 y)
AYA = adolescent and young adult; EBV = Epstein-Barr virus; NLPHL = nodular lymphocyte-predominant Hodgkin lymphoma.
a Adapted from Punnett et al.[14]

EBV and Hodgkin lymphoma

EBV has been implicated in the etiology of some cases of Hodgkin lymphoma. Some patients with Hodgkin lymphoma have high EBV titers, suggesting that a previous EBV infection may precede the development of Hodgkin lymphoma. EBV genetic material can be detected in Hodgkin and Reed-Sternberg (HRS) cells from some patients with Hodgkin lymphoma, most commonly in those with mixed-cellularity disease.[15] In children and adolescents with intermediate-risk Hodgkin lymphoma, EBV DNA in cell-free blood correlated with the presence of EBV in the tumor. EBV DNA found in cell-free blood 8 days after the initiation of therapy predicted an inferior event-free survival (EFS).[15]

The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:

• Histology. EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology (i.e., NLPHL).[16,17]
• Age. EBV positivity is more common in children younger than 10 years than in adolescents and young adults.[16,17]
• Low-income countries. The incidence of EBV tumor cell positivity for Hodgkin lymphoma in low-income countries ranges from 15% to 25% in adolescents and young adults.[16,17,18] A high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma is seen in low-income countries, and these cases are generally EBV positive (approximately 80%).[19]

EBV serologic status is not a prognostic factor for failure-free survival in young adult patients with Hodgkin lymphoma,[16,17,18,20] but plasma EBV DNA has been associated with an inferior outcome in adults.[21] However, children with intermediate-risk disease with higher levels of EBV DNA at diagnosis have better outcomes.[15] This also correlates with better outcomes for patients with mixed-cellularity disease treated with dose-dense chemotherapy (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide [ABVE-PC]). Patients with a previous history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma. These patients are not at increased risk of developing EBV-negative Hodgkin lymphoma.[22]

Immunodeficiency and Hodgkin lymphoma

Individuals with immunodeficiency have an increased risk of Hodgkin lymphoma,[23] although the risk of non-Hodgkin lymphoma is even higher.

Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:

• Hodgkin lymphoma usually occurs at a younger age and with histologies other than nodular sclerosing in patients with primary immunodeficiencies.[23]
• The risk of Hodgkin lymphoma increases as much as 50-fold over the general population in patients with autoimmune lymphoproliferative syndrome (ALPS).[24]
• Although it is not an AIDS-defining malignancy, the incidence of Hodgkin lymphoma appears to be higher in HIV-infected individuals, including children.[25,26]
• Recipients of solid organ transplants who take chronic immunosuppressive medications have a higher risk of Hodgkin lymphoma than the general population.[27]
• Hodgkin lymphoma is the second most common cancer type in children who have undergone a solid organ transplant.[28]

Clinical Presentation

The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from HRS cells and cell signaling within the tumor microenvironment:[29]

• Approximately 80% of patients present with painless adenopathy, most commonly involving the supraclavicular or cervical area.
• Mediastinal disease, which may be asymptomatic, is present in about 75% of adolescents and young adults with Hodgkin lymphoma, compared with only about 35% of young children with Hodgkin lymphoma. This difference reflects the greater prevalence of mixed-cellularity and lymphocyte-predominant (i.e., NLPHL) histology versus nodular-sclerosing histology in this age cohort.
• Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients.[30,31]
• Three specific constitutional symptoms (B symptoms) that have been correlated with prognosis are commonly used to assign risk in clinical trials. These symptoms include unexplained fever (temperature above 38.0°C orally), unexplained weight loss (10% of body weight within the 6 months preceding diagnosis), and drenching night sweats.[32]
• Female patients with large mediastinal masses and B symptoms are most likely to present with pericardial effusions.[33][Level of evidence C1]

Approximately 15% to 20% of patients have noncontiguous extranodal involvement (stage IV). The most common sites of extranodal involvement are the lungs, liver, bones, and bone marrow.[30,31]

Prognostic Factors

As the treatment of Hodgkin lymphoma improved, factors associated with outcome became more difficult to identify. However, several factors continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biological aggressiveness are frequently collinear.

Pretreatment factors

Pretreatment factors associated with an adverse outcome include the following:

• Advanced stage of disease.[34,35,36]
• Presence of B symptoms.[30,31,34]
• Presence of bulky disease.[30,34]
• Presence of a pericardial effusion.[33][Level of evidence C1]
• Presence of a pleural effusion.[37][Level of evidence B4]
• Elevated erythrocyte sedimentation rate.[38]
• Leukocytosis (white blood cell count of 11,500/mm³ or higher).[39]
• Anemia (hemoglobin lower than 11.0 g/dL).[39]
• Hypoalbuminemia.[34]
• Male sex.[31,39]

Prognostic factors identified in select multi-institutional studies include the following:

• In the Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH)-95 study, B symptoms, histology, and male sex were adverse prognostic factors for EFS on multivariate analysis.[31]
• In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male sex; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm³ or higher; and hemoglobin lower than 11.0 g/dL were significant prognostic factors for inferior disease-free survival and overall survival (OS). Prognosis was also associated with the number of adverse factors.[39]
• In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.[30]
• Factors associated with adverse outcome, many of which are collinear, were evaluated by multivariable analysis in the Children's Oncology Group (COG) AHOD0031 (NCT00025259) trial for 1,734 children with intermediate-risk Hodgkin lymphoma. The most robust predictors of outcome in this homogeneously treated cohort were stage IV disease, fever, a large mediastinal mass, and low albumin (<3.4 g/dL). The Childhood Hodgkin International Prognostic Score (CHIPS), highly predictive of EFS, was derived by giving a point for each adverse factor.[34] However, CHIPS requires further prospective validation.
• Pleural effusions have been shown to be an adverse prognostic finding in patients treated for low-stage Hodgkin lymphoma.[37][Level of evidence B4] The risk of relapse was 25% in patients with an effusion, compared with less than 15% in patients without an effusion. Patients with effusions were more often older (15 years vs. 14 years) and had nodular-sclerosing histology.
• A single-institution study showed that Black patients had a higher relapse rate than White patients, but OS was similar.[40] A COG analysis showed no difference in EFS by race or ethnicity. However, compared with non-Hispanic White children, Hispanic and non-Hispanic Black children had an inferior OS because of an increased postrelapse mortality rate.[41][Level of evidence A1]

Response to initial chemotherapy

The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important.[42,43,44] Response evaluation in previous generations of trials relied on computed tomography and gallium uptake; positron emission tomography (PET) scanning is now routinely used to assess early response in pediatric Hodgkin lymphoma.[45] Fluorine F 18-fludeoxyglucose PET avidity after two cycles of chemotherapy (PET2) for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[46,47,48] Reduction in PET avidity after one cycle of chemotherapy was associated with a favorable EFS outcome in children with limited-stage classical Hodgkin lymphoma.[38] Additional studies in children are ongoing to assess the role of early PET-based response in modifying therapy and predicting outcome.

Prognostic factors will continue to change because of risk stratification and choice of therapy, with parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy used to stratify therapeutic assignment.

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31. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.
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35. Milgrom SA, Kim J, Chirindel A, et al.: Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031. Pediatr Blood Cancer 68 (9): e29212, 2021.
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38. Keller FG, Castellino SM, Chen L, et al.: Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group. Cancer 124 (15): 3210-3219, 2018.
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40. Metzger ML, Castellino SM, Hudson MM, et al.: Effect of race on the outcome of pediatric patients with Hodgkin's lymphoma. J Clin Oncol 26 (8): 1282-8, 2008.
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42. Weiner MA, Leventhal B, Brecher ML, et al.: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 15 (8): 2769-79, 1997.
43. Landman-Parker J, Pacquement H, Leblanc T, et al.: Localized childhood Hodgkin's disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol 18 (7): 1500-7, 2000.
44. Friedman DL, Chen L, Wolden S, et al.: Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. J Clin Oncol 32 (32): 3651-8, 2014.
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47. Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007.
48. Dann EJ, Bar-Shalom R, Tamir A, et al.: Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 109 (3): 905-9, 2007.

Cellular Classification and Biological Correlates of Childhood Hodgkin Lymphoma

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Hodgkin and Reed-Sternberg [HRS] cells) or large mononuclear cell variants (lymphocytic and histiocytic cells). These cells are in a background of inflammatory cells consisting of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. The inflammatory cells are present in different proportions depending on the histological subtype. It has been conclusively shown that HRS cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells.[1,2,3]

The histological features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the tumor necrosis factor receptors family secreted by the HRS cells and cell signaling within the tumor microenvironment.[4,5,6]

The hallmark of Hodgkin lymphoma is the HRS cell and its variants,[7] which have the following features:

• The HRS cell is a binucleated or multinucleated giant cell with a bilobed nucleus and two large nucleoli that give a characteristic owl's eye appearance.[7]
• The malignant HRS cell comprises only about 1% of the abundant reactive cellular infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils in involved specimens.[7]
• HRS cells almost always express CD30. They express CD15 in about 70% of patients and CD20 in 6% to 10% of patients. As opposed to other cells of hematologic origin, HRS cells do not express CD45, CD19, or CD79A, which are typically expressed in other B-cell lymphomas.[8,9,10]
• In nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), the malignant cells equivalent to HRS cells are lymphocyte-predominant (LP) cells, previously named lymphocyte and histiocytic (L&H) cells and sometimes referred to as popcorn cells. They are usually mononuclear, with a markedly convoluted and lobated nucleus (hence popcorn cells). LP cells do not express CD30, but they do express CD20 and other B-cell surface antigens. This evidence shows that NLPHL is biologically distinct from other subtypes of Hodgkin lymphoma and, therefore, not considered to be classical Hodgkin lymphoma.

Hodgkin lymphoma can be divided into the following two broad pathological classes:[11,12]

• Classical Hodgkin lymphoma (cHL).
• Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

Classical Hodgkin Lymphoma (cHL)

cHL is divided into four subtypes, which are defined according to the number of HRS cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis.[3]

Characteristics of the four histological subtypes of cHL include the following:

• Nodular-sclerosing (NS) Hodgkin lymphoma. This histology accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents but only 55% of cases in younger children in the United States.[13]

  This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain an HRS cell variant called the lacunar cell. Transforming growth factor-beta (TGF-beta) may be responsible for the fibrosis in this subtype.

  A study of over 600 patients with NS Hodgkin lymphoma from three university hospitals in the United States showed that two haplotypes in the HLA class II region correlated with a 70% increased risk of developing NS Hodgkin lymphoma.[14] Another haplotype was associated with a 60% decreased risk of developing Hodgkin lymphoma. These haplotypes are thought to be associated with atypical immune responses that predispose patients to Hodgkin lymphoma.

• Mixed-cellularity (MC) Hodgkin lymphoma. This subtype is more common in young children than in adolescents and adults, accounting for approximately 20% of cases in children younger than 10 years, but only approximately 9% of cases in older children and adolescents aged 10 to 19 years in the United States.[13] A high percentage of MC Hodgkin lymphoma cases are Epstein-Barr virus positive.[15]

  HRS cells are frequent in a background of abundant normal reactive cells (lymphocytes, plasma cells, eosinophils, and histiocytes). Interleukin-5 may be responsible for the eosinophilia in MC Hodgkin lymphoma. This subtype can be difficult to distinguish from non-Hodgkin lymphoma.

• Lymphocyte-rich Hodgkin lymphoma. This subtype may have a nodular appearance, but immunophenotypical analysis shows a distinction between this form of Hodgkin lymphoma and NLPHL.[16] Lymphocyte-rich classical Hodgkin lymphoma cells express CD15 and CD30.
• Lymphocyte-depleted Hodgkin lymphoma. This subtype is rare in children. It is common in adult patients with HIV and older adults.

  This subtype is characterized by numerous large, bizarre malignant cells, many HRS cells, and few lymphocytes. Diffuse fibrosis and necrosis are common. Many cases previously diagnosed as lymphocyte-depleted Hodgkin lymphoma are now recognized as diffuse large B-cell lymphoma, anaplastic large cell lymphoma, or NS classical Hodgkin lymphoma with lymphocyte depletion.[17]

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

The frequency of NLPHL in the pediatric population ranges from 5% to 10% in different studies, with a higher frequency in children younger than 10 years than in children aged 10 to 19 years.[13] This type of Hodgkin lymphoma is most common in males younger than 18 years.[18,19]

Characteristics of NLPHL include the following:

• Patients generally present with localized, nonbulky, peripheral lymphadenopathy that rarely involves the mediastinum.[18,19] Less than 10% of patients have systemic B symptoms, although some patients with involved lymph nodes, especially cervical, may experience discomfort.[20]
• NLPHL is characterized by molecular and immunophenotypical evidence of B-lineage differentiation with the following distinctive features:
  • Large cells with multilobed nuclei, termed LP cells (previously referred to as L&H cells and sometimes referred to as popcorn cells), as opposed to HRS cells of cHL, express pan–B-cell antigens such as CD19, CD20, CD22, and CD79A. They are negative for CD15 and may or may not express CD30.[21] They also express the B-cell transcription factors OCT2 and BOB1.[22]
  • Reliable discrimination from non-Hodgkin lymphoma (i.e., diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and gray zone lymphoma) is problematic in diffuse subtypes with lymphocytic and histiocytic cells set against a diffuse background of reactive T cells.[23]
  • NLPHL can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell–rich B-cell lymphoma.[24]
  • Histological variants may impact event-free survival (EFS).[25]
  • Immunoglobulin (Ig) D expression connotes a distinct type of NLPHL that is associated with a very high male-to-female ratio (>10:1).[26,27] In one study, 87 of the 124 pediatric cases (70%) versus 32 of the 84 adult (>18 years) cases (38%) tested expressed IgD in LP cells (P < .0001). The median age of the IgD-positive patients was 14 years.[26] In a second study, the median age of IgD-positive patients was 21 years, compared with a median age of 44 years for the IgD-negative patients.[27] The IgD-positive patients were more likely to present with cervical node involvement (58%) than were the IgD-negative patients (18%). IgD expression was not associated with EFS.
• Pediatric patients (aged <20 years) have better outcomes than adult patients, even when controlling for other prognostic factors.[19] Chemotherapy and/or radiation therapy produce excellent long-term progression-free survival and overall survival in patients with NLPHL. However, radiation therapy alone should not be considered for prepubescent patients because the evidence-based doses necessary for tumor control are associated with musculoskeletal impairment. When radiation is administered with chemotherapy, lower radiation doses are effective. Late recurrences have been reported up to 10 years after initial therapy.[20,28,29]; [30][Level of evidence B4]
• Deaths of individuals with NLPHL are more frequently related to treatment complications and/or the development of subsequent neoplasms (including non-Hodgkin lymphoma) than refractory disease. This finding underscores the importance of judicious use of chemotherapy and radiation therapy at initial presentation and after recurrent disease.[28,29]

References:

1. Bräuninger A, Schmitz R, Bechtel D, et al.: Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 118 (8): 1853-61, 2006.
2. Mathas S: The pathogenesis of classical Hodgkin's lymphoma: a model for B-cell plasticity. Hematol Oncol Clin North Am 21 (5): 787-804, 2007.
3. Pizzi M, Tazzoli S, Carraro E, et al.: Histology of pediatric classic Hodgkin lymphoma: From diagnosis to prognostic stratification. Pediatr Blood Cancer 67 (5): e28230, 2020.
4. Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005.
5. Steidl C, Connors JM, Gascoyne RD: Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol 29 (14): 1812-26, 2011.
6. Diefenbach C, Steidl C: New strategies in Hodgkin lymphoma: better risk profiling and novel treatments. Clin Cancer Res 19 (11): 2797-803, 2013.
7. Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002.
8. Portlock CS, Donnelly GB, Qin J, et al.: Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease. Br J Haematol 125 (6): 701-8, 2004.
9. von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin's disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997.
10. Tzankov A, Zimpfer A, Pehrs AC, et al.: Expression of B-cell markers in classical Hodgkin lymphoma: a tissue microarray analysis of 330 cases. Mod Pathol 16 (11): 1141-7, 2003.
11. Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002.
12. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.
13. Bazzeh F, Rihani R, Howard S, et al.: Comparing adult and pediatric Hodgkin lymphoma in the Surveillance, Epidemiology and End Results Program, 1988-2005: an analysis of 21 734 cases. Leuk Lymphoma 51 (12): 2198-207, 2010.
14. Cozen W, Li D, Best T, et al.: A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119 (2): 469-75, 2012.
15. Lee JH, Kim Y, Choi JW, et al.: Prevalence and prognostic significance of Epstein-Barr virus infection in classical Hodgkin's lymphoma: a meta-analysis. Arch Med Res 45 (5): 417-31, 2014.
16. Anagnostopoulos I, Hansmann ML, Franssila K, et al.: European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 96 (5): 1889-99, 2000.
17. Slack GW, Ferry JA, Hasserjian RP, et al.: Lymphocyte depleted Hodgkin lymphoma: an evaluation with immunophenotyping and genetic analysis. Leuk Lymphoma 50 (6): 937-43, 2009.
18. Hall GW, Katzilakis N, Pinkerton CR, et al.: Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a Children's Cancer and Leukaemia Group report. Br J Haematol 138 (6): 761-8, 2007.
19. Gerber NK, Atoria CL, Elkin EB, et al.: Characteristics and outcomes of patients with nodular lymphocyte-predominant Hodgkin lymphoma versus those with classical Hodgkin lymphoma: a population-based analysis. Int J Radiat Oncol Biol Phys 92 (1): 76-83, 2015.
20. Marks LJ, Pei Q, Bush R, et al.: Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 65 (12): e27375, 2018.
21. Shankar A, Daw S: Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents--a comprehensive review of biology, clinical course and treatment options. Br J Haematol 159 (3): 288-98, 2012.
22. Stein H, Marafioti T, Foss HD, et al.: Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97 (2): 496-501, 2001.
23. Boudová L, Torlakovic E, Delabie J, et al.: Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 102 (10): 3753-8, 2003.
24. Kraus MD, Haley J: Lymphocyte predominance Hodgkin's disease: the use of bcl-6 and CD57 in diagnosis and differential diagnosis. Am J Surg Pathol 24 (8): 1068-78, 2000.
25. Untanu RV, Back J, Appel B, et al.: Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 65 (1): , 2018.
26. Huppmann AR, Nicolae A, Slack GW, et al.: EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38 (3): 316-24, 2014.
27. Prakash S, Fountaine T, Raffeld M, et al.: IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol 30 (5): 585-92, 2006.
28. Chen RC, Chin MS, Ng AK, et al.: Early-stage, lymphocyte-predominant Hodgkin's lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28 (1): 136-41, 2010.
29. Jackson C, Sirohi B, Cunningham D, et al.: Lymphocyte-predominant Hodgkin lymphoma--clinical features and treatment outcomes from a 30-year experience. Ann Oncol 21 (10): 2061-8, 2010.
30. Appel BE, Chen L, Buxton AB, et al.: Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group. J Clin Oncol 34 (20): 2372-9, 2016.

