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Originally published as JCO Early Release 10.1200/JCO.2003.05.086 on July 28 2003 © 2003 American Society for Clinical Oncology
Down Syndrome and Acute Myeloid Leukemia: The Paradox of Increased Risk for Leukemia and Heightened Sensitivity to ChemotherapyGeorgia Ginopolis Chair for Pediatric Cancer and Hematology, Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit, MI
IN DECEMBER 1990, at the 22nd Annual Meeting of the American Society of Hematology, investigators from the Pediatric Oncology Group (POG; now part of Children’s Oncology Group [COG]) initially presented the unique responsiveness of acute myeloid leukemia (AML) in children with Down syndrome (DS) compared with AML in children without DS, followed by a more complete report in 1992.1,2 Publications before these two reports either commented on the rather dismal outcome of AML in children with DS3 or the lack of any significant difference in survival from children without DS,4 with one anecdotal exception—a comment published in 1989 by Lie,5 noting a possible superior outcome. Since then, the high curability of AML in children with DS has been the subject of numerous publications, supported by the molecular, biochemical, and pharmacologic bases for the markedly superior outcome compared with AML in children without DS. Although all 12 DS children with AML enrolled on the original study POG 8498 achieved complete remission and were long survivors, subsequent publications, while noting the continuing evidence for the high curability ( In this issue of the Journal of Clinical Oncology, Gamis et al8 examine the experience with AML in children with DS treated on CCG (Children’s Cancer Group, now also part of the COG) study 2891 and report that among children with DS with AML, age older than 2 years may be a relative poor-risk feature. Multivariate analysis of data showed that children with DS who were 2 years or older at diagnosis had an increased risk of relapse (odds ratio 4.9; P = .006). An implication is that in DS children over 2 years AML may be biologically similar to de novo AML, hence the poorer response. Several questions emerge as a result. Is the Leukemia in DS Biologically Different Based on Age at Diagnosis? A closer examination of the data of Gamis et al suggests that the risk varies within age groups: "Patients who had AML that was diagnosed between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%, those older than 2 to 4 years (n = 58) had a 70% EFS, and those older than 4 years (n = 9) had a 28% EFS." Thus, for children with DS who are older than 4 years, the EFS is markedly inferior, and is the same as for non-DS children without DS with AML receiving the "standard timing 4 day course" of the dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin (DCTER) regimen (EFS 21% standard induction- see abstract of Gamis et al8). No data are presented separately for the 2 to 3 and 3 to 4 years age groups, nor are there any details of the individual cases of those older than 4 years. Regardless, the markedly inferior outcome in those 4 years or older would create a "Will Rogers" phenomenon, whether the age cut is at 2 or 3 years, because of stage or risk migration.9 Since the overwhelming majority of children with DS with AML are younger than 3 years of age and only 14% (23 of 161) were older than 36 months in the Gamis et al report, one could argue that if age-related biologic differences in the nature of AML in children with DS existed, a better age cut may be beyond 36 or 48 months of age. The increased risk for AML in children with DS is well known.6,10,11 Children with DS are also known to have a form of spontaneously resolving leukemia, which is variously referred to as transient myeloproliferative disorder (TMD) or transient leukemia. Zipursky et al10,11 have noted that infants with DS who had TMD have a higher risk for the later development of AMkL, usually by 3 years of age. Recent studies have shown that nonactivating mutations of GATA1 are present in virtually all cases of DS-AML (all of the studied cases to date were in those younger than 4 years) and that the same mutations are seen in TMD cases as well.12–16 Further, in paired samples of TMD and AMkL in the same child, identical GATA1 mutations were noted.13 Backtracking studies in childhood acute lymphocytic leukemia and AML suggest an in utero origin of a leukemic clone in the majority of cases, and a suggestion that the leukemic load at birth may be lower in those with leukemia diagnosed later in childhood.17–19 Thus, an important question to be pursued from the report of Gamis et al8 is whether DS-AML cases older than 2 years lack prior history of TMD and GATA1 mutations? If so, it would clearly indicate a different biologic origin and possibly a difference in response. What Is the Optimal Therapy for DS-AML? The superior outcome in DS became obvious only after the inclusion of high-dose cytarabine (Ara-C; HiDAC) in the treatment of childhood AML. Thus, the prevailing opinion is that two or more courses of HiDAC post–remission induction may be necessary for optimal therapy. However, the 100% EFS reported by the POG investigators, based on the POG 8498 AML regimen, has not been duplicated in subsequent studies by POG or by other groups.20–23 Successor studies to POG 8498 eliminated the historic combination course of prednisone, vincristine, methotrexate, and 6-mercaptopurine (POMP), plus the final four courses of conventional dose Ara-C, and sought to intensify the postinduction courses. At the same time, recognition of the unique responsiveness of AML in children with DS lead both to greater enrollment of DS cases on therapeutic studies and the recognition of risk for toxicity and the potential for mortality from infections.24,25 Gamis et al observed no increase in mortality rate in children with DS, but did observe high pulmonary toxicity during induction, including the need for ventilatory support and an increased incidence of mucositis and skin toxicity (perhaps from Ara-C) during intensification. Prolonged induction toxicity may result in premature patient withdrawal from a clinical trial because of concerns from both parents and physicians of putting a developmentally challenged child through excessive toxicity. Studies from Nordic countries and from Germany have shown that undertreated children with DS with AML had markedly inferior outcomes.21,22 Such vagaries in small cohorts may have a profound effect on the eventual outcomes, and it would therefore be of interest to know how many patients completed all courses of chemotherapy in the older age groups of children with DS in the CCG 2891 study. Results with intensively-timed DCTER arm of CCG 2891 in children with DS were worse than with standard-timed DCTER.6 Furthermore, Kojima et al26 obtained an 80% 8-year EFS with two to eight courses of conventional-dose daunorubicin or etoposide, and Ara-C in a 3+3+7-day combination. Hence, moderate-intensity therapy (as in the Japanese study or standard 3+7 combination of daunorubicin + Ara-C, followed by two courses of HiDAC for six doses, each given after full recovery of counts) seems to be the most optimal therapy. Could the Difference in Outcome by Age Observed by Gamis et al Have a Pharmacologic or Biochemical Basis? No studies were done, and hence, only speculations are possible. There are several genes on chromosome 21 that not only alter the sensitivity to Ara-C, but also to anthracyclines and other drugs in both specific and nonspecific manners.24,27–29
De novo modulation of cytarabine metabolism.
