Childhood Myeloid Proliferations Associated With Down Syndrome Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Myeloid Proliferations Associated With Down Syndrome

Myeloid leukemias that arise in children with Down syndrome, particularly in patients younger than 4 years, are a distinct subset of acute myeloid leukemia (AML) characterized by the co-existence of trisomy 21 and GATA1 variants within the leukemic blasts that are often, but not always, megakaryoblastic.

This distinct leukemia is further subdivided into two types:[1]

• Transient abnormal myelopoiesis (TAM): A transient newborn and young-infant version, which spontaneously remits over time.
• Myeloid leukemia of Down syndrome (MLDS): An unremitting but chemosensitive version that appears later, between the ages of 90 days and 3 years.

It is important to recognize the possibility of these versions in both children with Down syndrome phenotypes and in those who have mosaic trisomy 21, which can be solely present in the leukemic blasts. If possible, newborns with apparent AML should not begin therapy until genetic testing results have been returned.[2]

In older children with megakaryocytic AML, it is important to rule out the presence of co-existing trisomy 21 and GATA1 variants. These children may be successfully treated with the lower-intensity chemotherapy regimens that are used for children with myeloid leukemia associated with Down syndrome.[3]

References:

1. Lange B: The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br J Haematol 110 (3): 512-24, 2000.
2. Gamis AS, Smith FO: Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 159 (3): 277-87, 2012.
3. de Rooij JD, Branstetter C, Ma J, et al.: Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 49 (3): 451-456, 2017.

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.[2] 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.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• 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.[3] 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. Wolfson J, Sun CL, Wyatt L, et al.: Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome. Cancer Epidemiol Biomarkers Prev 26 (3): 312-320, 2017.
3. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.

Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome

Incidence

Approximately 10% of neonates with Down syndrome develop TAM (also termed transient myeloproliferative disorder [TMD]).[1] This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days). However, TAM has been reported to remit as late as 20 months.[2] The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.[3]

Clinical Presentation and Risk Groups

Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[2,3,4,5,6] When TAM is detected, it is either in a proliferative, worsening phase or it has already converted to a resolving, improving phase. Observation over time is needed to determine which phase is present. Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[3,4,6] In one report, death occurred in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM. The remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.[3]

The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[3]

• Low risk. Includes those without hepatomegaly or life-threatening symptoms (38% of patients and an overall survival [OS] rate of 92% ± 8%).
• Intermediate risk. Includes those with hepatomegaly alone (40% of patients and an OS rate of 77% ± 12%).
• High risk. Includes those with hepatomegaly and life-threatening symptoms (21% of patients and an OS rate of 51% ± 19%).

Molecular Features

Genomics of TAM

TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive variants involving the GATA1 gene in the presence of trisomy 21.[7,8] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[4]

GATA1 variants are present in most, if not all, children with Down syndrome who have either TAM or acute megakaryoblastic leukemia (AMKL).[7,9,10,11] GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. X-linked GATA1 variants result in the absence of the full-length GATA1 protein, leaving only the normally minor variant, a truncated GATA1s transcription factor that has decreased activity.[7,8] This confers increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly explaining the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[12]

A 2024 analysis screened 143 TAM samples for additional somatic variants in the abnormal cells. With the exception of rare STAG2 variants, the study found no additional abnormalities beyond the typical GATA1 abnormality.[13]

Approximately 20% of infants with TAM and Down syndrome eventually develop AML. Most of these cases are diagnosed within the first 3 years of life.[4,8]

Treatment of TAM

While observation is appropriate for most infants with TAM, therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:

• Exchange transfusion.
• Leukapheresis.
• Low-dose cytarabine. Of these approaches, only cytarabine has been shown to consistently reduce TAM complications and related mortality.[3,6]; [14][Level of evidence B4] Cytarabine dosing has ranged from 0.4 to 1.5 mg/kg per dose given intravenously (IV) or subcutaneously (SC) once to twice daily for 4 to 12 days.[6] This dosing schedule has produced similar efficacies and less toxicity than higher doses given in continuous 5-day infusions, which led to prolonged severe neutropenia.[3] A prospective trial examined the use of low-dose cytarabine (1.5 mg/kg per day IV or SC for 7 days) to treat symptomatic patients. This trial reported a significant reduction in early death using this regimen, compared with similar patients in the historical control group (12% ± 5% vs. 33% ± 7%, respectively; P = .02).[14][Level of evidence B4]