Genomics of Hodgkin Lymphoma

Genomics of Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma has a molecular profile that differs from that of non-Hodgkin lymphomas. The exception is primary mediastinal B-cell lymphoma, which shares many genomic and cytogenetic characteristics with Hodgkin lymphoma.[1,2] Characterization of genomic alterations for Hodgkin lymphoma is challenging because malignant Hodgkin and Reed-Sternberg (HRS) cells make up only a small percentage of the overall tumor mass. Because of this finding, special methods, such as microdissection of HRS cells or flow cytometry cell sorting, are required before applying molecular analysis methods.[2,3,4,5] Hodgkin lymphoma genomic alterations can also be assessed using special sequencing methods applied to circulating cell-free DNA (cfDNA) in peripheral blood of patients with Hodgkin lymphoma.[6,7]

The genomic alterations observed in Hodgkin lymphoma fall into several categories, including immune evasion alterations, JAK-STAT pathway alterations, alterations leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation, and others:

• Multiple genomic alterations contribute to immune evasion in Hodgkin lymphoma.
  • Copy number gain or amplification at chromosome 9p24 is observed in most cases of Hodgkin lymphoma.[8,9] This region encodes the immune checkpoint genes CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2). These genomic alterations lead to increased expression of these checkpoint proteins.[8,9]
  • Gene fusions involving CIITA, which is the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, were reported in 15% of Hodgkin lymphoma cases.[10] Similar alterations are found in primary mediastinal B-cell lymphoma, and they lead to decreased CIITA protein expression and loss of MHC class II expression.[10,11]
  • Beta-2-microglobulin (the invariant chain of the MHC class I) frequently shows decreased/absent expression in HRS cells, with accompanying decreased MHC class I expression.[12] Inactivating variants in B2M, the gene that encodes beta-2-microglobulin, are common in Hodgkin lymphoma and lead to reduced expression of MHC class I.[2,4] Inactivating variants in B2M occur more frequently in Epstein-Barr virus (EBV)-negative Hodgkin lymphoma than in EBV-positive Hodgkin lymphoma,[2] which explains the higher rates of beta-2 microglobulin and MHC class I expression for EBV-positive Hodgkin lymphoma, compared with EBV-negative Hodgkin lymphoma.[12]
• Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:
  • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated by variants in 60% to 70% of Hodgkin lymphoma cases.[3] In a study of pediatric Hodgkin lymphoma using cfDNA collected before treatment, SOCS1 was the most frequently altered gene, with variants in 60% of all cases and approximately 80% of cases in which genomic alterations were detected in cfDNA.[13]
  • Activating STAT6 variants occurring at hot spots in the DNA-binding domain are observed in approximately 30% of Hodgkin lymphoma cases.[2,3]
  • The chromosome 9p region that contains CD274 and PDCD1LG2, which shows gains and amplifications in Hodgkin lymphoma, also contains JAK2.[2,3,14] Chromosome 9p gain/amplification is thought to further augment JAK-STAT pathway signaling.[14]
  • Inactivating variants in PTPN1, a phosphatase that inhibits JAK-STAT pathway signaling, were observed in approximately 20% of Hodgkin lymphoma cases.[2,15]
  • Variants in other genes affecting JAK-STAT pathway signaling have also been reported, including JAK1, STAT3, STAT5B, and CSF2RB.[2,3]
• Genomic alterations leading to NF-kappaB activation are also common in Hodgkin lymphoma.
  • The REL gene at chromosome 2p16.1 shows genomic gain or amplification in approximately one-third of Hodgkin lymphoma cases.[2,16]
  • EBV-positive Hodgkin lymphoma expresses the EBV latent membrane protein 1 (LMP1) at the cell surface. This protein acts like a constitutively activated receptor of the TNF receptor family to cause activation of the NF-kappaB pathway.[17]
  • Inactivating variants in genes that inhibit NF-kappaB pathway signaling, including TNFAIP3, NFKBIA, and NFKBIE, are common in Hodgkin lymphoma. Inactivation of the gene products for these genes leads to NF-kappaB pathway activation. TNFAIP3 is the most commonly altered inhibitor of NF-kappaB pathway signaling, and loss of function alterations occur by either variants or by focal 6q23.3 or arm-level 6q loss.[2,18]TNFAIP3 genomic alterations are much more common in EBV-negative Hodgkin lymphoma than in EBV-positive Hodgkin lymphoma, suggesting that LMP1 expression in EBV-positive Hodgkin lymphoma obviates the need for TNFAIP3 loss of function.[2,18]
• Other genes with variants in Hodgkin lymphoma include XPO1, RBM38, ACTB, ARID1A, and GNA13.[2,3,6]
• An evaluation of a large cohort of both pediatric and adult patients (N = 366) with classical Hodgkin lymphoma profiled by ctDNA revealed two molecular clusters based on variant profiles. The H1 cluster is characterized by younger age, higher mutational burden, and variants in NF-kappaB and JAK/STAT signaling. The H2 cluster is distributed more evenly across age groups, has a lower mutational burden, and more frequent somatic copy number alterations.[7]
• Hodgkin lymphoma is derived from a B-cell progenitor, and HRS cells generally do not express B-cell surface antigens. HRS cells do have immunoglobulin (Ig) heavy and light chain V gene rearrangements typical of B cells.[19,20] Although Ig genes have undergone rearrangements in HRS cells, the rearrangements are nonproductive and B-cell receptor is not expressed.

Genomics of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

The lymphocyte-predominant (LP) cells of NLPHL have distinctive genomic characteristics compared with the HRS cells of Hodgkin lymphoma. As with Hodgkin lymphoma, genomic characterization is complicated by the low percentage of malignant cells within a tumor mass.

• LP cells express B-cell antigens (e.g., CD19, CD20, CD22, and CD79A) and B-cell transcription factors (e.g., OCT2 and BOB1).[21,22]
• The expression of Bcl-6 and the presence of somatic hypervariants in the variable region of rearranged Ig heavy chain genes point to a germinal center derivation for LP cells.[23,24]
• IgD expression connotes a distinct type of NLPHL that is associated with a very high male-to-female ratio (>10:1).[25,26] An evaluation of the antigenic specificity of the B-cell receptor in cases of IgD-positive NLPHL found that in 7 of 8 cases (6 of 8 patients aged ≤18 years), the B-cell receptor recognized the DNA-directed RNA polymerase (RpoC) from Moraxella catarrhalis.[27] High-titer, light-chain-restricted anti-RpoC IgG1 serum-antibodies were observed in these patients. In addition, MID/hag is a superantigen expressed by M. catarrhalis that binds to the Fc domain of IgD and activates IgD-positive B cells. These observations support a role for M. catarrhalis in the development and maintenance of IgD-positive NLPHL.
• Genomic analysis of NLPHL is limited to a small number of patients using gene panels to evaluate microdissected specimens containing LP cells. Genes with recurring variants include SOCS1 (an inhibitor of JAK-STAT pathway signaling), DUSP2 (a dual specificity phosphatase that is a negative regulator of the MAP kinase pathway), JUNB (a transcription factor in the activator protein-1 family), and SGK1 (a serine-threonine kinase).[28,29,30]

References:

1. Mottok A, Hung SS, Chavez EA, et al.: Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma. Blood 134 (10): 802-813, 2019.
2. Wienand K, Chapuy B, Stewart C, et al.: Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion. Blood Adv 3 (23): 4065-4080, 2019.
3. Tiacci E, Ladewig E, Schiavoni G, et al.: Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood 131 (22): 2454-2465, 2018.
4. Reichel J, Chadburn A, Rubinstein PG, et al.: Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 125 (7): 1061-72, 2015.
5. Maura F, Ziccheddu B, Xiang JZ, et al.: Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells. Blood Cancer Discov 4 (3): 208-227, 2023.
6. Spina V, Bruscaggin A, Cuccaro A, et al.: Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 131 (22): 2413-2425, 2018.
7. Alig SK, Shahrokh Esfahani M, Garofalo A, et al.: Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling. Nature 625 (7996): 778-787, 2024.
8. Roemer MG, Advani RH, Ligon AH, et al.: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol 34 (23): 2690-7, 2016.
9. Roemer MGM, Redd RA, Cader FZ, et al.: Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. J Clin Oncol 36 (10): 942-950, 2018.
10. Steidl C, Shah SP, Woolcock BW, et al.: MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471 (7338): 377-81, 2011.
11. Mottok A, Woolcock B, Chan FC, et al.: Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Rep 13 (7): 1418-1431, 2015.
12. Roemer MG, Advani RH, Redd RA, et al.: Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status. Cancer Immunol Res 4 (11): 910-916, 2016.
13. Desch AK, Hartung K, Botzen A, et al.: Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma. Leukemia 34 (1): 151-166, 2020.
14. Green MR, Monti S, Rodig SJ, et al.: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116 (17): 3268-77, 2010.
15. Gunawardana J, Chan FC, Telenius A, et al.: Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet 46 (4): 329-35, 2014.
16. Steidl C, Telenius A, Shah SP, et al.: Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 116 (3): 418-27, 2010.
17. Gires O, Zimber-Strobl U, Gonnella R, et al.: Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J 16 (20): 6131-40, 1997.
18. Schmitz R, Hansmann ML, Bohle V, et al.: TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206 (5): 981-9, 2009.
19. Küppers R, Rajewsky K, Zhao M, et al.: Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci U S A 91 (23): 10962-6, 1994.
20. Kanzler H, Küppers R, Helmes S, et al.: Hodgkin and Reed-Sternberg-like cells in B-cell chronic lymphocytic leukemia represent the outgrowth of single germinal-center B-cell-derived clones: potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Blood 95 (3): 1023-31, 2000.
21. Shankar A, Daw S: Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents--a comprehensive review of biology, clinical course and treatment options. Br J Haematol 159 (3): 288-98, 2012.
22. Stein H, Marafioti T, Foss HD, et al.: Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97 (2): 496-501, 2001.
23. Braeuninger A, Küppers R, Strickler JG, et al.: Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 94 (17): 9337-42, 1997.
24. Falini B, Bigerna B, Pasqualucci L, et al.: Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease. Blood 87 (2): 465-71, 1996.
25. Huppmann AR, Nicolae A, Slack GW, et al.: EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38 (3): 316-24, 2014.
26. Prakash S, Fountaine T, Raffeld M, et al.: IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol 30 (5): 585-92, 2006.
27. Thurner L, Hartmann S, Neumann F, et al.: Role of Specific B-Cell Receptor Antigens in Lymphomagenesis. Front Oncol 10: 604685, 2020.
28. Hartmann S, Schuhmacher B, Rausch T, et al.: Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma. Leukemia 30 (4): 844-53, 2016.
29. Mottok A, Renné C, Willenbrock K, et al.: Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood 110 (9): 3387-90, 2007.
30. Schuhmacher B, Bein J, Rausch T, et al.: JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma. Haematologica 104 (2): 330-337, 2019.

Diagnosis and Staging Information for Childhood Hodgkin Lymphoma

Staging and evaluation of disease status is undertaken at diagnosis, early in the course of chemotherapy, and at the end of chemotherapy.

Diagnostic and Staging Evaluation

The diagnostic and staging evaluation is critical for the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:

• History of systemic symptoms.
• Physical examination.
• Laboratory studies, including complete blood count, chemistry panel with albumin, and erythrocyte sedimentation rate.
• Anatomical imaging, including chest x-ray and computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, chest, abdomen, and pelvis. MRI has the advantage of limiting radiation exposure.[1,2]
• Functional imaging, including positron emission tomography (PET)-CT or PET-MRI.[2]

Systemic symptoms

The following three constitutional symptoms (B symptoms) correlate with prognosis and are used in assignment of stage:

• Unexplained fever with temperatures above 38.0°C orally.
• Unexplained weight loss of 10% within the 6 months preceding diagnosis.
• Drenching night sweats.

Additional Hodgkin-associated constitutional symptoms that lack prognostic significance include the following:

• Pruritus.
• Alcohol-induced nodal pain.

Physical examination

• All node-bearing areas, including the Waldeyer ring, should be assessed by careful physical examination.
• Enlarged nodes should be measured to establish a baseline for evaluation of therapy response.

Laboratory studies

• Hematological and chemical blood parameters (e.g., albumin) show nonspecific changes that may correlate with disease extent.
• Abnormalities of peripheral blood counts may include neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis.
• Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein, if abnormal at diagnosis, may be useful in follow-up evaluation.[3]

Anatomical imaging

Anatomical information from CT or MRI is complemented by PET functional imaging, which is sensitive in determining initial sites of involvement, particularly in sites too small to be considered clearly involved by CT or MRI criteria. Collaboration across international groups to harmonize definitions is ongoing.[2,4] Metabolic tumor volume calculations may enhance the prognostic utility of PET scans.[5]

Definition of bulky disease

Historically, the presence of bulky disease, especially mediastinal bulk, predicted an increased risk of local failure and resulted in the incorporation of bulk as an important factor in treatment assignment. The definition of bulk has varied across pediatric protocols and evolved over time with advances in diagnostic imaging technology.[4]

The criteria for bulky mediastinal and nonmediastinal disease are as follows:

• Mediastinal. In North American protocols, the posteroanterior chest radiograph remains important because the criterion for bulky mediastinal lymphadenopathy is defined by the ratio of the diameter of the mediastinal lymph node mass to the maximal diameter of the rib cage on an upright chest radiograph, usually at the level of the diaphragm. A ratio of 33% or higher is considered bulky. In contrast, the EuroNet-Pediatric Hodgkin Lymphoma Group defines mediastinal bulk by the volume of the largest contiguous lymph node mass being 200 mL or more on CT.[6]

  These two definitions differ from the published consensus guidelines from the International Conference on Malignant Lymphomas Imaging Group (Lugano), which defines bulk as a mass 10 cm or larger seen unidimensionally on CT.[6]

• Nonmediastinal. The criteria for bulky peripheral, nonmediastinal lymphadenopathy have also varied over the years in cooperative group study protocols, and this disease characteristic has not been consistently used for treatment stratification. In contemporary U.S. protocols, bulky peripheral lymphadenopathy is defined as greater than 6 cm, with aggregates measured transversely or cranial-caudal. In EuroNet protocols, peripheral adenopathy is again defined as a volume of 200 mL or more, which is generally larger than a 6-cm unidimensional mass.

Criteria for lymphomatous involvement by CT or MRI

Defining strict CT or MRI size criteria for lymphomatous nodal involvement is complicated by several factors, such as size overlap between what proves to be benign reactive hyperplasia versus malignant lymphadenopathy, the implication of nodal clusters, and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size and the frequent occurrence of reactive hyperplasia.

General concepts to consider for defining lymphomatous involvement by CT or MRI include the following:

• Contiguous nodal clustering or matting is highly suggestive of lymphomatous involvement.
• Any focal mass lesion large enough to characterize in a visceral organ is considered lymphomatous involvement unless the imaging characteristics indicate an alternative etiology.
• Criteria for nodal involvement may vary by cooperative group or protocol.[4]
  • Children's Oncology Group (COG) and EuroNet protocols consider lymph nodes abnormal if the long axis is greater than 2 cm, regardless of the short axis and PET avidity. Lymph nodes with a long axis measuring between 1 cm and 2 cm are only considered abnormal if they are part of a conglomerate of nodes and are fluorine F 18-fludeoxyglucose (18F-FDG) PET positive.
  • In the Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) GPOH-HD-2002 study, nodal involvement was defined as node size greater than 2 cm in largest diameter. The node was not involved if it was less than 1 cm and was considered questionable if it was between 1 cm and 2 cm. The decision on involvement was then made based on additional clinical evidence.[7]
  • In an analysis of 47,828 imaging measurements from 2,983 adult and pediatric patients with lymphoma enrolled in ten multicenter clinical trials, a single dimension measurement of 15 mm or more constituted involvement.[8]

Functional imaging

The recommended functional imaging procedure for initial staging is PET, using the radioactive glucose analogue 18F-FDG.[2,9,10] 18F-FDG PET identifies areas of increased metabolic activity, specifically anaerobic glycolysis. PET-CT, which integrates functional and anatomical tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent 18F-FDG avidity has been correlated with poor prognosis and the need for additional therapy in posttreatment evaluation.[11,12,13]; [14][Level of evidence B4] Whole-body MRI, with diffusion-weighted imaging, compares favorably to PET-CT for staging of pediatric Hodgkin lymphoma.[15]

Newer factors to consider for using PET for prognostication include metabolic tumor volume, tumor dissemination on PET (Dmax), and total lesion surface.[5,16]

General concepts to consider for defining lymphomatous involvement by 18F-FDG PET include the following:

• Concordance between PET and CT data is generally high for nodal regions but may be significantly lower for extranodal sites. In one study analyzing pediatric patients with Hodgkin lymphoma, assessment of initial staging comparing PET and CT data demonstrated concordance of approximately 86% overall. Concordance rates were significantly lower for the spleen, lung nodules, bone, and pleural and pericardial effusions.[17] A meta-analysis of nine clinical studies showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma. Focal involvement was highly predictive of bone marrow involvement.[18,19]
• Integration of data acquired from PET scans can lead to changes in staging.[6,20]
• Staging criteria using PET and CT scan information is protocol dependent. Generally, areas of PET positivity that do not correspond to an anatomical lesion by clinical examination or CT scan size criteria should be disregarded in staging, with the possible exception of focally PET-positive bone marrow findings.
• A suspected anatomical lesion that is PET negative should not be considered involved unless proven by biopsy.

18F-FDG PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions, including thymic rebound commonly observed after completion of lymphoma therapy. 18F-FDG avidity in normal tissues, such as brown fat in the neck, may confound interpretation of the presence of nodal involvement by lymphoma.[9]

Visual PET criteria are scored according to uptake involved by lymphoma from the Deauville 5-point scale, from 1 to 5, as described in Table 2. Calculation of metabolic tumor volume is an evolving approach that may enhance the prognostic utility of PET scans.[5] The COG and EuroNet definitions of PET response of lymph nodes or nodal masses are described in Table 3.

Table 2. Deauville Score Criteria

Deauville Score (Visual Score)	Criteria
1	No uptake.
2	Uptake ≤ mediastinal blood pool.
3	Uptake > mediastinal blood pool and ≤ normal liver.
4	Moderately increased uptake > normal liver.
5	Markedly increased uptake > normal liver.

Table 3. Children's Oncology Group and EuroNet Definition of PET Response of Lymph Node or Nodal Masses

Timing of 18F-FDG PET	18F-FDG PET Avidity
18F-FDG = fluorine F 18-fludeoxyglucose; PET = positron emission tomography.
Baseline PET (PET 0) response visual threshold uses mediastinal blood pool as the reference activity:	18F-FDG PET positive is defined as visual score 3, 4, 5.
	18F-FDG PET negative is defined as visual score 1, 2.
Interim postcycle 2 PET (PET 2) response visual threshold uses normal liver as the reference activity:	18F-FDG PET positive is defined as visual score 4, 5.
	18F-FDG PET negative is defined as visual score 1, 2, 3.
End of chemotherapy PET (PET 4 or 5) response visual threshold also uses mediastinal blood pool as the reference activity:	18F-FDG PET positive is defined as visual score 3, 4, 5.
	18F-FDG PET negative is defined as visual score 1, 2.

Establishing the Diagnosis of Hodgkin Lymphoma

After a careful physiological and radiographic evaluation of the patient, the least invasive procedure should be used to establish the diagnosis of lymphoma. However, this should not be interpreted to mean that a needle biopsy is the optimal methodology. Small fragments of lymphoma tissue are often inadequate for diagnosis, resulting in the need for second procedures that delay the diagnosis.

If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. The likelihood of obtaining sufficient tissue should be carefully considered when selecting a biopsy procedure. Other issues to consider include the following:

• Type of biopsy procedure.
  • Aspiration cytology alone is not recommended because of the lack of stromal tissue, the small number of cells present in the specimen, and the difficulty of classifying Hodgkin lymphoma into one of the subtypes.
  • An image-guided biopsy may be used to obtain diagnostic tissue from intra-thoracic or intra-abdominal lymph nodes. Based on the involved sites of disease, alternative procedures to consider may include thoracoscopy, mediastinoscopy, and laparoscopy. Thoracotomy or laparotomy is rarely needed to access diagnostic tissue.
  • A meta-analysis of nine clinical studies including both pediatric and adult patients showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma.[18] Based on these studies, a consensus group no longer recommends bone marrow biopsy in the initial evaluation of adults with Hodgkin lymphoma, with PET-CT being used instead to identify bone marrow involvement.[6] For more information, see the Stage Information for HL section in Hodgkin Lymphoma Treatment.
  • Because bone marrow involvement is relatively rare in pediatric patients with Hodgkin lymphoma, bilateral bone marrow biopsy might be considered only in patients with advanced disease (stage III or stage IV) and/or B symptoms.[21]
• Procedure-related complications.
  • Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[22] After careful planning with the anesthesiologist, peripheral lymph node biopsy or image-guided core-needle biopsy of mediastinal lymph nodes may be feasible using light sedation and local anesthesia before proceeding to more invasive procedures.
  • If airway compromise precludes a diagnostic operative procedure, preoperative treatment with steroids or low-dose, localized radiation therapy should be considered, although the latter can be technically difficult if the patient cannot recline. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks associated with general anesthesia or heavy sedation are alleviated.

Lugano Staging Classification for Hodgkin Lymphoma

Stage is determined by anatomical evidence of disease using CT or MRI scanning in conjunction with functional imaging. The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma (see Table 4).[23] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[24] with some modifications 18 years later from the Cotswolds meeting.[25] Staging is independent of the imaging modality used.

Table 4. Lugano Classification Applicable for Pediatric Hodgkin Lymphomas^a

Stage	Description
Note: Hodgkin lymphoma uses A or B designation with stage group.
a Adapted from AJCC: Pediatric Hodgkin and non-Hodgkin lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 959–65.[23,26]
b Stage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors.
c The definition of disease bulk varies according to lymphoma histology. In the Lugano classification, bulk in Hodgkin lymphoma is defined as a mass greater than one third of the thoracic diameter on CT of the chest or a mass >10 cm.
Limited stage
I	Involvement of a single lymphatic site (i.e., nodal region, Waldeyer's ring, thymus, or spleen).
IE	Single extralymphatic site in the absence of nodal involvement (rare in Hodgkin lymphoma).
II	Involvement of two or more lymph node regions on the same side of the diaphragm.
IIE	Contiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.
II bulky b	Stage II with disease bulk. c
Advanced stage
III	Involvement of lymph node regions on both sides of the diaphragm; or nodes above the diaphragm with spleen involvement.
IV	Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; ornoncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease orany extralymphatic organ involvement in nodal stage III disease. Stage IV includesany involvement of the bone marrow, liver, or lungs (other than by direct extension in stage IIE disease).
Designations applicable to any stage
A	No symptoms.
B	Fever (temperature >38.0ºC), drenching night sweats, unexplained loss of >10% of body weight within the preceding 6 months.
E	Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.
S	Splenic involvement.

Extralymphatic disease resulting from direct extension of an involved lymph node region is designated E. Extralymphatic disease can cause confusion in staging. For example, the designation E is not appropriate for cases of widespread disease or diffuse extralymphatic disease (e.g., large pleural effusion that is cytologically positive for Hodgkin lymphoma), which should be considered stage IV. If pathological proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Current practice is to assign a clinical stage based on findings of the clinical evaluation. However, pathological confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.

Risk Stratification

After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the pediatric research groups, and often even between different studies conducted by the same group, as summarized in Table 5.[27]

Table 5. Differences in Risk Stratification Between Pediatric Hodgkin Lymphoma Study Groups and Protocols^a

Study Group	Risk Group (Protocol)	Stage I	Stage II	Stage III	Stage IV
COG = Children's Oncology Group; EuroNet-PHL = European Network for Pediatric Hodgkin Lymphoma; TG = treatment group; TL = treatment level.
a Adapted from Mauz-Körholz et al.[27]
b EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with an erythrocyte sedimentation rate of ≥30 mm/hour and/or bulk of ≥200 mL were treated in TG2 (intermediate risk).
COG	Low (AHOD0431)	IA	IIA
	Intermediate (AHOD0031)	IA with extranodal or bulky disease; IB	IIA with extranodal or bulky disease; IIB	IIIA	IVA
	High (AHOD0831)			IIIB	IVB
EuroNet-PHL-C1b	Low (TG1)	IA; IB	IIA
	Intermediate (TG2)	IA or IB with extranodal disease or risk factors	IIA with extranodal disease or risk factors; IIB	IIIA
	High (TG3)		IIB with extranodal disease	IIIA with extranodal disease; IIIB	IVA; IVB
EuroNet-PHL-C2	Low (TL1)	IA; IB	IIA
	Intermediate (TL2)	IA or IB with extranodal disease or risk factors	IIA with extranodal disease or risk factors; IIB	IIIA
	High (TL3)		IIB with extranodal disease	IIIA with extranodal disease; IIIB	IVA; IVB
Pediatric Hodgkin Consortium	Low (HOD99/HOD08)	IA	IIA with fewer than 3 nodal sites
	Intermediate (HOD05)	IA with extranodal disease or mediastinal bulk; IB	IIA with extranodal disease or mediastinal bulk	IIIA
	High (HOD99/HLHR13)		IIB	IIIB	IVA; IVB

The COG has collaborated with adult cancer cooperative groups for the treatment of patients with Hodgkin lymphoma. In these trials, risk stratification is similar to that of adult patients (i.e., early stage [stage I/II] and advanced stage [stage III/IV]).

Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.[4]

Response Assessment

Risk classification may be further refined by assessing response after initial cycles of chemotherapy or at the completion of chemotherapy.

Interim response assessment

The interim response to initial therapy, which may be assessed on the basis of volume reduction of disease, functional imaging status, or both, is an important prognostic variable in both early- and advanced-stage pediatric Hodgkin lymphoma.[28,29]; [14][Level of evidence B4]

Definitions for interim response are variable and protocol specific but can range from 2-dimensional reductions in size of greater than 50% to the achievement of a complete response, with 2-dimensional reductions in tumor size of greater than 75% or 80% or a volume reduction of greater than 95% by anatomical imaging or resolution of 18F-FDG PET avidity.[7,30,31]

The rapidity of response to early therapy has been used in risk stratification to titrate therapy in an effort to augment therapy in higher-risk patients or to reduce therapy in rapidly responding patients, which might, in turn, reduce the risk of late effects while maintaining efficacy.[28,29,31,32]

The significance of new pulmonary lesions found on CT scan at the time of interim analysis was evaluated in a retrospective study of 1,300 patients enrolled in the EuroNet-PHL-C1 trial. New nodules were common (119 patients; 9.2%) and most (97%) were smaller than 10 mm. These nodules occurred regardless of initial lung involvement or whether a patient had a relapse. Of the 119 patients with new lung lesions, 17 (14%) subsequently had a relapse or progression. Of these patients, 11 patients had relapse staging imaging available for central review. In all 11 patients, the new lesions seen at interim analysis had all resolved on relapse staging. New lung lesions occurred in 102 patients (7.8%) without subsequent relapse. The authors concluded that most new nodules at interim staging are likely not malignant and require no further action.[33]

Trials using interim response to titrate therapy

Several studies have evaluated the use of interim response to titrate additional therapy:

1. The Pediatric Oncology Group used a response-based therapy approach consisting of dose-dense doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) for intermediate-stage and advanced-stage patients, in combination with 21 Gy involved-field radiation therapy (IFRT).[31]
   • The dose-dense approach permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response on CT imaging after three ABVE-PC cycles.
   • The 5-year event-free survival (EFS) rates were comparable for rapid early responders (86%; treated with three cycles of ABVE-PC) and slow early responders (83%; treated with five cycles of ABVE-PC). All patients received 21 Gy of regional radiation therapy.
2. The Children's Cancer Group (CCG) (CCG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) regimen, followed by a sex-tailored consolidation, for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[32]
   1. For rapid early responding girls, an additional four courses of cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine (COPP/ABV) without IFRT was given in an effort to reduce breast cancer risk.
   2. Rapid early responding boys received two cycles of ABVD followed by IFRT.
   3. Slow early responders received four additional courses of BEACOPP and IFRT.
      • Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four BEACOPP cycles. The 5-year EFS rate among the cohort was 94% (median follow-up, 6.3 years).
3. The COG AHOD0031 (NCT00025259), AHOD0831 (NCT01026220), and AHOD0431 (NCT00302003) trials also used interim response to titrate therapy. The AHOD0031 trial was designed to evaluate this paradigm of care by randomly assigning patients to receive either standard or response-based therapy. For more information, see the Evolution of North American cooperative and consortium trial results section.

The use of interim PET to titrate therapy

The EuroNet Hodgkin lymphoma trials use a similar early response assessment definition of PET positivity, which is a Deauville score of greater than 3 after two cycles of vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin) (OEPA).[34]

1. GPOH studies use stringent criteria for treatment group 1 (TG1) patients that include at least 95% reduction in tumor volume or less than 2 mL residual volume on CT. Patients achieving these metrics will have radiation therapy omitted. Treatment group 2 (TG2) and treatment group 3 (TG3) patients received radiation therapy despite their potential morphological complete response (see Table 5).[7]
2. The COG AHOD1331 (NCT02166463) initial therapeutics clinical trial for patients with high-risk Hodgkin lymphoma uses 18F-FDG PET assessment, graded by a 5-point visual scale or Deauville criteria after two chemotherapy cycles, to define a rapid early-responding lesion for which radiation will be omitted. A mass of any size is permitted for a complete response designation if the PET is negative. The results of using the latter criteria are not yet available, so it may not be considered standard of care.

End of chemotherapy response assessment

Restaging is carried out after all initial chemotherapy is completed. It may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:

• Defining complete response. The definition of complete response may vary by cooperative group or protocol.
  • The International Working Group (IWG) defined complete response for adults with Hodgkin lymphoma in terms of complete metabolic response as assessed by 18F-FDG PET, even when a persistent mass is present.[35] These criteria were endorsed in the Lugano classification, with the recommendation for a 5-point scale to assess response.[6,36] COG protocols have adopted this approach for defining complete response.
  • Previous studies have varied in the use of findings from the clinical examination, anatomical imaging, and functional imaging to assess response. Although complete response can be defined as absence of disease by clinical examination and/or imaging studies, complete response in Hodgkin lymphoma trials is often defined by a greater than 80% reduction of disease and a change from initial positivity to negativity on functional imaging.[37] This definition is necessary in Hodgkin lymphoma because fibrotic residual disease is common, particularly in the mediastinum. In some studies, such patients are designated as having an unconfirmed complete response.
• Timing of PET scanning after completing therapy. Timing of PET scanning after completing therapy is an important issue.
  • For patients treated with chemotherapy alone, PET scanning is ideally performed a minimum of 3 weeks after the completion of therapy, while patients whose last treatment modality was radiation therapy should not undergo PET scanning until 8 to 12 weeks postradiation.[35]
• Screening frequency and overscreening.
  • A COG study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. Most relapses occurred within the first year after therapy and were detected based on symptoms, laboratory, or physical findings. The method of detection of late relapse, whether by imaging or clinical change, did not affect overall survival. Routine use of CT at the intervals used in this study did not improve outcome.[38] Other investigations have supported the concept of reduced frequency of imaging.[39,40]
  • Caution should be used in diagnosing relapsed or refractory disease based solely on anatomical and functional imaging because false-positive results are not uncommon.[41,42,43] Consequently, pathological confirmation of refractory or recurrent disease is recommended before modification of therapeutic plans.

References:

1. Afaq A, Fraioli F, Sidhu H, et al.: Comparison of PET/MRI With PET/CT in the Evaluation of Disease Status in Lymphoma. Clin Nucl Med 42 (1): e1-e7, 2017.
2. Mhlanga J, Alazraki A, Cho SY, et al.: Imaging recommendations in pediatric lymphoma: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper. Pediatr Blood Cancer 70 (Suppl 4): e29968, 2023.
3. Haase R, Vilser C, Mauz-Körholz C, et al.: Evaluation of the prognostic meaning of C-reactive protein (CRP) in children and adolescents with classical Hodgkin's lymphoma (HL). Klin Padiatr 224 (6): 377-81, 2012.
4. Flerlage JE, Kelly KM, Beishuizen A, et al.: Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement. Pediatr Blood Cancer 64 (7): , 2017.
5. Milgrom SA, Kim J, Chirindel A, et al.: Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031. Pediatr Blood Cancer 68 (9): e29212, 2021.
6. Cheson BD, Fisher RI, Barrington SF, et al.: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32 (27): 3059-68, 2014.
7. Mauz-Körholz C, Hasenclever D, Dörffel W, et al.: Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. J Clin Oncol 28 (23): 3680-6, 2010.
8. Younes A, Hilden P, Coiffier B, et al.: International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol 28 (7): 1436-1447, 2017.
9. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004.
10. Hernandez-Pampaloni M, Takalkar A, Yu JQ, et al.: F-18 FDG-PET imaging and correlation with CT in staging and follow-up of pediatric lymphomas. Pediatr Radiol 36 (6): 524-31, 2006.
11. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006.
12. Lopci E, Burnelli R, Guerra L, et al.: Postchemotherapy PET evaluation correlates with patient outcome in paediatric Hodgkin's disease. Eur J Nucl Med Mol Imaging 38 (9): 1620-7, 2011.
13. Sucak GT, Özkurt ZN, Suyani E, et al.: Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival. Ann Hematol 90 (11): 1329-36, 2011.
14. Lopci E, Mascarin M, Piccardo A, et al.: FDG PET in response evaluation of bulky masses in paediatric Hodgkin's lymphoma (HL) patients enrolled in the Italian AIEOP-LH2004 trial. Eur J Nucl Med Mol Imaging 46 (1): 97-106, 2019.
15. Spijkers S, Littooij AS, Kwee TC, et al.: Whole-body MRI versus an FDG-PET/CT-based reference standard for staging of paediatric Hodgkin lymphoma: a prospective multicentre study. Eur Radiol 31 (3): 1494-1504, 2021.
16. Gallamini A, Filippi A, Camus V, et al.: Toward a paradigm shift in prognostication and treatment of early-stage Hodgkin lymphoma. Br J Haematol : , 2024.
17. Robertson VL, Anderson CS, Keller FG, et al.: Role of FDG-PET in the definition of involved-field radiation therapy and management for pediatric Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 80 (2): 324-32, 2011.
18. Adams HJ, Kwee TC, de Keizer B, et al.: Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol 25 (5): 921-7, 2014.
19. Cistaro A, Cassalia L, Ferrara C, et al.: Italian Multicenter Study on Accuracy of 18F-FDG PET/CT in Assessing Bone Marrow Involvement in Pediatric Hodgkin Lymphoma. Clin Lymphoma Myeloma Leuk 18 (6): e267-e273, 2018.
20. Cheng G, Servaes S, Zhuang H: Value of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan versus diagnostic contrast computed tomography in initial staging of pediatric patients with lymphoma. Leuk Lymphoma 54 (4): 737-42, 2013.
21. Simpson CD, Gao J, Fernandez CV, et al.: Routine bone marrow examination in the initial evaluation of paediatric Hodgkin lymphoma: the Canadian perspective. Br J Haematol 141 (6): 820-6, 2008.
22. Anghelescu DL, Burgoyne LL, Liu T, et al.: Clinical and diagnostic imaging findings predict anesthetic complications in children presenting with malignant mediastinal masses. Paediatr Anaesth 17 (11): 1090-8, 2007.
23. Link MP, Jaffe ES, Leonard JP: Pediatric Hodgkin and non-Hodgkin lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 959-65.
24. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971.
25. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989.
26. Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
27. Mauz-Körholz C, Metzger ML, Kelly KM, et al.: Pediatric Hodgkin Lymphoma. J Clin Oncol 33 (27): 2975-85, 2015.
28. Keller FG, Castellino SM, Chen L, et al.: Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group. Cancer 124 (15): 3210-3219, 2018.
29. Friedman DL, Chen L, Wolden S, et al.: Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. J Clin Oncol 32 (32): 3651-8, 2014.
30. Keller FG, Nachman J, Constine L: A phase III study for the treatment of children and adolescents with newly diagnosed low risk Hodgkin lymphoma (HL). [Abstract] Blood 116 (21): A-767, 2010.
31. Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009.
32. Kelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group. Blood 117 (9): 2596-603, 2011.
33. Stoevesandt D, Ludwig C, Mauz-Körholz C, et al.: Pulmonary lesions in early response assessment in pediatric Hodgkin lymphoma: prevalence and possible implications for initial staging. Pediatr Radiol 54 (5): 725-736, 2024.
34. Hasenclever D, Kurch L, Mauz-Körholz C, et al.: qPET - a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging 41 (7): 1301-8, 2014.
35. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
36. Barrington SF, Mikhaeel NG, Kostakoglu L, et al.: Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32 (27): 3048-58, 2014.
37. Molnar Z, Simon Z, Borbenyi Z, et al.: Prognostic value of FDG-PET in Hodgkin lymphoma for posttreatment evaluation. Long term follow-up results. Neoplasma 57 (4): 349-54, 2010.
38. Voss SD, Chen L, Constine LS, et al.: Surveillance computed tomography imaging and detection of relapse in intermediate- and advanced-stage pediatric Hodgkin's lymphoma: a report from the Children's Oncology Group. J Clin Oncol 30 (21): 2635-40, 2012.
39. Hartridge-Lambert SK, Schöder H, Lim RC, et al.: ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early-stage, nonbulky Hodgkin lymphoma. Cancer 119 (6): 1203-9, 2013.
40. Friedmann AM, Wolfson JA, Hudson MM, et al.: Relapse after treatment of pediatric Hodgkin lymphoma: outcome and role of surveillance after end of therapy. Pediatr Blood Cancer 60 (9): 1458-63, 2013.
41. Nasr A, Stulberg J, Weitzman S, et al.: Assessment of residual posttreatment masses in Hodgkin's disease and the need for biopsy in children. J Pediatr Surg 41 (5): 972-4, 2006.
42. Meany HJ, Gidvani VK, Minniti CP: Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 48 (4): 399-402, 2007.
43. Picardi M, De Renzo A, Pane F, et al.: Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48 (9): 1721-7, 2007.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Transplant surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.

Treatment of Newly Diagnosed Children and Adolescents With Hodgkin Lymphoma

History of Treatment for Hodgkin Lymphoma

Children and adolescents with Hodgkin lymphoma have achieved long-term survival rates after treatment with radiation therapy, multiagent chemotherapy, and combined-modality therapy. In select cases of localized nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), complete surgical resection may be curative and obviate the need for cytotoxic therapy.

Treatment options for children and adolescents with Hodgkin lymphoma include the following:

1. Radiation therapy as a single modality.
   • Recognition of the excess adverse effects of high-dose radiation therapy on musculoskeletal development in children motivated investigations of multiagent chemotherapy alone or with lower radiation doses (15–25.5 Gy) and reduced treatment volumes (involved sites). It also led clinicians to abandon the use of radiation as a single modality except in select situations.[1,2,3]
   • Radiation therapy alone may rarely be considered for adolescents and young adults with NLPHL.[4]
   • Recognition of the excess risk of cardiovascular disease and subsequent neoplasms in adult survivors who were treated for Hodgkin lymphoma during childhood led to the restriction of radiation therapy in contemporary trials and the reduction in volume and dose when used.[5,6]
2. Multiagent chemotherapy.
   • The establishment of the non–cross-resistant combinations of mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone (MOPP) developed in the 1960s and doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) developed in the 1970s made long-term survival possible for patients with advanced and unfavorable (e.g., bulky, symptomatic) Hodgkin lymphoma.[7,8]

     MOPP-related sequelae include a dose-related risk of infertility and subsequent myelodysplasia and leukemia.[2,9] The use of MOPP-derivative regimens substituting less leukemogenic and gonadotoxic alkylating agents (e.g., cyclophosphamide) for mechlorethamine or restricting cumulative alkylating agent dose exposure reduces this risk.[10] However, COPP-based regimens (substituting cyclophosphamide for mechlorethamine) are not commonly used in contemporary treatment protocols because of the restricted availability of procarbazine in many parts of the world.

     ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin.[11,12,13] The cumulative dose of these agents has been proactively restricted in pediatric patients to reduce this risk.