Risk Factors for the Development of AML After Resolution of TAM

Subsequent development of myeloid leukemia of Down syndrome (MLDS) is seen in 10% to 30% of children with TAM. It has been reported at a mean age of 16 months (range, 1–30 months).[2,3,15] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent MLDS.[4] An additional risk factor reported in two studies is the late resolution of TAM, measured by either time to complete resolution of signs of TAM (defined as resolution beyond the median, 47 days from diagnosis) or by persistence of minimal residual disease (MRD) in the peripheral blood at week 12 of follow-up.[3]; [14][Level of evidence B4]

The use of cytarabine for TAM symptoms or persistent MRD in TAM has failed to show a reduction in later MLDS, as reported in large observational cohort studies.[3,6] In a prospective single-arm trial designed to assess whether cytarabine treatment for TAM could prevent the development of later MLDS, no benefit was found when compared with historical controls (19% ± 4% vs. 22% ± 4%, respectively; P = .88).[14][Level of evidence B4]

References:

1. Gamis AS, Smith FO: Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 159 (3): 277-87, 2012.
2. Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993.
3. Gamis AS, Alonzo TA, Gerbing RB, et al.: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 118 (26): 6752-9; quiz 6996, 2011.
4. Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.
5. Muramatsu H, Kato K, Watanabe N, et al.: Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142 (4): 610-5, 2008.
6. Klusmann JH, Creutzig U, Zimmermann M, et al.: Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111 (6): 2991-8, 2008.
7. Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.
8. Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003.
9. Groet J, McElwaine S, Spinelli M, et al.: Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361 (9369): 1617-20, 2003.
10. Rainis L, Bercovich D, Strehl S, et al.: Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102 (3): 981-6, 2003.
11. Wechsler J, Greene M, McDevitt MA, et al.: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32 (1): 148-52, 2002.
12. Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005.
13. Sato T, Yoshida K, Toki T, et al.: Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms. Blood 143 (25): 2627-2643, 2024.
14. Flasinski M, Scheibke K, Zimmermann M, et al.: Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study. Blood Adv 2 (13): 1532-1540, 2018.
15. Ravindranath Y, Abella E, Krischer JP, et al.: Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80 (9): 2210-4, 1992.

Myeloid Leukemia of Down Syndrome (MLDS)

General Information

Children with Down syndrome have a 10-fold to 45-fold increased risk of leukemia when compared with children without Down syndrome.[1] However, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 variants and increased sensitivity to cytarabine.[2,3,4,5,6,7] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.[8]

Prognosis of Children With MLDS

Outcome is generally favorable for children with Down syndrome who develop AML. This is called myeloid leukemia of Down syndrome (MLDS) in the World Health Organization (WHO) classification.[9,10,11] For more information, see the sections on General Information About Childhood Myeloid Malignancies and World Health Organization (WHO) Classification System for Childhood AML in Childhood Acute Myeloid Leukemia Treatment.

Prognostic factors for children with MLDS include the following:

• Age. The prognosis is particularly good (event-free survival [EFS] rates exceeding 85%) in children aged 4 years or younger at diagnosis. This age group accounts for the vast majority of patients with MLDS.[10,11,12,13] Children with MLDS who are older than 4 years have a significantly worse prognosis. These patients should undergo the therapy that is used in children with AML without Down syndrome, unless a GATA1 variant is found.[14]
• White blood cell (WBC) count. A large international Berlin-Frankfurt-Münster (BFM) retrospective study of 451 children with MLDS (aged >6 months and <5 years) observed a 7-year EFS rate of 78% and a 7-year overall survival (OS) rate of 79%. In multivariate analyses, WBC count (≥20 × 10⁹ /L) and age (>3 years) were independent predictors of lower EFS. The 7-year EFS rate for the older population (>3 years) and for the higher WBC-count population still exceeded 60%.[15]
• AML karyotype. The presence of trisomy 8 has been shown to adversely impact prognosis.[13] In another study, complex karyotypes (≥3 independent abnormalities) were associated with an increased cumulative incidence of relapse (CIR) rate at 2 years (30.8% compared with 7.5% in patients without complex karyotypes; P = .001).[16]
• Minimal residual disease (MRD). MRD at the end of induction 1 was found to be a strong prognostic factor.[11,17] This finding was consistent with the BFM finding that early response correlated with improved OS.[13] However, a negative MRD status at the end of induction 1 did not identify a favorable-risk group of patients who could receive reduced chemotherapy.[16]