     In an effort to reduce chemotherapy-related toxicity, hybrid regimens alternating MOPP and ABVD or derivative therapy were developed. They use lower total cumulative doses of alkylators, doxorubicin, and bleomycin.[14,15]

     With the use of a cardioprotectant and replacing bleomycin with other agents, ABVD-based regimens are being used more in pediatric patients.[16]

   • Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.[17]

     Etoposide-related sequelae include an increased risk of subsequent myelodysplasia and leukemia that appears to be rare when etoposide is used in restricted doses in pediatric Hodgkin lymphoma regimens.[18,19]

   • Pediatric trials have used procarbazine-free standard backbone regimens, such as doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) in North America [20,21] and vincristine, etoposide, prednisone, doxorubicin; cyclophosphamide, vincristine, prednisone, dacarbazine (OEPA-COPDAC) in Europe.[22] Both of these regimens represent dose-dense therapies that use six drugs to maximize intensity without exceeding thresholds of toxicity.
3. Multiagent chemotherapy alone versus combined-modality therapy.
   • Treatment with non–cross-resistant chemotherapy alone offers advantages in low-income countries lacking radiation facilities and trained personnel, as well as diagnostic imaging modalities needed for clinical staging. This treatment option also avoids the potential long-term growth inhibition, organ dysfunction, and solid tumor induction associated with radiation.
   • Chemotherapy-alone treatment protocols usually prescribe higher cumulative doses of alkylating agent and anthracycline chemotherapy, which may produce acute- and late-treatment morbidity from myelosuppression, cardiac toxic effects, gonadal injury, and subsequent leukemia. However, more recent trials are designed to significantly reduce these risks, especially in those with chemotherapy-responsive disease.[20]
   • In general, the use of combined chemotherapy and low-dose involved-site radiation therapy (LD-ISRT) broadens the spectrum of potential toxicities, while reducing the severity of individual drug-related or radiation-related toxicities. The results of prospective and controlled randomized trials indicate that combined-modality therapy, compared with chemotherapy alone, produces a superior event-free survival (EFS). However, because of effective second-line therapy, overall survival (OS) has not differed among the groups studied.[23,24]

Contemporary Treatment of Hodgkin Lymphoma

Contemporary treatment of pediatric patients with Hodgkin lymphoma uses a risk-adapted and response-based paradigm that assigns the length and intensity of therapy based on disease-related factors such as stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy by functional and anatomical imaging. Age, sex, and histological subtype may also be considered in treatment planning.

Treatment options for childhood Hodgkin lymphoma include the following:

1. Radiation therapy.
2. Chemotherapy.

Risk designation

Risk designation depends on favorable and unfavorable clinical features, as follows:

• Favorable clinical features include localized nodal involvement in the absence of B symptoms and bulky disease. Risk factors considered in other studies include the number of involved nodal regions, presence of hilar adenopathy, size of peripheral lymphadenopathy, and extranodal extension.[25]
• Unfavorable clinical features include the presence of B symptoms, bulky mediastinal or peripheral lymphadenopathy, extranodal extension of disease, and advanced (stages IIIB–IV) disease.[25] In most clinical trials, bulky mediastinal lymphadenopathy is designated when the ratio of the maximum measurement of mediastinal lymphadenopathy to intrathoracic cavity on an upright chest radiograph equals or exceeds 33%. Notably, the definition of bulk is trial specific. For more information, see the Definition of bulky disease section.

  Pleural effusions have been shown to be an adverse prognostic finding in patients treated for low-stage Hodgkin lymphoma.[26][Level of evidence B4] The risk of relapse was 25% in patients with an effusion, compared with less than 15% in patients without an effusion. Patients with effusions were more often older (15 years vs. 14 years) and had nodular-sclerosing histology.

  Localized disease (stages I, II, and IIIA) with unfavorable features may be treated similarly to advanced-stage disease in some treatment protocols or treated with therapy of intermediate intensity.[25]

Inconsistency in risk categorization across studies often makes comparison of study outcomes challenging.

Risk-adapted treatment paradigms

No single treatment approach is ideal for all pediatric and young adult patients because of differences in age-related developmental status and sex-related sensitivity to chemotherapy toxicity.

• The general treatment strategy for children and adolescents with Hodgkin lymphoma is chemotherapy, with or without radiation.
  • The rapidity and degree of response may determine the number of cycles and intensity of chemotherapy as well as the radiation dose and volume. The primary exception to this strategy is in patients with NLPHL, when surgical resection has been advocated for stage I disease with a single resectable node in the United States [27] and for any resectable disease in Europe.[28]
  • Sex-based regimens were designed because male patients are vulnerable to gonadal toxicity from alkylating-agent chemotherapy, and female patients have a substantial risk of breast cancer after chest irradiation. In addition, males may experience a higher risk of cardiovascular disease after chest irradiation, which suggests limiting radiation exposure in males.[29]

Ongoing trials for patients with favorable disease are evaluating the effectiveness of treatment with fewer cycles of combination chemotherapy alone that limit doses of anthracyclines, alkylating agents, and radiation therapy. Contemporary trials for patients with intermediate/unfavorable disease are testing whether chemotherapy and radiation therapy can be limited in patients who achieve a rapid early response to dose-intensive chemotherapy regimens. Trials have and are also testing the efficacy of regimens integrating novel, potentially less-toxic agents such as brentuximab vedotin and immune modulating therapies such as checkpoint inhibitors.[30]

Histology-based therapy

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)

The use of combination chemotherapy and/or radiation therapy can produce excellent long-term progression-free survival (PFS) and OS in patients with NLPHL.[27,31,32] Late recurrences have been reported and are typically responsive to re-treatment. Because deaths observed among individuals with this histological subtype are frequently related to complications from cytotoxic therapy or transformation to non-Hodgkin lymphoma, risk-adapted treatment assignment is particularly important for limiting exposure to agents with established dose-related toxicities.[31,32]

Histological subtype may direct therapy in patients with stage I, completely resected NLPHL, whose initial treatment may be surgery alone.[27]

Evidence (surgery alone for localized NLPHL):

1. Although treatment of adult patients with NLPHL has traditionally involved high-dose radiation alone, treatment of children originally involved chemotherapy plus LD-ISRT. Standard of care in pediatric NLPHL at present is unclear but may include chemotherapy alone or, for limited disease, complete resection of isolated nodal disease without chemotherapy. Surgical resection of localized disease produces a prolonged disease-free survival in a substantial proportion of patients, obviating the need for immediate cytotoxic therapy.[27,28,33,34] Even if cytotoxic therapy is required, the possibility of avoiding chemotherapy and radiation in prepubertal children is advantageous.
2. Results from a single-arm Children's Oncology Group (COG) trial support the strategy of observation after surgical resection of a single node and treatment with limited chemotherapy for children with favorable stage IA or IIA NLPHL.[27][Level of evidence B1] To date, there is no evidence that this approach increases the risk of transformation to non-Hodgkin lymphoma.
   • A total of 178 patients were treated with surgical resection alone for single-node disease (n = 52), chemotherapy alone after complete response (CR) to three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) (n = 115), or chemotherapy with low-dose involved-field radiation therapy (LD-IFRT) (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11). The 5-year EFS rate was 85.5%, and the OS rate was 100%.
   • The 5-year EFS rate was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.

Advanced-stage NLPHL is very rare. There is no consensus regarding the optimal treatment for this disease, although outcomes for patients are excellent when they are treated according to standard regimens for intermediate-risk or high-risk Hodgkin lymphoma.

Evidence (chemotherapy for NLPHL with unfavorable characteristics):

1. In a retrospective review of 41 patients with advanced-stage NLPHL, many different chemotherapy regimens were used; some included rituximab.[35][Level of evidence C1]
   • The OS rate was 98%, with the only death resulting from a subsequent neoplasm.
2. In a retrospective analysis, 97 intermediate-risk patients with NLPHL were treated in COG study AHOD0031 (NCT00025259).[36]
   • These patients demonstrated a higher CR rate than patients with classical histology. The 5-year EFS rate was marginally superior in patients with NLPHL (91.2%) than in patients with classical Hodgkin lymphoma (83.2%).
   • Most patients treated with four cycles of the ABVE-PC regimen achieved a rapid early response with a CR status and demonstrated excellent EFS and OS without IFRT. This finding suggests that the dose-dense, response-based protocol therapy designed for patients with classical Hodgkin lymphoma may have been more intensive than necessary for patients with NLPHL.

Retrospective case series report on responses with rituximab alone [37] or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [38] in adults with NLPHL. However, pediatric data have not been reported.

A summary of treatment approaches for NLPHL can be found in Table 10. Both children and adults have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[27,28,33,39] In patients with NLPHL, transformation to aggressive large B-cell lymphoma rarely occurs. When it does, it substantially increases the risk of mortality.[40] In adults with NLPHL, a variant immunoarchitectural pattern has been associated with a higher risk of progression to aggressive lymphoma and more advanced disease.[41] Among long-term survivors of NLPHL, death is more likely to result from treatment-related toxicity (both acute and long-term) than from lymphoma.[42,43]

Mixed-cellularity Hodgkin lymphoma

In addition to variable responses by histology for NLPHL, differences by mixed-cellularity histology have also been observed. COG investigators reported a 4-year EFS rate of 95.2% for children with stage I or stage II mixed-cellularity histology treated with minimal AV-PC therapy (and only rarely requiring radiation therapy). This EFS rate was significantly better than the 75.8% EFS rate for patients who had nodular-sclerosing histology (P = .008).[44]

Radiation Therapy

As previously mentioned, most newly diagnosed children are treated with risk-adapted chemotherapy, either alone or in combination with consolidative radiation therapy. Radiation therapy volumes can vary and have protocol-specific definitions, but they generally encompass lymph node sites initially involved at the time of diagnosis, without extensive inclusion of uninvolved regions, or positron emission tomography (PET)-avid sites at either interim or end-of-therapy assessment. Radiation therapy field reductions are made to account for tumor regression with chemotherapy.[45]

One study investigated the effects of central review of the interim fluorine F 18-fludeoxyglucose (18F-FDG) PET–computed tomography (CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted COG AHOD1331 (NCT02166463) study for pediatric patients with high-risk Hodgkin lymphoma. The study evaluated the results of 573 patients after two cycles of chemotherapy. There was good agreement between central and institutional iPET analysis, with a concordance rate of 89.7% (514 of 573). Of 126 patients who were considered iPET positive by institutional review, 30% were found to be iPET negative by central review. Thus, these patients could avoid being treated with radiation therapy. Conversely, of 447 patients who were considered iPET negative by institutional review, 4.7% were considered positive by central review, which led to these patients receiving radiation therapy.[46]

Radiation volume

With advancements in systemic therapy, radiation therapy field definitions have become increasingly restricted. Radiation therapy is no longer needed to sterilize all disease. Advances in radiological imaging allow for a more precise radiation target definition. With effective chemotherapy and contemporary treatments using lower radiation doses (<21 Gy) and reduced volumes (ISRT), contralateral uninvolved sites are not irradiated.

General trends in radiation treatment volume are summarized as follows:

• Historical regional radiation therapy fields (e.g., mantle, subtotal, or total nodal) have been replaced by involved-nodal radiation therapy (INRT) or ISRT. In select situations, such as adolescents and young adults treated with radiation alone for NLPHL, IFRT is used.
• INRT defines the treatment volume using the prechemotherapy PET-CT scan that is obtained with the patient in a position similar to the position to be used at the time of radiation therapy. This volume is later contoured onto the postchemotherapy-planning CT scan. The final treatment volume only includes the initially involved nodes with a margin, typically 2 cm.[47,48,49] The subsequent EuroNet-PHL-C2 trial employs INRT.
• ISRT, used in contemporary COG trials, is used when optimal prechemotherapy imaging (PET-CT in a position similar to the position to be used at the time of radiation therapy) is not available to the radiation oncologist. Because the delineation of the area of involvement is less precise, a somewhat larger treatment volume is contoured than for INRT, typically at least 2 cm around the nodes where the lymphoma was located before chemotherapy was given. The exact volume will depend on the individual case scenario.[45] There are several situations in which this definition is further modified, such as when inappropriately large volumes of sensitive normal tissues might be exposed.[50]
• Modified involved-field radiation therapy is the term used in the EuroNet-PHL-C1 trial to describe treatment volumes that contain the involved lymph node(s) as seen before chemotherapy plus radiation planning margins of 1 cm to 2 cm, depending on the area of involvement. These volumes are comparable to ISRT fields, although the development preceded the widespread availability of CT-based planning.

Breast-sparing radiation therapy plans using proton therapy are under evaluation to determine whether there is a statistically significant reduction in dose.[51] Ongoing studies seek to determine whether doses to other critical organs, such as the heart and lungs, can be reduced with proton therapy, without compromising survival outcomes.[52][Level of evidence C1] Long-term results are pending.

ISRT or INRT treatment planning

Radiation therapy planning that uses CT scans obtained during the simulation procedure is a requirement for contemporary INRT or ISRT. Fusion of staging imaging (CT or PET-CT) with the planning CT dataset can facilitate delineation of the treatment volume. Radiation therapy planning scans that encompass the full extent of organs at risk (e.g., lungs) are important so that normal tissue exposures can be calculated accurately.

Definitions that are important in planning radiation therapy include the following:

1. Prechemotherapy or presurgery gross tumor volume (GTV): Imaging abnormalities of nodal or non-nodal tissues at initially involved sites.
2. Postchemotherapy GTV: Imaging abnormalities at initially involved sites that remain abnormal after chemotherapy.
3. Postchemotherapy clinical target volume (CTV): Abnormal tissues originally involved with lymphoma but taking into account the reduction in the axial (transverse) diameter that has occurred with chemotherapy. This delineation requires consideration of the expected routes of disease spread and the quality of pretreatment imaging.
4. Internal target volume (ITV): Encompasses the CTV, with an added margin to account for variation in shape and motion within the patient (e.g., breathing).
5. Planning target volume (PTV): Encompasses the ITV or CTV and accounts for variation in daily setup for radiation; generally, 0.5 cm to 1 cm.
6. Boost radiation therapy: Some protocols, such as the EuroNet-PHL-C1 protocol, give additional radiation therapy (a boost) to sites with a poor response and/or bulky residual disease after initial chemotherapy. These volumes were determined after completion of all chemotherapy. This approach is sometimes used for patients with residual areas of PET avidity after chemotherapy.
7. Organ at risk determination and dose constraints: Because of the importance of long-term tissue injury after radiation, the dose to normal tissues is kept as low as reasonably achievable while adequately treating the PTV. Some specific organ radiation dose tolerances guide these decisions, and these organs are considered organs at risk.

The treatment volume for unfavorable or advanced disease is somewhat variable and often protocol-specific. Large-volume radiation therapy may compromise organ function and limit the intensity of second-line therapy if relapse occurs. In patients with intermediate or advanced disease, who often have multifocal/extranodal disease, the current standard of therapy includes postchemotherapy ISRT that limits radiation exposure to large portions of the body.[45,50] For example, in the AHOD0031 trial, radiation therapy was given to involved sites at diagnosis,[20] but in the AHOD1331 trial, it was given to bulky mediastinal disease and to slow responding disease sites (based on interim PET scan).[53] There is emerging evidence for omitting radiation therapy entirely in patients who have a complete, PET-based response. Thus, in the S1826 trial, radiation therapy was given only to patients with residual, metabolically active posttherapy sites as defined on PET.[30]

Radiation dose

The dose of radiation also varies and is often protocol specific.

General considerations regarding radiation dose include the following:

• Doses of 15 Gy to 25 Gy are typically used, with modifications based on patient age, the presence of bulky or residual (postchemotherapy) disease, and normal tissue concerns. Contemporary studies (Euronet-PHL-C1 and C2, AHOD1331, AHOD1721, and S1826) also allow for consideration of dose augmentation to 30 Gy to 36 Gy to residual PET-avid (Deauville score of 4 and, rarely, 5) sites after chemotherapy. This is because of the continued relapses in involved sites even after combined-modality therapy.[20,54]
• Some protocols have prescribed a boost of 5 Gy to 10 Gy in regions with suboptimal response to chemotherapy.[55] This approach has not been formally evaluated to quantitate the risk-benefit relationship, and it clearly increases the risk of radiation-associated late effects on heart, lungs, and breast tissues.

Technical considerations

Technical considerations for the use of radiation therapy to treat Hodgkin lymphoma include the following:

• A linear accelerator with a beam energy of 6 mV is desirable because of its penetration, well-defined edge, and homogeneity throughout an irregular treatment field.
• Three-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) are standard techniques in the treatment of lymphoma. Appropriate CT-based, image-guided treatment planning and delivery are standard, preferably with fusion of staging CT and PET imaging with radiation therapy planning CT datasets to delineate the target volumes.[45]
• Data are accumulating regarding the efficacy of IMRT and the decrease in median dose to normal surrounding tissues. Some uncertainty exists about the potential for increased late effects from IMRT, particularly subsequent neoplasms, because a larger area of the body receives a low dose compared with conventional techniques (although the mean dose to a volume may be decreased).
• Proton therapy is being investigated and may further decrease the mean dose to the surrounding normal tissue compared with IMRT or 3-D CRT, without increasing the volume of normal tissue receiving lower-dose radiation.[56]
• Individualized immobilization devices are preferable for young children to ensure accuracy and reproducibility.
• Attempts should be made to exclude or position breast tissue under the lung/axillary shielding.
• When the decision is made to include some or all of a critical organ (such as liver, kidney, or heart) in the radiation field, then normal tissue constraints are critical, depending on the chemotherapy used and patient age.
• Whole-lung irradiation (~10 Gy), with partial transmission blocks or intensity modulation, was historically a consideration in the setting of overt pulmonary nodules that had not achieved a CR.[20,21,55] However, it may be used in exceptional situations.

Role of LD-ISRT in childhood and adolescent Hodgkin lymphoma

Because all children and adolescents with Hodgkin lymphoma receive chemotherapy, an important question is whether patients who achieve a rapid early response or a CR to chemotherapy require radiation therapy. Conversely, the judicious use of LD-ISRT may permit a reduction in the intensity or duration of chemotherapy below toxicity thresholds that would not be possible if single-modality chemotherapy was used, thus decreasing overall acute and late toxicities.

The treatment approach for pediatric Hodgkin lymphoma should focus on maximizing disease control and minimizing risks of late toxicity associated with both radiation therapy and chemotherapy. Key points to consider regarding the role of radiation include the following:

• The use of LD-IFRT or ISRT in children with Hodgkin lymphoma may permit reduction in duration or intensity of chemotherapy and, as a result, dose-related toxicity of anthracyclines, alkylating agents, and bleomycin. This treatment may preserve cardiopulmonary and gonadal function and reduce the risk of subsequent leukemia.
• Radiation has been used as an adjunct to multiagent chemotherapy in clinical trials for low-, intermediate-, and high-risk pediatric Hodgkin lymphoma. The goal is to reduce risk of relapse in initially involved sites that do not show sufficient early or end-of-therapy responses to treatment, with the intent of preventing toxicity associated with second-line therapy.

  Compared with chemotherapy alone, adjuvant radiation has, in most studies, produced a superior EFS for children with intermediate-risk and high-risk Hodgkin lymphoma who achieve a CR to multiagent chemotherapy. But it does not clearly improve OS because of the success of second-line therapy.[24]

  However, the intermediate-risk Hodgkin lymphoma study (AHOD0031 [NCT00025259]) did not show a benefit for IFRT in patients who achieved a rapid CR to chemotherapy (defined as >60% reduction in 2-dimensional tumor burden after two cycles and metabolic remission and >80% reduction after four cycles). The 4-year EFS rate was 87.9% for patients with rapid responses who were randomly assigned to IFRT versus 84.3% (P = .11) for patients with rapid responses who were not assigned to IFRT. The OS rate was 98.8% in both groups.[20] In a subset analysis of patients with anemia and bulky limited-stage disease, the EFS rate was 89.3% for patients with rapid early responses or complete remissions who received IFRT, compared with 77.9% for patients who did not receive IFRT (P = .019).[57][Level of evidence B1]

  Adjuvant radiation therapy may be associated with an increased risk of late effects or mortality.[58]

• Radiation consolidation may facilitate local disease control in individuals with refractory or recurrent disease, especially in those who have limited or bulky sites of disease progression/recurrence or persistent disease that does not completely respond to chemotherapy.[59,60]
• The radiation dose to breast, heart, thyroid, and lung tissue received by patients in contemporary COG trials is 55% to 85% lower than the dose received by survivors analyzed in the Childhood Cancer Survivors Study (CCSS). This finding should be considered when estimating the risk of late toxicity associated with modern radiation therapy.[61] However, a Stanford report identified a significant risk of breast cancer in children with Hodgkin lymphoma despite being treated with low-dose radiation therapy. The regimen used from 1970 to 1990 prescribed IFRT of 15 Gy to 25.5 Gy. At a median follow-up of 20.6 years, 18 of 110 children treated with radiation therapy in this dose range developed one or more subsequent malignant neoplasms, including 6 patients who developed breast carcinomas.[62]

Finally, an inherent assumption is made in a trial comparing chemotherapy alone versus chemotherapy and radiation that the effect of radiation on EFS will be uniform across all patient subgroups. However, it is not clear how histology, presence of bulky disease, presence of B symptoms, or other variables affect the efficacy of postchemotherapy radiation.

Chemotherapy

Many chemotherapy combinations have been used to effectively treat pediatric patients with Hodgkin lymphoma. Many of the agents in original MOPP and ABVD regimens continue to be used. Etoposide has been incorporated into some pediatric treatment regimens as an effective alternative to alkylating agents, in an effort to reduce gonadal toxicity and enhance antineoplastic activity. Current treatment approaches for pediatric patients with Hodgkin lymphoma use procarbazine-free standard backbone regimens, such as ABVE-PC in North America [20,21] and OEPA-COPDAC in Europe.[22] Both of these regimens represent dose-dense therapies that use six drugs to maximize intensity without exceeding thresholds of toxicity. In North America, pediatric patients with Hodgkin lymphoma are treated with ABVD-based regimens. However, bleomycin has been replaced by other agents (i.e., brentuximab vedotin or nivolumab), and the cardioprotectant dexrazoxane has been used to reduce the risk of late effects.

Combination chemotherapy regimens used in trials are summarized in Table 6.

Table 6. Chemotherapy Regimens for Children and Adolescents With Hodgkin Lymphoma

Name	Drugs	Dosage	Route	Days
IV = intravenous; PO = oral.
a ABVE-PC modifications during the P9425 study included reducing bleomycin to 5 units/m2 on day 0 and administering prednisone on days 0 to 7 (instead of days 0–9). In subsequent studies, doxorubicin dose was reduced to 25 mg/m2 in all trials, and for high-risk Hodgkin lymphoma, use of cyclophosphamide was increased to 600 mg/m2 on days 1 and 2.
COPDAC[22]	Cyclophosphamide	600 mg/m2	IV	1, 8
	Vincristine (Oncovin)	1.4 mg/m2	IV	1, 8
	Prednisone	40 mg/m2	PO	1–15
	Dacarbazine	250 mg/m2	IV	1–3
CAPDAC[63]	Brentuximab vedotin substituted for vincristine in COPDAC	1.2 mg/kg	IV	1, 8
OEPA[22]	Vincristine (Oncovin)	1.5 mg/m2	IV	1, 8, 15
	Etoposide	125 mg/m2	IV	3–6
	Prednisone	60 mg/m2	PO	1–15
	Doxorubicin (Adriamycin)	40 mg/m2	IV	1, 15
AEPA[63]	Brentuximab vedotin substituted for vincristine in OEPA	1.2 mg/kg	IV	1, 8, 15
ABVD[8]	Doxorubicin (Adriamycin)	25 mg/m2	IV	1, 15
	Bleomycin	10 units/m2	IV	1, 15
	Vinblastine	6 mg/m2	IV	1, 15
	Dacarbazine	375 mg/m2	IV	1, 15
N-AVD[30]	Doxorubicin (Adriamycin)	25 mg/m2	IV	1, 15
	Vinblastine	6 mg/m2	IV	1, 15
	Dacarbazine	375 mg/m2	IV	1, 15
	Nivolumab	Age 12–17 y: 3 mg/kg (240 mg maximum); age 18 y or older: 240 mg	IV	1, 15
ABVE-PC a[21]	Doxorubicin (Adriamycin)	30 mg/m2	IV	0, 1
	Bleomycin	10 units/m2	IV	0, 7
	Vincristine (Oncovin)	1.4 mg/m2(maximum dose, 2.8 mg/m2)	IV	0, 7
	Etoposide	75 mg/m2	IV	0–4
	Prednisone	40 mg/m2	PO	0–9
	Cyclophosphamide	800 mg/m2	IV	0
Bv-AVE-PC(bleomycin omitted and brentuximab vedotin added to the ABVE-PC regimen)[53]	Brentuximab vedotin	1.8 mg/kg	IV	1
	Vincristine	1.4 mg/m2(maximum dose, 2.8 mg/m2)	IV	8
BEACOPP[64]	Bleomycin	10 units/m2	IV	7
	Etoposide	200 mg/m2	IV	0–2
	Doxorubicin (Adriamycin)	35 mg/m2	IV	0
	Cyclophosphamide	1,200 mg/m2	IV	1, 8
	Vincristine (Oncovin)	2 mg/m2	IV	7
	Prednisone	40 mg/m2	PO	0–13
	Procarbazine	100 mg/m2	PO	0–6
CVP[65]	Cyclophosphamide	500 mg/m2	IV	1
	Vinblastine	6 mg/m2	IV	1, 8
	Prednisolone	40 mg/m2	PO	1–8
AV-PC[27,44]	Doxorubicin (Adriamycin)	25 mg/m2	IV	1, 2
	Vincristine	1.4 mg/m2(maximum dose, 2.8 mg/m2)	IV	1, 8
	Prednisone	20 mg/m2	PO	1–7
	Cyclophosphamide	600 mg/m2	IV	1, 2

Evolution of North American cooperative and consortium trial results

A series of North American trials have evaluated response-based and risk-adapted therapy.

Evidence (response-based and risk-adapted therapy):

1. The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy with ABVE [66] for patients with favorable low-stage disease and dose-dense ABVE-PC for patients with unfavorable advanced-stage disease in combination with 21 Gy IFRT.[21]
   • Children and adolescents with low-risk Hodgkin lymphoma (stages I, IIA, IIIA1) treated with IFRT (25.5 Gy) after achieving CR to two cycles of doxorubicin, bleomycin, vincristine, and etoposide (DBVE) had outcomes comparable to those not in CR after two cycles of DBVE who were then treated with a total of four cycles of DBVE and IFRT (25.5 Gy). This response-dependent approach permitted reduction in chemotherapy exposure in 45% of patients.[66]
   • A dose-dense, early response–based treatment approach with ABVE-PC permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles.[21][Level of evidence B1]
   • The 5-year EFS rate was comparable for patients with rapid early responses (86%) and slow early responses (83%) who were treated with three and five cycles of ABVE-PC, respectively, followed by radiation therapy (21 Gy). Patients who received dexrazoxane had more hematological and pulmonary toxicity.[21]
   • Although etoposide is associated with an increased risk of therapy-related acute myeloid leukemia with 11q23 abnormalities, the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.[18,67]
2. A large COG study (COG-59704) evaluated response-adapted therapy featuring four cycles of a dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP), followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[64][Level of evidence B4] For girls with rapid early responses, an additional four courses of COPP/ABV (without IFRT) were given. Boys with rapid early responses received two cycles of ABVD followed by IFRT. Patients with slow early responses received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girls' therapy was intended to reduce the risk of breast cancer. Key findings include the following:[64]
   • Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four cycles of BEACOPP.
   • The 5-year EFS rate was 94%, with a median follow-up time of 6.3 years.
   • Early intensification followed by less-intense response-based therapy resulted in high EFS.

   However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of newer and safer strategies.

3. The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:
   • Nonalkylating-agent chemotherapy (e.g., methotrexate or etoposide) instead of alkylating-agent chemotherapy results in an inferior EFS among patients with unfavorable clinical presentations.[68,69]
   • The combination of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) is an effective regimen (10-year EFS rate, 89%) for children and adolescents with favorable-risk disease (low-stage NLPHL and classical Hodgkin lymphoma without B symptoms or bulky disease) when used in combination with response-based LD-IFRT (15–25.5 Gy).[70]
   • Patients with favorable-risk Hodgkin lymphoma treated with four cycles of VAMP chemotherapy alone who achieved an early CR had a comparable 5-year EFS rate to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).[71]
4. The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]
   1. Patients with rapid early responses (defined by CT imaging after two cycles) received two additional ABVE-PC cycles, followed by CR evaluation.
      • Patients with rapid early responses with CR at the end of chemotherapy (based on CT imaging and negative PET or gallium scans) were randomly assigned to receive either IFRT or no additional therapy.
      • Patients with rapid early responses with less than a CR were nonrandomly assigned to IFRT.
   2. Patients with slow early responses were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All patients with slow early responses were assigned to receive IFRT.

   Key 4-year OS and EFS outcomes from this trial include the following:

   • Early response was an important prognostic factor. The overall EFS rate was 85.0% and significantly higher (P < .001) for patients with rapid early responses (86.9%) than for patients with slow early responses (77.4%).
   • The OS rate was 97.8% and significantly higher (P < .001) for patients with rapid early responses (98.5%) than for patients with slow early responses (95.3%).
   • Approximately 45% of patients had rapid early responses and achieved CR by the end of chemotherapy. For this population, the EFS rate did not differ significantly (P = .11) among those who were randomly assigned to IFRT (87.9%) versus no IFRT (84.3%). The OS rate was 98.8% (95% confidence interval [CI], 96.8%–99.5%) for those receiving IFRT and 98.8% (95% CI, 96.9%–99.6%) for those receiving chemotherapy alone.
   • Despite achieving rapid early response or CR, stage I or stage II patients with bulky mediastinal adenopathy and anemia had significantly better EFS when randomly assigned to IFRT after four cycles of ABVE-PC.[57]
   • Approximately 20% of patients had slow early responses. For this population, the EFS rate did not differ significantly (P = .11) among those who were randomly assigned to DECA (79.3%) versus no DECA (75.2%).
   • Study results confirm the prognostic significance of early chemotherapy response and support the safety of no IFRT, based on rapid early response with CR by the end of chemotherapy.

   An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

5. The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44]
   • At 4 years, the OS rate was 99.6%, with 49.0% in remission after treatment with minimal chemotherapy alone and 88.8% in remission without receiving high-dose chemotherapy with stem cell rescue or more than 21 Gy of IFRT.[44]
   • Factors predicting favorable EFS after a limited chemotherapy response-based approach included mixed-cellularity histology, low erythrocyte sedimentation rate, and negative 18F-FDG PET after one cycle.[44]
   • Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]
     • For patients with rapid early responses, the 10-year PFS rate was 96.6% with IFRT and 84.1% without IFRT (P = .10).
     • For patients with slow early responses, the 10-year PFS rate was 80.9% with IFRT and 64% without IFRT (P =.03).
     • Among the 90 patients with rapid early responses who did not receive IFRT, all 14 relapses included an initial disease site.
     • Among the 45 patients with slow early responses who did not receive IFRT, 14 of the 16 relapses occurred in the initial disease site.
     • This 3-year study was amended during the second year. All patients with equivocal or positive PET findings after one cycle were treated with IFRT, even if they achieved a CR after three cycles.
6. In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]
   • After a median follow-up period of 42.1 months, the 3-year EFS rates were 92.1% (95% CI, 88.4%–94.7%) for patients who received Bv-AVE-PC and 82.5% (95% CI, 77.4%–86.5%; P = .0002) for patients who received ABVE-PC.
   • The cumulative incidence of relapse was significantly lower for patients who received Bv-AVE-PC (7.5%; 95% CI, 4.9%–10.9%) than for patients who received ABVE-PC (17.1%; 95% CI, 12.9%–21.8%).
   • Radiation therapy was administered to patients with slow-responding lesions confirmed by PET2 imaging (defined as a five-point scale score >3) and to patients with any large mediastinal masses. The percentage of patients who received radiation therapy was similar between the two arms of the study (52.7% for Bv-AVE-PC and 55.7% for ABVE-PC).
   • Rates of febrile neutropenia, infection complications, and neuropathy were similar between the two arms of the study.
   • The U.S. Food and Drug Administration approved brentuximab vedotin in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients aged 2 years and older with previously untreated high-risk classical Hodgkin lymphoma.
7. The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). There were 976 eligible patients with newly diagnosed stage III or stage IV Hodgkin lymphoma who were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]
   • Patients aged 12 to 17 years accounted for approximately 25% of the study's total accrual.
   • Patients with stage IV Hodgkin lymphoma represented 62% to 65% of enrollees, and B symptoms were present in 56% to 58% of patients.
   • Results for this study were released early at a planned interim analysis because the primary PFS endpoint crossed the protocol-specified monitoring boundary.
   • The 1-year PFS rate favored nivolumab-AVD over brentuximab vedotin-AVD (94% versus 86%, respectively) after a median follow-up of 12.1 months. The hazard ratio (HR) was 0.48 (99% CI, 0.27–0.87). The HR for the cohort of patients who were aged 12 to 17 years was the same as the HR for the overall study population.
   • Less than 1% of patients in either arm received consolidative radiation therapy.
   • Nivolumab-AVD was well-tolerated, with low rates of immune-related adverse events: hypothyroidism of any grade (7%), febrile neutropenia (5%), and grade 3 or higher peripheral neuropathy (1%).
   • Both nivolumab-AVD and brentuximab vedotin-AVD were shown to be effective without radiation therapy and with less alkylator agents. However, patients who received nivolumab-AVD had a superior short-term EFS.
   • While further follow-up is required, the authors suggested that nivolumab-AVD will likely be a new standard therapy for patients with advanced-stage Hodgkin lymphoma.

Evolution of European multicenter trial results

European investigators have conducted a series of risk-adapted trials evaluating sex-based treatments featuring multiagent chemotherapy with vincristine, prednisone, procarbazine, and doxorubicin (OPPA)/COPP and IFRT.

Key findings from these trials include the following:

1. Substitution of cyclophosphamide for mechlorethamine in the MOPP combination results in a low risk of subsequent myelodysplasia/leukemia.[10]
2. Omission of procarbazine from the OPPA combination and substitution of methotrexate for procarbazine in the COPP combination (OPA/COMP) results in a substantially inferior EFS.[73]
3. Substitution of etoposide for procarbazine in the OPPA combination (OEPA) in boys produces comparable EFS to that of girls treated with OPPA and is associated with hormonal parameters, suggesting lower risk of gonadal toxicity.[74]
4. Omission of radiation for patients completely responding (defined as complete resolution or only minor residuals in all previously involved regions using clinical examination and anatomical imaging) to risk-based and sex-based OEPA or OPPA/COPP chemotherapy results in a significantly lower EFS in intermediate-risk and high-risk patients than in irradiated patients (79% vs. 91%), but no difference among nonirradiated and irradiated patients assigned to the favorable-risk group.[24]
5. Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate-risk and high-risk patients.[22][Level of evidence B4]
6. A large, multinational, randomized trial (EuroNet-PHL-C1) investigated whether radiation therapy could be omitted in children (aged <18 years) with intermediate- and advanced-stage classical Hodgkin lymphoma who achieved a morphological and adequate metabolic response to early chemotherapy with OEPA. The trial also studied whether modified consolidation with COPDAC (substituting dacarbazine for procarbazine in COPP) reduced gonadotoxicity.[75][Level of evidence B1]
   • At a median follow-up of 66.5 months, the 5-year EFS rate was 90.1% (95% CI, 87.5%–92.7%) for patients who responded adequately to early chemotherapy with OEPA followed by COPP or COPDAC.
   • In the analysis according to protocol treatment, the 5-year EFS rate was 89.9% (95% CI, 87.1%–92.8%) for individuals randomly assigned to COPP (n = 444) versus 86.1% (95% CI, 82.9%–89.4%) for those randomly assigned to COPDAC (n = 448). Similar results were observed in the intent-to-treat analysis.
   • In a subgroup analysis (unplanned), the 5-year EFS rate among those with adequate early response to OEPA was 91.9% (95% CI, 88.1%–95.9%) with COPP and 82.9% (77.2%–89.0%) with COPDAC, but there was no difference in OS.
   • A posttreatment semen analysis included 45 men at the 40-month follow-up. COPP appeared to be more gonadotoxic (19 of 23 men were azoospermic) than COPDAC (0 of 22 men were azoospermic). Biomarker analyses that included follicle-stimulating hormone (FSH) and inhibin B also suggested higher prevalence of gonadotoxicity after COPP than COPDAC. Similarly, based on biomarker analyses limited to 113 women, FSH was significantly increased in 55 women who were randomly assigned to receive COPP, compared with 58 women who were randomly assigned to receive COPDAC.
7. Another EuroNet-PHL-C1 trial investigated whether radiation therapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.[76]
   • Among 738 patients with early-stage disease (median follow-up period, 63.3 months), 714 patients were assigned to and received therapy in treatment group 1.
   • Among the 713 patients in the intention-to-treat group, 440 had adequate responses to two cycles of OEPA and did not receive radiation therapy. The 5-year EFS rate was 86.5% (95% CI, 83.3%–89.8%).
   • The 5-year EFS rate was 88.6% (95% CI, 84.8%–92.5%) for the 273 patients with adequate responses to chemotherapy who also received radiation therapy.
   • The study findings suggested that radiation therapy can be omitted in patients with early-stage classical Hodgkin lymphoma who have had adequate responses to OEPA chemotherapy.
8. An open-label, single-arm, multicenter trial (NCT01920932) evaluated two cycles of AEPA (brentuximab vedotin substituted for vincristine in the OEPA regimen) and four cycles of CAPDAC (brentuximab vedotin substituted for vincristine in the COPDAC regimen) in 77 patients aged 18 years or younger with stage IIB, IIIB, or IV classical Hodgkin lymphoma. Residual node radiation therapy (25.5 Gy) was given at the end of all chemotherapy and only to nodal sites that did not achieve a CR at the early-response assessment after two cycles of therapy.[63][Level of evidence B4]
   • The 3-year EFS rate (median follow-up, 3.4 years) was 97.4%, and the OS rate was 98.7%.
   • The AEPA and CAPDAC regimens were well tolerated and allowed for omission of radiation therapy in 35% of the treated patients.
   • Only 4% of patients experienced grade 3 neuropathy.
   • Compared with historical controls, residual node radiation volumes in patients requiring radiation were very small, sparing healthy surrounding tissue.

Accepted Risk-Adapted Treatment Strategies

Contemporary trials for pediatric Hodgkin lymphoma involve a risk-adapted, response-based treatment approach that titrates the length and intensity of chemotherapy and dose of radiation on the basis of disease-related factors, including stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy as determined by functional imaging. In addition, vulnerability related to age and sex is also considered in treatment planning.

Classical Hodgkin lymphoma, low-risk disease

Table 7 summarizes the results of treatment approaches used for pediatric patients with low-risk Hodgkin lymphoma.

Table 7. Treatment Approaches for Pediatric Patients With Low-Risk Hodgkin Lymphoma

Chemotherapy (No. of Cycles)a	Radiation (Gy)	Stage	No. of Patients	Event-Free Survival Rate (No. of Years of Follow-up)	Survival Rate (No. of Years of Follow-up)
CS = clinical stage; IFRT = involved-field radiation therapy; N/A = not applicable; No. = number.
a For more information about the chemotherapy regimens, see Table 6.
b Included patients with nodular lymphocyte-predominant Hodgkin lymphoma.
OEPA (2)[24]	IFRT (20–35)	I, IIA	281	94% (5)	N/A
	None		113	97% (5)
ABVD[77]	IFRT (21–35)	I–IV	209	85% (5)	97% (5)
ABVE (2-4)b[66]	IFRT (25.5)	IA, IIA, IIIA1, without bulky disease	51	91% (6)	98% (6)
AV-PC[44]	None	IA, IIA, without bulky disease	278	79.9% (4)	99.6% (4)
	Response-based IFRT (21)

Classical Hodgkin lymphoma, intermediate-risk disease

Table 8 summarizes the results of treatment approaches used for pediatric patients with intermediate-risk Hodgkin lymphoma.

Table 8. Treatment Approaches for Pediatric Patients With Intermediate-Risk Hodgkin Lymphoma

Chemotherapy (No. of Cycles)a	Radiation (Gy)	Stage	No. of Patients	Event-Free Survival Rate (No. of Years of Follow-up)	Survival Rate (No. of Years of Follow-up)
CR = complete response; CS = clinical stage; E = extralymphatic; IFRT = involved-field radiation therapy; N/A = not applicable; RER = rapid early response; SER = slow early response.
a For more information about the chemotherapy regimens, see Table 6.
OEPA (2) + COPDAC (2)[22]	IFRT (20–35)	IE, IIB, IIE A, IIIA	139	88.3% (5)	98.5% (5)
ABVE-PC (3–5)[21]	IFRT (21)	IIA/IIIA, if bulky disease	53	84% (5)	95% (5)
ABVE-PC: RER/CR[20]	IFRT (21)	IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease	380	87.9% (4)	98.8% (4)
ABVE-PC: RER/CR[20]	None	IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease	382	84.3% (4)	98.8% (4)
ABVE-PC: SER: +DECA[20]	IFRT (21)	IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease	153	79.3% (4)	96.5% (4)
ABVE-PC: SER: -DECA[20]	IFRT (21)		151	75.2% (4)	94.3% (4)

Classical Hodgkin lymphoma, high-risk disease

Table 9 summarizes the results of treatment approaches used for pediatric patients with high-risk Hodgkin lymphoma.