Approximately 29% to 47% of patients with Down syndrome present with myelodysplastic neoplasms (MDS) (<20% blasts) but their outcomes are similar to those with AML.[10,11,13]

Treatment of Newly Diagnosed Childhood MLDS

Appropriate therapy for younger children (aged ≤4 years) with MLDS is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[4,9,10,11,12,13,14,18,19]

Treatment options for newly diagnosed children with MLDS include the following:

1. Chemotherapy.

Evidence (chemotherapy):

1. In a Children's Oncology Group (COG) trial for newly diagnosed children with MLDS (AAML0431 [NCT00369317]), 204 children received a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[10,11] Intrathecal doses were reduced from seven to two total injections, and intensification included two cycles of cytarabine/etoposide.
   • When compared with the previous trial, these changes resulted in an overall improvement of approximately 10%.
   • The EFS rate was 89.9%, and the OS rate was 93%.
   • Relapse occurred in 14 patients and there were two treatment-related deaths, both related to pneumonia, neither of which occurred during induction 2.
   • No patient had central nervous system (CNS) involvement in this trial or the preceding COG A2971 trial.[10]
   • The only prognostic factor identified was MRD using flow cytometry on day 28 of induction 1. Among those who were MRD negative (≤0.01%), the disease-free survival (DFS) rate was 92.7%. In the 14.4% of patients who were MRD positive, the DFS rate was 76.2% (P = .011).
2. In the COG AAML1531 (NCT00369317) trial for children with newly diagnosed MLDS, removing the high-dose cytarabine cycle in those with standard-risk MLDS was unsuccessful.[16]
   • The interim analysis found that patients who did not receive high-dose cytarabine had a lower 2-year EFS rate of 85.6%, compared with the 2-year EFS rate of 93.5% for patients in the AAML0431 trial (P = .0002).
3. In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled. This trial focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced-therapy Down syndrome arm of AML-BFM 98.[13] As in the COG trials, no patient had CNS disease at diagnosis.
   • Outcomes were no worse despite reduction in chemotherapy. The OS rate was 89% (± 3%), and the EFS rate was 87% (± 3%), similar to that observed in AML-BFM 98 (OS rate, 90% ± 4% [P = NS]; EFS rate, 89% ± 4% [P = NS]). The CIR rate was 6% in both trials.
   • Nine patients relapsed, and seven of those patients died.
   • Patients with a good early response (<5% blasts by morphology before induction cycle 2, n = 123 [72%]) had better outcomes (OS rate, 92% ± 3% vs. 57% ± 16%, P < .0001; EFS rate, 88% ± 3% vs. 58% ± 16%, P = .0008; and CIR rate, 3% ± 2% vs. 27% ± 18%, P = .003).
   • Less toxicity was seen in this trial, and treatment-related mortality remained low (2.9% vs. 5%, P = .276).

   The following two prognostic factors were identified:[13]

   • Trisomy 8 was an adverse factor (n = 37; OS rate, 77% vs. 95%, P = .07; EFS rate, 73% ± 8% vs. 91% ± 4%, P = .018; CIR rate, 16% ± 7% vs. 3% ± 2%, P = .02).
   • This was confirmed in multivariate analysis, where lack of good early response and trisomy 8 maintained their adverse impact on relapse, with relative risks of 8.55 (95% confidence interval [CI], 1.96–37.29; P = .004) and 4.36 (95% CI, 1.24–15.39; P = .022), respectively.
4. A 2024 analysis included a cohort of Japanese patients with MLDS (n = 204) who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis. Somatic variants in 26 genes known to be driver genes in MLDS were identified again. These included variants in cohesin and cohesin-related proteins (43.6%), epigenetic regulators (39.2%), tyrosine kinases (25.5%), and genes important in the RAS pathway (11.8%). An additional 16 novel genes were also described. Of these, variants in two transcription factors (IRX1: 16.2%; ZBTB7A: 13.2%) were found, and functional studies confirmed their role as tumor suppressor genes that impacted signaling through MYC/E2F pathways. Structural variants were also observed. RUNX1 partial tandem duplications were seen in 13.7% of patients, which may result in partial loss of function of the gene. This causes upregulation expression through the addition of an extra promoter, which results in isoform disequilibrium, with RUNX1A bias versus RUNX1. Recent studies have shown that this disequilibrium contributes to MLDS pathogenesis. Variants of RUNX1, IRX1, and ZBTB7A also activate MYC/E2F genes, suggesting that targeting this pathway may provide therapeutic benefit.[20]
   • Four somatic alterations were associated with inferior outcomes in this study cohort.
     • Of 177 patients with comprehensive somatic testing, CDKN2A deletions and variants in ZBTB7A, TP53, and JAK2 were all associated with inferior outcomes.
     • If patients had at least one of these variants, EFS and OS rates were significantly lower than those of patients who lacked any four of these abnormalities (3-year EFS rates, 66.6% vs. 94.2%; P for unadjusted Cox regression < .001; 3-year OS rates, 69.0% vs. 95.6%; P for unadjusted Cox regression < .001).
     • In multivariable analysis, all of these abnormalities were associated with inferior outcomes.
     • Validation of these findings in additional cohorts is needed. However, these findings may help identify patients with higher-risk MLDS in the future.

Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[8,10,21] Children with MLDS who are older than 4 years have a significantly worse prognosis.[14] Although an optimal treatment for these children has not been defined, they are usually treated with AML regimens designed for children without Down syndrome.

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.

Treatment of Relapsed or Refractory Childhood MLDS

A small number of trials address outcomes in children with MLDS who relapse after initial therapy or who have refractory MLDS. In three prospective trials of children with newly diagnosed MLDS, outcomes were poor for those who relapsed (4 of 11, 2 of 9, and 2 of 12 patients who relapsed survived).[9,13,16] Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen. If a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplant (HSCT).

Treatment options for children with refractory or relapsed MLDS include the following:

1. Chemotherapy, which may be followed by an allogeneic HSCT.

Evidence (treatment of children with refractory or relapsed MLDS):

Four analyses have specifically examined children with relapsed or refractory MLDS.[22,23,24,25]

1. The Japanese Pediatric Leukemia/Lymphoma Study Group reported the outcomes of 29 patients with relapsed (n = 26) or refractory (n = 3) MLDS. As expected with Down syndrome, the children in this cohort were very young (median age, 2 years); relapses were almost all early (median, 8.6 months; 80% <12 months from diagnosis); and 89% had M7 French-American-British classification.[22][Level of evidence C1]
   • In contrast to the excellent outcomes achieved after initial therapy, only 50% of the children attained a second remission, and the 3-year OS rate was 26%. Attainment of second remission was more successful the later the relapse occurred after completing initial therapies.
   • Approximately one-half of the children underwent allogeneic transplant, and no advantage was noted for transplant compared with chemotherapy. However, the number of patients was small.
2. A Center for International Blood and Marrow Transplant Research study of children with MLDS who underwent allogeneic HSCT reported the following results:[23][Level of evidence C1]
   • A similarly poor outcome, with a 3-year OS rate of 19%.
   • The main cause of failure after transplant was relapse, which exceeded 60%. Survival was significantly worse for patients who relapsed early.
   • The transplant-related mortality was approximately 20%.
3. A Japanese registry study reported better survival after transplant of children with MLDS using reduced-intensity conditioning regimens compared with myeloablative approaches. However, the number of patients was very small (n = 5), and the efficacy of reduced-intensity approaches in children with MLDS requires further study.[24][Level of evidence C2]
4. The largest study to date was conducted by a consortium of pediatric cooperative groups and select North American institutions. The study retrospectively evaluated children with MLDS to determine their outcomes and prognostic factors for survival after relapse or refractory disease.[25]
   • The most common site of relapse was bone marrow (61 of 62 patients), and no CNS relapses were reported.
   • Median time to relapse was 6.8 months, and 82% of relapses occurred within 12 months of initial diagnosis.
   • Time to relapse, use of HSCT, and attainment of second complete remission (CR) before transplant were prognostically significant.
   • For the entire cohort, the OS rate was 22.1%, the EFS rate was 20.9%, and the cumulative relapse rate was 79.1%.
   • The median time from relapse or refractory disease to time of death was 5.1 months (0.4–41 months).
   • The 3-year OS rate was 46% for those who achieved remission (45% of patients).
   • HSCT was performed in 29 patients. Undergoing HSCT in second CR was critically important, with 6 of 19 patients relapsing after HSCT if initially in second CR, compared with 9 of 10 patients relapsing if they went to transplant when not in second CR. Among the 29 HSCT recipients, the 3-year OS rate was 39.8%, and the EFS rate was 36.7%.
   • Only 3 of 33 patients who received chemotherapy alone ultimately survived (3-year OS and EFS rates, 6.4%).