Table 9. Treatment Approaches for Pediatric Patients With High-Risk Hodgkin Lymphoma

Chemotherapy (No. of Cycles)a	Radiation (Gy)	Stage	No. of Patients	Event-Free Survival Rate (No. of Years of Follow-up)	Survival Rate (No. of Years of Follow-up)
E = extralymphatic; IFRT = involved-field radiation therapy; ISRT = involved-site radiation therapy; N/A = not applicable; No. = number; PFS = progression-free survival.
a For more information about the chemotherapy regimens, see Table 6.
OEPA (2) + COPDAC (4)[22]	IFRT (20–35)	IIE B, IIIE A/B, IIIB, IVA/B	239	86.9% (5)	94.9% (5)
ABVE-PC (3-5)[21,78]	IFRT (21)	IIB, IIIB, IV	163	85% (5)	95% (5)
AEPA (2); CAPDAC (4)[63]	Individual residual nodal (25.5)	IIB, IIIB, IV	77	97.4% (3)	98.7% (3)
Bv-AVE-PC (5)[53]	ISRT	IIB + Bulk, IIIB, IV	587	92.1% (3)	99.3% (3)
N-AVD (6)[30]	None	III, IV	489 total (120 aged 12–17 y)	PFS: 94% (1)	99% (1)

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

NLPHL

Table 10 summarizes the results of treatment approaches used for pediatric patients with NLPHL, some of which feature surgery alone for completely resected disease and limited cycles of chemotherapy with or without LD-IFRT. Because of the relative rarity of this subtype, most trials are limited by small cohort numbers and nonrandom allocation of treatment.

Table 10. Treatment Approaches for Pediatric Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Chemotherapy (No. of Cycles)a	Radiation (Gy)	No. of Patients	Event-Free Survival Rate (No. of Years of Follow-up)	Survival Rate (No. of Years of Follow-up)
IFRT = involved-field radiation therapy; N/A = not applicable; No. = number.
a For more information about the chemotherapy regimens, see Table 6.
b Single lymph node surgically resected.
c All involved lymph nodes surgically resected.
CVP (3)[65]	None	55	74% (5)	100% (5)
Noneb[27]	Noneb	52	77% (5)	100% (5)
AV-PC[27]	None	124	85.5% (5)	100% (5)
	IFRT (21)	11
Nonec[28]	None	51	67% (2)	100% (2)

Treatment of Adolescents and Young Adults With Hodgkin Lymphoma

The treatment approach for adolescents and young adults with Hodgkin lymphoma may vary based on community referral patterns and age restrictions at pediatric cancer centers. The optimal approach is debatable.

In patients with intermediate-risk or high-risk disease, the standard of care in adult oncology practices typically involves at least six cycles of ABVD chemotherapy that delivers a cumulative anthracycline dose of 300 mg/m².[79,80] For more information, see Hodgkin Lymphoma Treatment. In late-health outcome studies of pediatric cancer survivors, the risk of anthracycline cardiomyopathy has been shown to exponentially increase after exposure to cumulative anthracycline doses of 250 to 300 mg/m².[81,82] Subsequent need for mediastinal radiation can further enhance the risk of several late cardiac events.[83] In an effort to optimize disease control and preserve both cardiac and gonadal function, pediatric regimens for low-risk disease most often feature a restricted number of cycles of ABVD derivative combinations. For those with intermediate-risk and high-risk disesase, alkylating agents and etoposide are integrated into anthracycline-containing regimens.

No prospective studies of efficacy or toxicity in adolescent or young adults treated with pediatric versus adult regimens have been reported; however, some secondary analyses have been conducted.[84]

1. A retrospective review documented the outcomes of patients aged 17 to 22 years treated in the Eastern Cooperative Oncology Group (ECOG) trials E2496 (NCT00003389) or Stanford V versus the COG trial AHOD0031 (NCT00025259).[85][Level of evidence C2]
   • The 5-year failure-free survival (FFS) rates were 68% for patients in the ECOG trial and 81% for patients in the COG trial, with OS rates of 89% and 97%, respectively.
   • Limitations of this study include differences in the study populations. More adolescents and young adults aged 17 to 22 years in the E2496 study had stage III or IV disease and B symptoms, whereas more adolescents and young adults aged 17 to 22 years in the AHOD0031 study had bulky disease and received radiation (although with smaller doses than those in E2496). Some of these differences were addressed using a propensity score analysis that confirmed inferior FFS for adolescents and young adults in the E2496 trial than those in the AHOD0031 trial. The study was also not a prospective randomized trial.
2. A comprehensive review of differences in outcomes between adolescent and young adult patients treated in pediatric versus adult trials was published.[86] In a retrospective analysis, adolescents (aged ≥15 years) who were treated in risk- and response-adapted Children's Oncology Group Hodgkin lymphoma trials had worse EFS and OS rates than children (aged <15 years). These trials included AHOD0431 (NCT00302003) for low-risk patients, AHOD0031 [NCT00025259] for intermediate-risk patients, and AHOD0831 (NCT01026220) for high-risk patients.[87]
   • After a median follow-up of 7.4 years, the unadjusted 5-year EFS rates were 80% for older patients and 86% for younger patients (HR, 1.38).
   • The unadjusted 5-year OS rates were 96% for older patients and 99% for younger patients (HR, 2.50). In multivariable modeling, older patients were more likely to die than younger patients (HR, 3.08).
   • Outcomes varied by histology for older patients. Older patients with non-mixed cellularity histology experienced a significantly increased risk of having an event, compared with younger patients with the same histology (HR, 1.32). Older patients with mixed cellularity had significantly worse unadjusted 5-year EFS rates (77%) than younger patients (94%) (HR, 2.93 unadjusted). This result remained significant after multivariable modeling (HR, 3.72).

The optimal approach for adolescents and young adults with Hodgkin lymphoma is complicated by critical but understudied variables. Factors such as tumor biology, disease control, supportive care needs, and long-term toxicities in adolescents and young adults with Hodgkin lymphoma require further research.

Adolescent and young adult patients with Hodgkin lymphoma should consider participating in a clinical trial. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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42. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999.
43. Sandoval C, Venkateswaran L, Billups C, et al.: Lymphocyte-predominant Hodgkin disease in children. J Pediatr Hematol Oncol 24 (4): 269-73, 2002.
44. Keller FG, Castellino SM, Chen L, et al.: Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group. Cancer 124 (15): 3210-3219, 2018.
45. Hodgson DC, Dieckmann K, Terezakis S, et al.: Implementation of contemporary radiation therapy planning concepts for pediatric Hodgkin lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group. Pract Radiat Oncol 5 (2): 85-92, 2015 Mar-Apr.
46. Hoppe BS, McCarten KM, Pei Q, et al.: Importance of Central Imaging Review in a Pediatric Hodgkin Lymphoma Trial Using Positron Emission Tomography Response Adapted Radiation Therapy. Int J Radiat Oncol Biol Phys 116 (5): 1025-1030, 2023.
47. Girinsky T, van der Maazen R, Specht L, et al.: Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines. Radiother Oncol 79 (3): 270-7, 2006.
48. Campbell BA, Voss N, Pickles T, et al.: Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin's lymphoma: a question of field size. J Clin Oncol 26 (32): 5170-4, 2008.
49. Maraldo MV, Aznar MC, Vogelius IR, et al.: Involved node radiation therapy: an effective alternative in early-stage hodgkin lymphoma. Int J Radiat Oncol Biol Phys 85 (4): 1057-65, 2013.
50. Wirth A, Mikhaeel NG, Aleman BMP, et al.: Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lymphoma Radiation Oncology Group Guidelines. Int J Radiat Oncol Biol Phys 107 (5): 909-933, 2020.
51. Andolino DL, Hoene T, Xiao L, et al.: Dosimetric comparison of involved-field three-dimensional conformal photon radiotherapy and breast-sparing proton therapy for the treatment of Hodgkin's lymphoma in female pediatric patients. Int J Radiat Oncol Biol Phys 81 (4): e667-71, 2011.
52. Tringale KR, Modlin LA, Sine K, et al.: Vital organ sparing with proton therapy for pediatric Hodgkin lymphoma: Toxicity and outcomes in 50 patients. Radiother Oncol 168: 46-52, 2022.
53. Castellino SM, Pei Q, Parsons SK, et al.: Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma. N Engl J Med 387 (18): 1649-1660, 2022.
54. Dharmarajan KV, Friedman DL, Schwartz CL, et al.: Patterns of relapse from a phase 3 Study of response-based therapy for intermediate-risk Hodgkin lymphoma (AHOD0031): a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 92 (1): 60-6, 2015.
55. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.
56. Hoppe BS, Flampouri S, Su Z, et al.: Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 84 (2): 449-55, 2012.
57. Charpentier AM, Friedman DL, Wolden S, et al.: Predictive Factor Analysis of Response-Adapted Radiation Therapy for Chemotherapy-Sensitive Pediatric Hodgkin Lymphoma: Analysis of the Children's Oncology Group AHOD 0031 Trial. Int J Radiat Oncol Biol Phys 96 (5): 943-950, 2016.
58. Yeh JM, Diller L: Pediatric Hodgkin lymphoma: trade-offs between short- and long-term mortality risks. Blood 120 (11): 2195-202, 2012.
59. Constine LS, Yahalom J, Ng AK, et al.: The Role of Radiation Therapy in Patients With Relapsed or Refractory Hodgkin Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 100 (5): 1100-1118, 2018.
60. Daw S, Hasenclever D, Mascarin M, et al.: Risk and Response Adapted Treatment Guidelines for Managing First Relapsed and Refractory Classical Hodgkin Lymphoma in Children and Young People. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group. Hemasphere 4 (1): e329, 2020.
61. Zhou R, Ng A, Constine LS, et al.: A Comparative Evaluation of Normal Tissue Doses for Patients Receiving Radiation Therapy for Hodgkin Lymphoma on the Childhood Cancer Survivor Study and Recent Children's Oncology Group Trials. Int J Radiat Oncol Biol Phys 95 (2): 707-11, 2016.
62. O'Brien MM, Donaldson SS, Balise RR, et al.: Second malignant neoplasms in survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and chemotherapy. J Clin Oncol 28 (7): 1232-9, 2010.
63. Metzger ML, Link MP, Billett AL, et al.: Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation. J Clin Oncol 39 (20): 2276-2283, 2021.
64. Kelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group. Blood 117 (9): 2596-603, 2011.
65. Shankar A, Hall GW, Gorde-Grosjean S, et al.: Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin's lymphoma - an Anglo-French collaborative report. Eur J Cancer 48 (11): 1700-6, 2012.
66. Tebbi CK, Mendenhall NP, London WB, et al.: Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1259-65, 2012.
67. Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25 (5): 493-500, 2007.
68. Friedmann AM, Hudson MM, Weinstein HJ, et al.: Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation. J Clin Oncol 20 (14): 3088-94, 2002.
69. Hudson MM, Krasin M, Link MP, et al.: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease. J Clin Oncol 22 (22): 4541-50, 2004.
70. Donaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease. J Clin Oncol 25 (3): 332-7, 2007.
71. Metzger ML, Weinstein HJ, Hudson MM, et al.: Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma. JAMA 307 (24): 2609-16, 2012.
72. Parekh A, Keller FG, McCarten KM, et al.: Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis. Blood 140 (10): 1086-1093, 2022.
73. Schellong G: The balance between cure and late effects in childhood Hodgkin's lymphoma: the experience of the German-Austrian Study-Group since 1978. German-Austrian Pediatric Hodgkin's Disease Study Group. Ann Oncol 7 (Suppl 4): 67-72, 1996.
74. Schellong G, Pötter R, Brämswig J, et al.: High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin's Disease Study Group. J Clin Oncol 17 (12): 3736-44, 1999.
75. Mauz-Körholz C, Landman-Parker J, Balwierz W, et al.: Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol 23 (1): 125-137, 2022.
76. Mauz-Körholz C, Landman-Parker J, Fernández-Teijeiro A, et al.: Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study. Lancet Oncol 24 (3): 252-261, 2023.
77. Marr KC, Connors JM, Savage KJ, et al.: ABVD chemotherapy with reduced radiation therapy rates in children, adolescents and young adults with all stages of Hodgkin lymphoma. Ann Oncol 28 (4): 849-854, 2017.
78. Kelly KM, Cole PD, Pei Q, et al.: Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): a report from the Children's Oncology Group. Br J Haematol 187 (1): 39-48, 2019.
79. Viviani S, Zinzani PL, Rambaldi A, et al.: ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med 365 (3): 203-12, 2011.
80. Chisesi T, Bellei M, Luminari S, et al.: Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol 29 (32): 4227-33, 2011.
81. van der Pal HJ, van Dalen EC, van Delden E, et al.: High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30 (13): 1429-37, 2012.
82. Blanco JG, Sun CL, Landier W, et al.: Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group. J Clin Oncol 30 (13): 1415-21, 2012.
83. Bhakta N, Liu Q, Yeo F, et al.: Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 17 (9): 1325-34, 2016.
84. Kahn JM, Kelly KM: Adolescent and young adult Hodgkin lymphoma: Raising the bar through collaborative science and multidisciplinary care. Pediatr Blood Cancer 65 (7): e27033, 2018.
85. Henderson TO, Parsons SK, Wroblewski KE, et al.: Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis. Cancer 124 (1): 136-144, 2018.
86. Flerlage JE, Metzger ML, Bhakta N: The management of Hodgkin lymphoma in adolescents and young adults: burden of disease or burden of choice? Blood 132 (4): 376-384, 2018.
87. Kahn JM, Pei Q, Friedman DL, et al.: Survival by age in paediatric and adolescent patients with Hodgkin lymphoma: a retrospective pooled analysis of children's oncology group trials. Lancet Haematol 9 (1): e49-e57, 2022.

Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents

Because children and adolescents with Hodgkin lymphoma have excellent responses to frontline therapy, second-line (salvage) therapy has only been evaluated in a limited capacity. Because primary therapy fails in relatively few patients, no uniform second-line treatment strategy exists for this population.[1]

Adverse prognostic factors after relapse include the following:[2][Level of evidence C1]

• The presence of B symptoms (fever, weight loss, and night sweats) and extranodal disease.[3]
• Early relapse (occurring 3–12 months from the end of therapy).[4,5]
• Inadequate response to initial second-line therapy.[5]

Children with localized favorable relapses (≥12 months after completing therapy) whose original therapy involved reduced cycles of risk-adapted chemotherapy alone or chemotherapy with low-dose, small-volume radiation therapy (consolidation therapy) have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[6,7]

Treatment options for children and adolescents with refractory or recurrent Hodgkin lymphoma include the following:

1. Chemotherapy and targeted therapy.
2. Checkpoint inhibitor therapy.
3. Chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT).
4. Chemotherapy followed by allogeneic HSCT.
5. Involved-site radiation therapy (ISRT).

Chemotherapy and Targeted Therapy

Chemotherapy is the recommended second-line therapy. The choice of specific agents, dose intensity, and number of cycles is determined by the initial therapy, disease characteristics at progression/relapse, and response to second-line therapy.

Agents used alone or in combination regimens in the treatment of refractory or recurrent pediatric Hodgkin lymphoma include the following:

• Ifosfamide, carboplatin, and etoposide (ICE).[8]
• Ifosfamide and vinorelbine, with or without bortezomib.[9][Level of evidence B4]; [10][Level of evidence C3]
• Ifosfamide, gemcitabine, and vinorelbine.[11][Level of evidence C1]
• Vinorelbine and gemcitabine.[12]; [13][Level of evidence C2]
• Vinorelbine, gemcitabine, and dexamethasone.[14][Level of evidence C1]
• Etoposide, prednisolone, ifosfamide, and cisplatin (EPIC).[15]
• Cytosine arabinoside, cisplatin, and etoposide (APE).[16]
• High-dose methotrexate, ifosfamide, etoposide, and dexamethasone (MIED).[17]
• Etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHAP).[18]
• Dexamethasone, high-dose cytarabine, and cisplatin (DHAP).[19]
• Rituximab (for patients with CD20-positive disease) alone or in combination with second-line chemotherapy.[20]
• Brentuximab vedotin has been evaluated in adults with Hodgkin lymphoma. The U.S. Food and Drug Administration (FDA) indications for brentuximab vedotin in adult patients are as follows: (1) classical Hodgkin lymphoma after failure of autologous HSCT or after failure of at least two previous multiagent chemotherapy regimens in patients who are not autologous HSCT candidates, and (2) classical Hodgkin lymphoma at high risk of relapse or progression, as postautologous HSCT consolidation therapy. For more information, see the Treatment of Recurrent Classic HL section in Hodgkin Lymphoma Treatment.
  1. A phase II trial in 102 adults with Hodgkin lymphoma whose disease relapsed after autologous HSCT showed the following:[21,22,23,24]
     • A complete remission rate of 34% and a partial remission rate of 40% was observed.[21,22,23]
     • Patients who achieved a complete remission (n = 34) had a 3-year progression-free survival (PFS) rate of 58% and a 3-year overall survival (OS) rate of 73%, with only 6 of 34 patients proceeding to allogeneic HSCT while in remission.
     • Further follow-up demonstrated a 5-year OS rate of 41% and a PFS rate of 22%. However, patients who achieved a complete remission (38%) had a 5-year OS rate of 64% and a PFS rate of 52%.[24][Level of evidence B4]
  2. The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients. Clearance and volume of brentuximab vedotin significantly correlates with weight (P < .001), and its area under the curve and C max are lower in children than in adults with weekly dosing.[25]
  3. The Children's Oncology Group phase I/II AHOD1221 (NCT01780662) study investigated treatment with brentuximab vedotin and gemcitabine in 46 children and young adults with primary refractory Hodgkin lymphoma or early relapse.[26]
     • The recommended phase II dose of brentuximab vedotin was 1.8 mg/kg.
     • Twenty-four of 42 patients (57%; 95% confidence interval [CI], 41%–72%) treated at this dose level experienced a complete response within the first four cycles. Four of 13 patients (31%) with partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle four. By modern response criteria, these are also complete responses, increasing the complete response to 28 of 42 patients (67%; 95% CI, 51%–80%).
     • Compared with alternate second-line regimens, brentuximab vedotin with gemcitabine offers the advantage of avoiding agents, such as anthracyclines, alkylators, or epipodophyllotoxins, that are associated with late treatment-related sequelae.
  4. Several small retrospective studies have evaluated the outcomes of pediatric and young adult patients with refractory or relapsed Hodgkin lymphoma treated with brentuximab vedotin and bendamustine. Overall results demonstrate tolerability, response, and the potential for this combination to serve as a bridge treatment to HSCT.[27,28][Level of evidence C1]
     1. One study evaluated the outcomes of 32 patients (median age, 16 years) who received up to six cycles of treatment with brentuximab vedotin (1.8 mg/kg) on day 1 and bendamustine (90–120 mg/m²) on days 2 and 3.[27]
        • At the end of treatment, the overall response rate was 81%.
        • The 3-year OS rate was 78.1%, and the 3-year PFS rate was 67%.
     2. A multicenter study from four academic centers evaluated 29 patients (median age, 16 years) who received a median of three cycles of brentuximab vedotin (1.8 mg/kg) on day 1 and bendamustine (90 mg/m²) on days 1 and 2 of 3-week cycles.[28]
        • Nineteen patients (66%) achieved a complete metabolic response, and 23 patients (79%) achieved an objective response.
        • The 3-year posttreatment event-free survival rate was 65%, and the OS rate was 89%.

  There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin with chemotherapy.

Checkpoint Inhibitor Therapy

Treatments that block the interaction between programmed death-1 (PD-1) and its ligands have shown high levels of activity in adults with Hodgkin lymphoma.

Evidence (nivolumab):

1. The anti–PD-1 antibody nivolumab induced objective responses in 20 of 23 adult patients (87%) with relapsed Hodgkin lymphoma.[29]
2. In a phase I/II study of children with refractory malignancies, single-agent nivolumab was tolerable and showed antitumor activity.[30][Level of evidence C3]
   • Among ten children with Hodgkin lymphoma, there was one complete response, two partial responses, and five cases of stable disease.
3. In a phase II study, pediatric and young adult patients (70% were <18 years) with relapsed or refractory Hodgkin lymphoma were treated with nivolumab and brentuximab vedotin.[31]
   • After four induction cycles of nivolumab plus brentuximab vedotin, 59% of patients (23 of 43) achieved a complete metabolic response.
   • Patients without a complete metabolic response also received intensification therapy with brentuximab vedotin and bendamustine before undergoing autologous HSCT. After intensification therapy and before consolidation therapy, 94% of patients achieved a complete metabolic response.

The FDA approved nivolumab for adult patients with classical Hodgkin lymphoma who have relapsed or progressed after autologous HSCT and brentuximab vedotin or three or more lines of systemic therapy that included autologous HSCT.[29,32]

Evidence (pembrolizumab):

1. The anti–PD-1 antibody pembrolizumab produced an objective response rate of 65% in 31 heavily pretreated adult patients with Hodgkin lymphoma whose disease relapsed after receiving brentuximab vedotin.[33] For more information, see the Treatment of Recurrent Classic HL section in Hodgkin Lymphoma Treatment.
2. A phase II study of 210 adult patients (median age, 35 years; range, 18–76 years) with refractory/relapsed classical Hodgkin lymphoma who were treated with pembrolizumab reported the following:[34][Level of evidence C3]
   • An overall response rate of 69% (95% CI, 62.3%–75.2%), with a complete response rate of 22.4% (95% CI, 6.9%–28.6%).
3. In a multicenter, nonrandomized, open-label, single-arm phase I/II study, 15 pediatric patients with relapsed or refractory Hodgkin lymphoma were treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks.[35][Level of evidence C1]
   • Two patients achieved complete responses, and seven patients achieved partial responses, for an overall objective response rate of 60% (95% CI, 32.2%–83.7%).
   • Adverse events were documented in 97% of the 154 patients enrolled in the study; most were grades 1 to 2 toxicities.
   • Grades 3 to 5 events, seen in 45% of the cases, consisted mostly of anemia and lymphopenia.
   • Treatment interruptions were most commonly caused by transaminitis, hypertension, pleural effusion, and pneumonitis.
   • Two deaths were attributed to drug administration (one resulting from pulmonary edema and the other from pleural effusion and pneumonitis).

The FDA approved pembrolizumab for use in patients with refractory disease or relapse after three or more lines of therapy.

Trials are ongoing to determine the toxicity and efficacy of combining and/or comparing brentuximab vedotin and nivolumab with chemotherapy in pediatric patients with Hodgkin lymphoma.

Chemotherapy Followed by Autologous HSCT

Myeloablative chemotherapy with autologous HSCT is the recommended approach for patients who develop refractory disease during therapy or relapsed disease within 1 year after completing therapy.[8,36,37,38]; [39,40][Level of evidence C1] This approach is also recommended for patients who have recurrent, extensive disease after the first year of completing therapy or for those with recurrent disease after initial therapy that included intensive (alkylating agents and anthracyclines) multiagent chemotherapy and radiation therapy.

• Autologous HSCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality (TRM) associated with allogeneic transplant.[41] After autologous HSCT, the projected survival rate is 45% to 70%, and the PFS rate is 30% to 89%.[23,39,42,43]; [44,45][Level of evidence C1]
• Brentuximab vedotin as maintenance therapy, given for 1 year after autologous HSCT in adult patients with high risk of relapse or progression, demonstrated improved PFS in a randomized, placebo-controlled, phase III trial.[46]
• Brentuximab vedotin as consolidation therapy (after autologous HSCT) was evaluated in 67 pediatric patients with relapsed or refractory Hodgkin lymphoma. The median follow-up was 37 months, and the 3-year PFS rate was 85%. About 69% of these patients (46 of 67) received brentuximab vedotin at any point during the pre-HSCT salvage treatment, for either upfront therapy or reinduction therapy.[47]
• A multicenter, open-label, dose-escalation, phase I/II study evaluated the safety, maximum tolerated dose, and pharmacokinetics of brentuximab vedotin. The study identified a recommended phase II dose in 36 pediatric patients with relapsed or refractory classical Hodgkin lymphoma (n = 19) and anaplastic large cell lymphoma (n = 17). Toxicity was manageable (33% of patients had transient, limited-severity peripheral neuropathy), the maximum tolerated dose was not reached, and pediatric pharmacokinetics were similar to that of adults. The recommended phase II dose of brentuximab vedotin, 1.8 mg/m², was administered for up to 16 cycles (median, 10 cycles) in the phase II arm. In this arm, 47% of Hodgkin lymphoma participants achieved an overall response (33% complete response, 13% partial response), which provided a bridge to HSCT for some patients.[48][Level of evidence C1]
• The most commonly used preparative regimens for peripheral blood HSCT are either carmustine (BCNU), etoposide, cytarabine, melphalan (BEAM) or cyclophosphamide, carmustine, etoposide (CBV).[37,42,43,45]; [39,40][Level of evidence C1] Carmustine may produce significant pulmonary toxicity.[45]
• Other noncarmustine-containing preparative regimens have been used, including high-dose busulfan, etoposide, and cyclophosphamide [49] and lomustine, cytarabine, cyclophosphamide, and etoposide (LACE).[50][Level of evidence C1]

Adverse prognostic features for outcome after autologous HSCT include extranodal disease at relapse, bulky mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, poor response to chemotherapy, and a positive positron emission tomography (PET) scan before autologous HSCT.[2,42,43,45,51,52]

For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.

Chemotherapy Followed by Allogeneic HSCT

For patients who do not improve after autologous HSCT and patients with chemoresistant disease, allogeneic HSCT has been used with encouraging results.[15,41,53] Investigations of reduced-intensity allogeneic transplant that typically use fludarabine or low-dose total body irradiation to provide a nontoxic immunosuppression have demonstrated acceptable rates of TRM.[54,55,56,57]

For more information about transplant, see Pediatric Allogeneic Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.

Involved-Site Radiation Therapy (ISRT)

ISRT to sites of recurrent disease may enhance local control if these sites have not been previously irradiated. ISRT is generally administered after high-dose chemotherapy and stem cell rescue.[58] For patients who are not responsive to salvage therapy, ISRT may be considered before HSCT.[59,60] Consolidative ISRT is particularly appropriate in the following situations:[1]

• Low-risk patients whose PET scans are negative after standard-dose salvage chemotherapy.
• Select standard-risk and/or high-risk patients who are treated with high-dose chemotherapy and HSCT.

Response Rates for Primary Refractory Hodgkin Lymphoma

Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HSCT and radiation. However, some studies have reported that intensification of therapy followed by HSCT consolidation can achieve long-term survival.

Evidence (response to treatment of primary refractory Hodgkin lymphoma):

1. In one large series, the 5-year OS rate was 49% for patients with primary refractory Hodgkin lymphoma after receiving aggressive second-line therapy (high-dose chemoradiation therapy) and autologous HSCT.[61]
2. In a Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) study, patients with primary refractory Hodgkin lymphoma (progressive disease on therapy or relapse within 3 months from the end of therapy) had 10-year event-free survival (EFS) and OS rates of 41% and 51%, respectively.[4]
3. In a study of 53 adolescent patients (like those who participated in the GPOH study), EFS and OS rates were similar.[62] Chemosensitivity to standard-dose, second-line chemotherapy predicted better survival (OS rate, 66%), and tumors that remained refractory to chemotherapy did poorly (OS rate, 17%).[63]
4. Another group reported a PFS rate of 80% post-HSCT for chemosensitive patients, compared with 0% for those with chemoresistant disease.[39]

Second Relapse After Initial Treatment With Autologous HSCT

In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HSCT received brentuximab vedotin, with an objective response rate of 73% and a complete remission rate of 34%. Patients who achieved a complete remission (n = 34) had a 3-year PFS rate of 58% and a 3-year OS rate of 73%. Only 6 of 34 patients proceeded to allogeneic HSCT while in remission.[23][Level of evidence B4]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

Anti-CD30 chimeric antigen receptor (CAR) T-cell therapy clinical trials

Preliminary data on CAR T cells targeting CD30 have been published. In a phase I/II trial of 41 adults with multiply relapsed or refractory Hodgkin lymphoma, CD30 CAR T cells were administered after lymphoreduction with bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine.[64] Treated patients had a median of seven previous lines of therapy, including brentuximab vedotin, checkpoint inhibitors, and autologous and allogeneic HSCTs. The overall response rate was 72% for the 32 patients with active disease who received fludarabine-based lymphodepletion. For all evaluable patients, the 1-year PFS rate was 36%, and the OS rate was 94%. The CD30 CAR T-cell therapy was well tolerated.

A number of clinical trials of anti-CD30 CAR T-cell therapy for patients with relapsed Hodgkin lymphoma are listed on ClinicalTrials.gov. The following is an example of a national and/or institutional clinical trial that is currently enrolling patients younger than 18 years:

• RELY-30 (NCT02917083) (CD30 CAR T Cells With or Without Cyclophosphamide and Fludarabine in Treating Participants With Relapsed or Refractory CD30-Positive Lymphoma): Patients aged 12 years and older with relapsed or refractory Hodgkin lymphoma will receive CD30 CAR T-cell therapy after chemotherapy or autologous transplant in this phase I study.

Other clinical trials

Anti–PD-1 antibodies being studied in children with Hodgkin lymphoma include the following:

• Pembrolizumab (NCT02332668).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Daw S, Hasenclever D, Mascarin M, et al.: Risk and Response Adapted Treatment Guidelines for Managing First Relapsed and Refractory Classical Hodgkin Lymphoma in Children and Young People. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group. Hemasphere 4 (1): e329, 2020.
2. Metzger ML, Hudson MM, Krasin MJ, et al.: Initial response to salvage therapy determines prognosis in relapsed pediatric Hodgkin lymphoma patients. Cancer 116 (18): 4376-84, 2010.
3. Moskowitz CH, Nimer SD, Zelenetz AD, et al.: A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 97 (3): 616-23, 2001.
4. Schellong G, Dörffel W, Claviez A, et al.: Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol 23 (25): 6181-9, 2005.
5. Gorde-Grosjean S, Oberlin O, Leblanc T, et al.: Outcome of children and adolescents with recurrent/refractory classical Hodgkin lymphoma, a study from the Société Française de Lutte contre le Cancer des Enfants et des Adolescents (SFCE). Br J Haematol 158 (5): 649-56, 2012.
6. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.
7. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.
8. Cairo MS, Shen V, Krailo MD, et al.: Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. J Pediatr Hematol Oncol 23 (1): 30-8, 2001.
9. Horton TM, Drachtman RA, Chen L, et al.: A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study. Br J Haematol 170 (1): 118-22, 2015.
10. Trippett TM, Schwartz CL, Guillerman RP, et al.: Ifosfamide and vinorelbine is an effective reinduction regimen in children with refractory/relapsed Hodgkin lymphoma, AHOD00P1: a children's oncology group report. Pediatr Blood Cancer 62 (1): 60-4, 2015.
11. Marr K, Ronsley R, Nadel H, et al.: Ifosfamide, gemcitabine, and vinorelbine is an effective salvage regimen with excellent stem cell mobilization in relapsed or refractory pediatric Hodgkin lymphoma. Pediatr Blood Cancer 67 (4): e28167, 2020.
12. Cole PD, Schwartz CL, Drachtman RA, et al.: Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a children's oncology group report. J Clin Oncol 27 (9): 1456-61, 2009.
13. Jan MRU, Saeed H, Abubakar M, et al.: Response rates, long term outcomes and toxicity profile of gemcitabine and vinorelbine based outpatient chemotherapy regimen in primary progressive and relapsed childhood Hodgkin lymphoma. Leuk Lymphoma 61 (14): 3369-3377, 2020.
14. Ganesan P, Mehra N, Joel A, et al.: Gemcitabine, vinorelbine and dexamethasone: A safe and effective regimen for treatment of relapsed/refractory hodgkin's lymphoma. Leuk Res 84: 106188, 2019.
15. Shankar A, Hayward J, Kirkwood A, et al.: Treatment outcome in children and adolescents with relapsed Hodgkin lymphoma--results of the UK HD3 relapse treatment strategy. Br J Haematol 165 (4): 534-44, 2014.
16. Wimmer RS, Chauvenet AR, London WB, et al.: APE chemotherapy for children with relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer 46 (3): 320-4, 2006.
17. Sandlund JT, Pui CH, Mahmoud H, et al.: Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma. Ann Oncol 22 (2): 468-71, 2011.
18. Aparicio J, Segura A, Garcerá S, et al.: ESHAP is an active regimen for relapsing Hodgkin's disease. Ann Oncol 10 (5): 593-5, 1999.
19. Velasquez WS, Cabanillas F, Salvador P, et al.: Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 71 (1): 117-22, 1988.
20. Schulz H, Rehwald U, Morschhauser F, et al.: Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood 111 (1): 109-11, 2008.
21. Seattle Genetics, Inc: ADCETRIS (Brentuximab Vedotin): Prescribing Information. Bothell, Wa: Seattle Genetics, 2012. Available online. Last accessed February 14, 2023.
22. Younes A, Gopal AK, Smith SE, et al.: Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 30 (18): 2183-9, 2012.
23. Gopal AK, Chen R, Smith SE, et al.: Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood 125 (8): 1236-43, 2015.
24. Chen R, Gopal AK, Smith SE, et al.: Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128 (12): 1562-6, 2016.
25. Flerlage JE, Metzger ML, Wu J, et al.: Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma. Cancer Chemother Pharmacol 78 (6): 1217-1223, 2016.
26. Cole PD, McCarten KM, Pei Q, et al.: Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1-2 trial. Lancet Oncol 19 (9): 1229-1238, 2018.
27. Vinti L, Pagliara D, Buffardi S, et al.: Brentuximab vedotin in combination with bendamustine in pediatric patients or young adults with relapsed or refractory Hodgkin lymphoma. Pediatr Blood Cancer 69 (4): e29557, 2022.
28. Forlenza CJ, Gulati N, Mauguen A, et al.: Combination brentuximab vedotin and bendamustine for pediatric patients with relapsed/refractory Hodgkin lymphoma. Blood Adv 5 (24): 5519-5524, 2021.
29. Ansell SM, Lesokhin AM, Borrello I, et al.: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372 (4): 311-9, 2015.
30. Davis KL, Fox E, Merchant MS, et al.: Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol 21 (4): 541-550, 2020.
31. Harker-Murray P, Mauz-Körholz C, Leblanc T, et al.: Nivolumab and brentuximab vedotin with or without bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young adults. Blood 141 (17): 2075-2084, 2023.
32. Younes A, Santoro A, Shipp M, et al.: Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17 (9): 1283-94, 2016.
33. Armand P, Shipp MA, Ribrag V, et al.: Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol 34 (31): 3733-3739, 2016.
34. Chen R, Zinzani PL, Fanale MA, et al.: Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol 35 (19): 2125-2132, 2017.
35. Geoerger B, Kang HJ, Yalon-Oren M, et al.: Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol 21 (1): 121-133, 2020.
36. Rancea M, Monsef I, von Tresckow B, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev 6: CD009411, 2013.
37. Baker KS, Gordon BG, Gross TG, et al.: Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents. J Clin Oncol 17 (3): 825-31, 1999.
38. Akhtar S, Rauf SM, Elhassan TA, et al.: Outcome analysis of high-dose chemotherapy and autologous stem cell transplantation in adolescent and young adults with relapsed or refractory Hodgkin lymphoma. Ann Hematol 95 (9): 1521-35, 2016.
39. Shafer JA, Heslop HE, Brenner MK, et al.: Outcome of hematopoietic stem cell transplant as salvage therapy for Hodgkin's lymphoma in adolescents and young adults at a single institution. Leuk Lymphoma 51 (4): 664-70, 2010.
40. Claviez A, Sureda A, Schmitz N: Haematopoietic SCT for children and adolescents with relapsed and refractory Hodgkin's lymphoma. Bone Marrow Transplant 42 (Suppl 2): S16-24, 2008.
41. Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al.: An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 31 (8): 667-78, 2003.
42. Lieskovsky YE, Donaldson SS, Torres MA, et al.: High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol 22 (22): 4532-40, 2004.
43. Akhtar S, Abdelsalam M, El Weshi A, et al.: High-dose chemotherapy and autologous stem cell transplantation for Hodgkin's lymphoma in the kingdom of Saudi Arabia: King Faisal specialist hospital and research center experience. Bone Marrow Transplant 42 (Suppl 1): S37-S40, 2008.
44. Talleur AC, Flerlage JE, Shook DR, et al.: Autologous hematopoietic cell transplantation for the treatment of relapsed/refractory pediatric, adolescent, and young adult Hodgkin lymphoma: a single institutional experience. Bone Marrow Transplant 55 (7): 1357-1366, 2020.
45. Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011.
46. Moskowitz CH, Nademanee A, Masszi T, et al.: Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 385 (9980): 1853-62, 2015.
47. Forlenza CJ, Rosenzweig J, Mauguen A, et al.: Brentuximab vedotin after autologous transplantation in pediatric patients with relapsed/refractory Hodgkin lymphoma. Blood Adv 7 (13): 3225-3231, 2023.
48. Locatelli F, Mauz-Koerholz C, Neville K, et al.: Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study. Lancet Haematol 5 (10): e450-e461, 2018.
49. Wadehra N, Farag S, Bolwell B, et al.: Long-term outcome of Hodgkin disease patients following high-dose busulfan, etoposide, cyclophosphamide, and autologous stem cell transplantation. Biol Blood Marrow Transplant 12 (12): 1343-9, 2006.
50. Gupta A, Gokarn A, Rajamanickam D, et al.: Lomustine, cytarabine, cyclophosphamide, etoposide - An effective conditioning regimen in autologous hematopoietic stem cell transplant for primary refractory or relapsed lymphoma: Analysis of toxicity, long-term outcome, and prognostic factors. J Cancer Res Ther 14 (5): 926-933, 2018 Jul-Sep.
51. Jabbour E, Hosing C, Ayers G, et al.: Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer 109 (12): 2481-9, 2007.
52. Satwani P, Ahn KW, Carreras J, et al.: A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant 50 (11): 1416-23, 2015.
53. Cooney JP, Stiff PJ, Toor AA, et al.: BEAM allogeneic transplantation for patients with Hodgkin's disease who relapse after autologous transplantation is safe and effective. Biol Blood Marrow Transplant 9 (3): 177-82, 2003.
54. Carella AM, Cavaliere M, Lerma E, et al.: Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol 18 (23): 3918-24, 2000.
55. Robinson SP, Goldstone AH, Mackinnon S, et al.: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100 (13): 4310-6, 2002.
56. Devetten MP, Hari PN, Carreras J, et al.: Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant 15 (1): 109-17, 2009.
57. Robinson SP, Sureda A, Canals C, et al.: Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin's lymphoma: identification of prognostic factors predicting outcome. Haematologica 94 (2): 230-8, 2009.
58. Wadhwa P, Shina DC, Schenkein D, et al.: Should involved-field radiation therapy be used as an adjunct to lymphoma autotransplantation? Bone Marrow Transplant 29 (3): 183-9, 2002.
59. Constine LS, Yahalom J, Ng AK, et al.: The Role of Radiation Therapy in Patients With Relapsed or Refractory Hodgkin Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 100 (5): 1100-1118, 2018.
60. Tinkle CL, Williams NL, Wu H, et al.: Treatment patterns and disease outcomes for pediatric patients with refractory or recurrent Hodgkin lymphoma treated with curative-intent salvage radiotherapy. Radiother Oncol 134: 89-95, 2019.
61. Morabito F, Stelitano C, Luminari S, et al.: The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Bone Marrow Transplant 37 (3): 283-8, 2006.
62. Akhtar S, El Weshi A, Rahal M, et al.: High-dose chemotherapy and autologous stem cell transplant in adolescent patients with relapsed or refractory Hodgkin's lymphoma. Bone Marrow Transplant 45 (3): 476-82, 2010.
63. Moskowitz CH, Kewalramani T, Nimer SD, et al.: Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin's disease. Br J Haematol 124 (5): 645-52, 2004.
64. Ramos CA, Grover NS, Beaven AW, et al.: Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. J Clin Oncol 38 (32): 3794-3804, 2020.