References:

1. Marlow EC, Ducore J, Kwan ML, et al.: Leukemia Risk in a Cohort of 3.9 Million Children with and without Down Syndrome. J Pediatr 234: 172-180.e3, 2021.
2. Ravindranath Y: Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment. Pediatr Blood Cancer 44 (1): 1-7, 2005.
3. Ross JA, Spector LG, Robison LL, et al.: Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 44 (1): 8-12, 2005.
4. Gamis AS: Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review. Pediatr Blood Cancer 44 (1): 13-20, 2005.
5. Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44 (1): 33-9, 2005.
6. Crispino JD: GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer 44 (1): 40-4, 2005.
7. Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005.
8. Kudo K, Hama A, Kojima S, et al.: Mosaic Down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy. Int J Hematol 91 (4): 630-5, 2010.
9. Lange BJ, Kobrinsky N, Barnard DR, et al.: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91 (2): 608-15, 1998.
10. Sorrell AD, Alonzo TA, Hilden JM, et al.: Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group. Cancer 118 (19): 4806-14, 2012.
11. Taub JW, Berman JN, Hitzler JK, et al.: Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood 129 (25): 3304-3313, 2017.
12. Creutzig U, Reinhardt D, Diekamp S, et al.: AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19 (8): 1355-60, 2005.
13. Uffmann M, Rasche M, Zimmermann M, et al.: Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 129 (25): 3314-3321, 2017.
14. Gamis AS, Woods WG, Alonzo TA, et al.: Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol 21 (18): 3415-22, 2003.
15. Blink M, Zimmermann M, von Neuhoff C, et al.: Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. Haematologica 99 (2): 299-307, 2014.
16. Hitzler J, Alonzo T, Gerbing R, et al.: High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial. Blood 138 (23): 2337-2346, 2021.
17. Taga T, Tanaka S, Hasegawa D, et al.: Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome. Leukemia 35 (9): 2508-2516, 2021.
18. Ravindranath Y, Abella E, Krischer JP, et al.: Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80 (9): 2210-4, 1992.
19. Taga T, Shimomura Y, Horikoshi Y, et al.: Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study. Pediatr Blood Cancer 57 (1): 36-40, 2011.
20. Sato T, Yoshida K, Toki T, et al.: Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms. Blood 143 (25): 2627-2643, 2024.
21. Gamis AS, Alonzo TA, Gerbing RB, et al.: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 118 (26): 6752-9; quiz 6996, 2011.
22. Taga T, Saito AM, Kudo K, et al.: Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 120 (9): 1810-5, 2012.
23. Hitzler JK, He W, Doyle J, et al.: Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transplant 19 (6): 893-7, 2013.
24. Muramatsu H, Sakaguchi H, Taga T, et al.: Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome. Pediatr Blood Cancer 61 (5): 925-7, 2014.
25. Raghuram N, Hasegawa D, Nakashima K, et al.: Survival outcomes of children with relapsed or refractory myeloid leukemia associated with Down syndrome. Blood Adv 7 (21): 6532-6539, 2023.

Latest Updates to This Summary (09 / 16 / 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.

Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome

Added text to state that a 2024 analysis screened 143 TAM samples for additional somatic variants in the abnormal cells. With the exception of rare STAG2 variants, the study found no additional abnormalities beyond the typical GATA1 abnormality (cited Sato et al. as reference 13).

Myeloid Leukemia of Down Syndrome (MLDS)

Added text about the results of a 2024 analysis that included a cohort of Japanese patients with MLDS who were treated with uniform chemotherapy. Patients underwent extensive somatic testing to further define variants most commonly seen with this diagnosis (cited Sato et al. as reference 20).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

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 myeloid proliferations associated with Down syndrome. 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).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Myeloid Proliferations Associated With Down Syndrome Treatment are:

• Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Jessica Pollard, MD (Dana-Farber/Boston Children's Cancer and Blood Disorders Center)
• Michael A. Pulsipher, MD (Huntsman Cancer Institute at University of Utah)
• Rachel E. Rau, MD (University of Washington School of Medicine, Seatle Children's)
• Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)
• Sarah K. Tasian, MD (Children's Hospital of Philadelphia)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Myeloid Proliferations Associated With Down Syndrome Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq/myeloid-proliferations-down-syndrome-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 38630975]

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Last Revised: 2024-09-16