Late Effects From Childhood and Adolescent Hodgkin Lymphoma Therapy

Childhood and adolescent survivors of Hodgkin lymphoma may be at risk of developing numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging.[1,2] Adverse treatment effects may impact the following:

• Reproductive system (male gonadal toxicity and female gonadal toxicity).
• Endocrine system (thyroid abnormalities).
• Cardiovascular system.
• Risk of subsequent benign or malignant neoplasms.
• Oral/dental health.
• Pulmonary function.
• Musculoskeletal growth and development.
• Immune system.

In the past 30 to 40 years, pediatric Hodgkin lymphoma therapy has changed dramatically to limit exposure to radiation and chemotherapeutic agents, such as anthracyclines, alkylating agents, and bleomycin. When counseling individual patients about the risk of specific treatment complications, the era of treatment should be considered.

In this regard, Childhood Cancer Survivor Study (CCSS) investigators determined the incidence of serious health conditions among 2,996 five-year survivors of pediatric Hodgkin lymphoma (mean age, 35.8 years), compared outcomes by treatment era and strategies, and estimated risks associated with contemporary therapy.[3]

• The cumulative incidence of any grade 3 to 5 conditions by age 35 years was 31.4%. Females were twice as likely as males to experience these conditions (hazard ratio, 2.1).
• The decade-specific risk of grade 3 to 5 conditions declined by 20% from the 1970s to the 1990s (P trend = .002).
• Compared with survivors who were treated with chest radiation therapy of 35 Gy or higher in combination with an anthracycline or alkylating agent, patients who received contemporary regimens for low- or intermediate-risk disease had an estimated 40% reduction in risk of grade 3 to 5 conditions (HR, 0.6).
• The risk of grade 3 to 5 conditions in survivors who had a recurrence or underwent hematopoietic stem cell transplant (HSCT) was substantially elevated and similar to that of survivors treated with high-dose, extended-field radiation therapy.

Table 11 summarizes late health effects observed in Hodgkin lymphoma survivors, followed by a limited discussion of common late effects. For a full discussion of this topic, see Late Effects of Treatment for Childhood Cancer.

Table 11. Treatment Complications Observed in Hodgkin Lymphoma Survivors

Health Effects	Predisposing Therapy	Clinical Manifestations
Reproductive	Alkylating agent chemotherapy	Hypogonadism
	Gonadal irradiation	Infertility
Thyroid	Radiation impacting thyroid gland	Hypothyroidism
		Hyperthyroidism
		Thyroid nodules
Cardiovascular	Radiation impacting cardiovascular structures	Subclinical left ventricular dysfunction
		Cardiomyopathy
		Pericarditis
		Heart valve dysfunction
		Conduction disorder
		Coronary, carotid, subclavian vascular disease
		Myocardial infarction
		Stroke
	Anthracycline chemotherapy	Subclinical left ventricular dysfunction
		Cardiomyopathy
		Congestive heart failure
Subsequent neoplasms or disease	Alkylating agent chemotherapy	Myelodysplasia/acute myeloid leukemia
	Epipodophyllotoxins	Myelodysplasia/acute myeloid leukemia
	Radiation	Solid benign and malignant neoplasms
	Anthracycline chemotherapy	Breast cancer
Oral or dental	Any chemotherapy in a patient who has not developed permanent dentition	Dental maldevelopment (tooth or root agenesis, microdontia, root thinning and shortening, enamel dysplasia)
	Radiation impacting oral cavity and salivary glands	Salivary gland dysfunction
		Xerostomia
		Accelerated dental decay
		Periodontal disease
Pulmonary	Radiation impacting the lungs	Subclinical pulmonary dysfunction
	Bleomycin	Pulmonary fibrosis
Musculoskeletal	Radiation of musculoskeletal tissues in any patient who is not skeletally mature	Growth impairment
	Glucocorticosteroids	Bone mineral density deficit
		Multiple sclerosis
Immune	Splenectomy	Overwhelming post-splenectomy sepsis

Male Gonadal Toxicity

Important concepts related to male gonadal toxicity include the following:

• Gonadal irradiation and alkylating agent chemotherapy may produce testicular Leydig cell or germ cell dysfunction, with risk related to cumulative dose of both modalities.
• Hypoandrogenism associated with Leydig cell dysfunction may manifest as lack of sexual development; small, atrophic testicles; and sexual dysfunction. Hypoandrogenism also increases the risk of osteoporosis and metabolic disorders associated with chronic disease.[4,5]
• Testicular Leydig cells are relatively resistant to treatment toxicity compared with testicular germ cells. Survivors who are azoospermic after gonadal toxic therapy may maintain adequate testosterone production.[6,7,8]
• Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.[9,10]
• The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Pubertal status is not protective of chemotherapy-associated gonadal toxicity.[7,8]
• Chemotherapy regimens that do not include alkylating agents are not associated with male infertility. These regimens include doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine (ABVD); doxorubicin (Adriamycin), bleomycin, vincristine, etoposide (ABVE); vincristine (Oncovin), etoposide, prednisone, doxorubicin Adriamycin (OEPA); or vincristine, doxorubicin (Adriamycin), methotrexate, prednisone (VAMP).
• Prednisone and cyclophosphamide (ABVE-PC) and cyclophosphamide, vincristine, prednisone, dacarbazine (OEPA-COPDAC) are titrated to limit alkylating agent dose to below the usual threshold associated with male sterility. Investigations evaluating germ cell function in relation to single alkylating agent exposure suggest that the incidence of permanent azoospermia will be low if the cyclophosphamide dose is less than 7.5 g/m².[8,11]
• Chemotherapy regimens that include more than one alkylating agent, usually procarbazine in conjunction with cyclophosphamide (i.e., cyclophosphamide, vincristine [Oncovin], prednisone, procarbazine [COPP]), chlorambucil, or nitrogen mustard (MOPP), confer a high risk of permanent azoospermia if treatment exceeds three cycles.[12,13]

For more information, see the Testis section in Late Effects of Treatment for Childhood Cancer.

Female Gonadal Toxicity

Ovarian hormone production is linked to the maturation of primordial follicles. Depletion of follicles by alkylating agent chemotherapy can potentially affect both fertility and ovarian hormone production. Because of their greater complement of primordial follicles, the ovaries of young and adolescent girls are less sensitive to the effects of alkylating agents than the ovaries of older women. In general, girls maintain ovarian function at higher cumulative alkylating agent doses, compared with the germ cell function maintained in boys.

Important concepts related to female gonadal toxicity include the following:

• Most females treated with contemporary risk-adapted therapy will have menarche (if prepubertal at treatment) or regain normal menses (if pubertal at treatment) unless pelvic radiation therapy is given without oophoropexy. Current regimens used in pediatric oncology are tailored to minimize the risk of ovarian failure. Data presented below related to pediatric treatment before 1987 [14,15] or adult trials in Europe (European Organisation for Research and Treatment of Cancer H1–H9 trials) [16] are not likely reflective of the expected reproductive outcomes in the current era.
• Ovarian transposition to a lateral or medial region from the planned radiation volume may preserve ovarian function in young and adolescent girls who require pelvic radiation therapy for lymphoma.[17] Ovarian transposition did not appear to modify risk of premature ovarian insufficiency in a cohort of 49 long-term survivors of Hodgkin lymphoma enrolled in the St. Jude Lifetime Cohort Study who were treated with gonadotoxic therapy and underwent ovarian transposition before pelvic radiation therapy.[18]
• The risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation or dose-intensive alkylating agents for myeloablative conditioning before HSCT.[14,15] The risk of ovarian failure after treatment with contemporary regimens using lower cumulative doses of cyclophosphamide without procarbazine is anticipated to be lower.
• In the CCSS, investigators observed that Hodgkin lymphoma survivors were among the highest risk groups for acute ovarian failure and early menopause. In this cohort, the cumulative incidence of nonsurgical premature menopause among survivors treated with alkylating agents and abdominal or pelvic radiation approached 30%.[14,15] These patients were treated before 1986, usually with substantially higher doses of alkylating agents than are used in current regimens in the Children's Oncology Group (COG), EuroNet, or other consortiums.
• A German study demonstrated that parenthood for female survivors of Hodgkin lymphoma was similar to that of the general population, although parenthood was lower for survivors who received pelvic radiation therapy.[19]

For more information, see the Ovary section in Late Effects of Treatment for Childhood Cancer.

Thyroid Abnormalities

Abnormalities of the thyroid gland, including hypothyroidism, hyperthyroidism, and thyroid neoplasms, occur at a higher rate among survivors of Hodgkin lymphoma than in the general population.

• Hypothyroidism. Risk factors for hypothyroidism include increasing dose of radiation, female sex, and older age at diagnosis.[20,21,22] CCSS investigators reported a 20-year actuarial risk of 30% of developing hypothyroidism in Hodgkin lymphoma survivors treated with 35 Gy to 44.99 Gy of radiation and 50% for subjects whose thyroid received 45 Gy or more of radiation.

  Hypothyroidism develops most often in the first 5 years after treatment, but new cases have emerged more than 20 years after the cancer diagnosis.[21]

• Hyperthyroidism. Hyperthyroidism has been observed after treatment for Hodgkin lymphoma, with a clinical picture similar to that of Graves' disease.[23] Higher radiation dose has been associated with greater risk of hyperthyroidism.[21]
• Subsequent neoplasms. Thyroid neoplasms, both benign and malignant, have been reported with increased frequency after neck irradiation. The incidence of nodules varies substantially across studies (2%–65%) depending on the length of follow-up and detection methods used.[20,21,22]

  The relative risk (RR) of thyroid cancer is higher among Hodgkin lymphoma survivors (approximately 18-fold for the CCSS Hodgkin lymphoma cohort compared with the general population).[22] Risk factors for the development of thyroid nodules in Hodgkin lymphoma survivors reported by CCSS include time since diagnosis of more than 10 years (RR, 4.8; 95% confidence interval [CI], 3.0–7.8), female sex (RR, 4.0; 95% CI, 2.5–6.7), and radiation dose to thyroid higher than 25 Gy (RR, 2.9; 95% CI, 1.4–6.9).[22] The absolute risk of thyroid cancer is relatively low, with approximately 1% of the CCSS Hodgkin cohort developing thyroid cancer, with a median follow-up of approximately 15 years.[22]

  A single-institution Hodgkin lymphoma survivor cohort that included both adult and pediatric cases showed a cumulative incidence of thyroid cancer at 10 years from diagnosis of 0.26%, increasing to approximately 3% at 30 years from diagnosis. In this cohort, age younger than 20 years at Hodgkin lymphoma diagnosis and female sex were significantly associated with thyroid cancer.[24]

For more information, see the Thyroid Gland section in Late Effects of Treatment for Childhood Cancer summary.

Cardiac Toxicity

Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk of long-term cardiac toxicity. The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.[25,26,27]

Survivors of childhood Hodgkin lymphoma older than 50 years experience more than two times the number of chronic cardiovascular conditions and nearly five times the number of more severe (grades 3–5) cardiovascular conditions compared with community controls. Also, survivors have one severe, life-threatening, or fatal cardiovascular condition, on average.[28]

Cardiac mortality is higher for survivors of adolescent Hodgkin lymphoma than for survivors of young adult Hodgkin lymphoma. This finding was demonstrated in the Teenage and Young Adult Cancer Survivor Study cohort, with standardized mortality ratios (SMR) of 10.4 (95% CI, 8.1–13.3) for those diagnosed at age 15 and 19 years, compared with an SMR of 2.8 (95% CI, 2.3–3.4) for those diagnosed at age 35 to 39 years.[29]

Applying a model to predict late cardiac toxic effects of therapy, patients with intermediate- and high-risk Hodgkin lymphoma who were treated in four consecutive COG trials between 2002 and 2020 were assessed for risk of grade 3 to grade 5 cardiac disease at 30 years after completion of therapy. Over this time period, the percentage of patients who received mediastinal radiation therapy decreased from 50% to less than 1%, which led to lower cardiac radiation exposure. Anthracycline doses increased from 200 mg/m² to 300 mg/m². However, use of the cardioprotectant dexrazoxane increased from 0% to 80%. The results demonstrated the predicted risk of grade 3 to grade 5 cardiac disease at 30 years will decrease from 10% to 6%, which would be highly statistically significant. The 6% incidence of cardiac disease is similar to the predicted 5% incidence for the general population, which questions the necessity of current long-term cardiac monitoring guidelines.[30]

Radiation-associated cardiovascular toxicity

• Late effects of radiation to the heart may include the following:[31,32,33]
  • Delayed pericarditis.
  • Pancarditis, including pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
  • Cardiomyopathy.
  • Coronary artery disease.[26,32]
  • Functional valve injury.[26,34]
  • Conduction defects.

  The risks to the heart are related to the amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, and latency period.

• Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to higher radiation doses. This reduction should lower the risk of adverse cardiac events.
• Austrian-German investigators evaluated the development of cardiac disease (via patient self-report supplemented by physician report) in a cohort of 1,132 pediatric Hodgkin lymphoma survivors monitored for a median of 20 years. The 25-year cumulative incidence of heart disease increased with higher mediastinal radiation doses: 3% (unirradiated), 5% (20 Gy), 6% (25 Gy), 10% (30 Gy), and 21% (36 Gy). Valve defects were most common, followed by coronary artery disease, cardiomyopathy, rhythm disorders, and pericardial abnormalities.[34]
• In a study of adult survivors of Hodgkin lymphoma, vigorous exercise lowered the risk of cardiovascular events, independent of the treatment received.[35]
• Emerging data, not confined to patients with Hodgkin lymphoma but inclusive of other pediatric malignancies, suggest that a lower mean heart dose of 10 Gy to 15 Gy should be a goal in contemporary treatment protocols.[27]

Anthracycline-related cardiac toxicity

• Late complications related to anthracycline injury may include subclinical left ventricular dysfunction, cardiomyopathy, and congestive heart failure.[26]
• Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, treatment with cumulative doses of 250 mg/m² or higher, younger age at time of exposure, and increased time from exposure.[36]
• Prevention or amelioration of anthracycline-induced cardiomyopathy is important because anthracyclines are required in cancer therapy in more than one-half of children with newly diagnosed cancer.[37,38]
• Dexrazoxane (a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent) has been shown to prevent heart damage in adults and children treated with anthracyclines.[39] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy. Dexrazoxane has been associated with increased hematologic toxicity and typhlitis in children with Hodgkin lymphoma receiving ABVE-PC chemotherapy.[40]
• A number of trials have studied the risk of subsequent neoplasms following dexrazoxane administration, and none has found a significant association with subsequent neoplasms.[41,42] However, one study found a borderline statistical increase in subsequent neoplasms in patients randomly assigned to receive dexrazoxane. This increase was attributed to the administration of three topoisomerase inhibitors (doxorubicin, etoposide, and dexrazoxane) within 2 to 3 hours of each other.[43]
• Studies of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive cardiac toxicity.[44,45]

For more information, see the Late Effects of the Cardiovascular System section in Late Effects of Treatment for Childhood Cancer.

Subsequent Neoplasms

Series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[46,47,48,49,50,51,52,53]; [54][Level of evidence C1] Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer used.

• Subsequent neoplasms comprise two distinct groups:[55,56]
  • Myelodysplasia and acute myeloid leukemia (AML) related to chemotherapy.

    Subsequent hematological malignancy is related to the use of alkylating agents, anthracyclines, and etoposide and exhibit a brief latency period (<10 years from the primary cancer).[57] This excess risk is largely related to cases of myelodysplasia and subsequent AML.

    A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity.[43]

    Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[43,58,59]

    Chemotherapy-related myelodysplasia and AML are less prevalent after contemporary therapy because of the restriction of cumulative alkylating agent doses.[60,61]

    Among 1,711 intermediate-risk Hodgkin lymphoma survivors treated with response-adapted therapy in the COG AHOD0031 (NCT00025259) trial (median follow-up, 7.3 years), the 10-year cumulative incidence of subsequent malignancy was 1.3%, and the cumulative incidence of secondary myelodysplastic syndrome or AML was 0.2%. Of the three cases of secondary AML, the median time to onset was 2 years (range, 1.8–2.7 years).[62]

  • Solid neoplasms that are predominately related to radiation.

    Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, lung, and head and neck, with risk increasing with radiation dose.[51,53,63]; [54][Level of evidence C1] The risk of a solid subsequent neoplasm escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more. For more information about subsequent thyroid neoplasms, see the Thyroid Abnormalities section.

    Breast cancer is the most common therapy-related, solid, subsequent neoplasm after treatment of Hodgkin lymphoma:

    • The absolute excess risk of breast cancer ranges from 18.6 to 79 per 10,000 person-years, and the cumulative incidence ranges from 12% to 26%, with onset 25 to 30 years after radiation exposure.[50,64,65,66]
    • High risk of breast cancer has been found to increase as early as 8 years after radiation exposure, is rare before age 25 years, and continues to increase with time from exposure. Importantly, breast cancer in female childhood cancer survivors typically develops at least 25 years earlier than in the general population and often years before the ages recommended for population-based screening.[50]
    • The cumulative incidence of breast cancer by age 40 to 45 years ranges from 13% to 20%, compared with 1% for women in the general population.[50,64,66,67] This risk is similar to that observed for women with a BRCA gene variant, for whom the cumulative incidence of breast cancer ranges from 10% to 19% by age 40 years.[68]

    Breast cancer risk after radiation therapy:

    • The risk of breast cancer in female survivors of Hodgkin lymphoma is directly related to the dose of radiation therapy received over a range from 4 Gy to 40 Gy.[69] Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower RR of developing breast cancer than women receiving radiation therapy alone.[51,70]
    • CCSS investigators also demonstrated that breast cancer risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries.[71] The protective effect of alkylating chemotherapy and ovarian radiation is believed to be mediated through induction of premature menopause, suggesting that hormone stimulation contributes to the development of radiation-induced breast cancer.[72]

    Breast cancer risk after chemotherapy (includes survivors of Hodgkin lymphoma and other childhood, adolescent, and young adult malignancies):

    • Several cohort studies have demonstrated a dose-related increased risk of breast cancer among female survivors of childhood, adolescent, and young adult cancer treated with anthracycline chemotherapy.[73,74,75,76]
    • St. Jude Lifetime Cohort investigators observed that treatment with anthracycline doses of 250 mg/m² or higher was associated with increased breast cancer risk in survivors who did not have pathogenic (or likely pathogenic) cancer-predisposing variants and who did not receive chest radiation therapy.[76]
    • CCSS investigators reported an additive interaction between anthracyclines and chest radiation therapy, as the risk associated with this combination was higher than the sum of the individual risks.[74]
    • Evidence for risk of breast cancer after treatment with higher doses of alkylating agents without chest radiation therapy has been conflicting, with one study reporting an increased risk and others not observing this effect.[73,74,77]
    • The evidence is inconsistent about risks and dose thresholds for breast cancer after treatment with chemotherapy in women who did not receive chest radiation. Shared decision-making is recommended for planning breast cancer surveillance.[78]

Hereditary syndromes, other than high-risk breast cancer syndromes, and pathogenic variants may modify the effect of radiation exposure on breast cancer risk after childhood cancer.[79,80]

A study of women survivors who received chest radiation for Hodgkin lymphoma showed that one of the most important factors in obtaining breast cancer screenings per guidelines was recommendation from their treating physician.[81] Standard guidelines for routine breast screening are available. The COG guidelines recommend annual screening with magnetic resonance imaging and mammography for women beginning 8 years after treatment or at age 25 years, whichever is later.[81]

For more information, see the Subsequent Neoplasms section in Late Effects of Treatment for Childhood Cancer.

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Latest Updates to This Summary (10 / 11 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Childhood Hodgkin Lymphoma Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Lisa Giulino Roth, MD (Weil Cornell Medical College)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389170]

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Last Revised: 2024-10-11