Increased multidrug sensitivity in DS.
Epigenetic influences on treatment response in DS-AML. In summary, DS is a unique model for studying the association of leukemia (cancer) biology and therapeutic response. On the one hand, constitutional trisomy of chromosome 21 increases the risk for leukemia several-fold, but on the other, the leukemia is highly sensitive to chemotherapy. There is likely an Achilles’ heel associated with each of the somatic mutations and chromosomal aberrations, resulting in an increased risk for cancer; however, it is up to us to discover it. It is important to recognize that the molecular oncogenic event and the Achilles’ heel may not be one and the same. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES 1. Ravindranath YE, Krischer J, Civin CI, et al: Acute myeloid leukemia (AML) in Downs’ Syndrome (DS): A highly curable disease? Blood 76:311a, 1990 (abstr 1235)
2. 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 80:2210–2214, 1992
3. Levitt GA, Stiller CA, Chessells JM: Prognosis of Down’s syndrome with acute leukaemia. Arch Dis Child 65:212–216, 1990 4. Robison LL, Nesbit ME, Sather HN, et al: Down syndrome and acute leukemia in children: A 10-year retrospective survey from Children’s Cancer Study Group. J Pediatr 105:235–242, 1984[CrossRef][Medline] 5. Lie SO: Acute myelogenous leukaemia in children. Eur J Pediatr 148:382–388, 1989[CrossRef][Medline]
6. 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 91:608–615, 1998
7. Athale UH, Razzouk BI, Raimondi SC, et al: Biology and outcome of childhood acute megakaryoblastic leukemia: A single institution’s experience. Blood 97:3727–3732, 2001
8. Gamis AS, Alonzo TA, Buxton A, et al: Increased age at diagnosis has a significantly negative effect on outcome in children with Down’s syndrome and acute myeloid leukemia: A report from the Children’s Cancer Group Study, CCG-2891. J Clin Oncol 21:3415–3422, 2003 9. Feinstein AR, Sosin DM, Wells CK: The Will Rogers phenomenon: Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 312:1604–1608, 1985[Abstract] 10. Zipursky A, Poon A, Doyle J: Leukemia in Down syndrome: A review. Pediatr Hematol Oncol 9:139–149, 1992[Medline] 11. Zipursky A: Transient leukaemia: A benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120:930–938, 2003[CrossRef][Medline] 12. Wechsler J, Greene M, McDevitt MA, et al: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32:148–152, 2002[CrossRef][Medline]
13. Hitzler JK, Cheung J, Li Y, et al: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101:4301–4304, 2003 14. Groet J, McElwaine S, Spinelli M, et al: Acquired mutations in GATA1 in neonates with Down’s syndrome with transient myeloid disorder. Lancet 361:1617–1620, 2003[CrossRef][Medline] 15. 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 (in press), 2003
16. Mundschau G, Gurbuxani S, Gamis AS, et al: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101:4298–4300, 2003
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19. Mori H, Colman SM, Xiao Z, et al: Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA 99:8242–8247, 2002
20. Ravindranath Y, Yeager AM, Chang MN, et al: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood: Pediatric Oncology Group. N Engl J Med 334:1428–1434, 1996 21. Lie SO, Jonmundsson G, Mellander L, et al: A population-based study of 272 children with acute myeloid leukaemia treated on two consecutive protocols with different intensity: Best outcome in girls, infants, and children with Down’s syndrome — Nordic Society of Paediatric Haematology and Oncology (NOPHO). Br J Haematol 94:82–88, 1996[CrossRef][Medline] 22. Creutzig U, Ritter J, Vormoor J, et al: Myelodysplasia and acute myelogenous leukemia in Down’s syndrome: A report of 40 children of the AML-BFM Study Group. Leukemia 10:1677–1686, 1996[Medline]
23. Craze JL, Harrison G, Wheatley K, et al: Improved outcome of acute myeloid leukaemia in Down’s syndrome. Arch Dis Child 81:32–37, 1999 24. Ravindranath Y, Taub JW: Down syndrome and acute myeloid leukemia. Lessons learned from experience with high-dose Ara-C containing regimens. Adv Exp Med Biol 457:409–414, 1999[Medline] 25. Zubizarreta PA, Alfaro E: High toxicity of AML-BFM treatment strategy in Down’s syndrome: Report of a single pediatric institution. Blood 88:178b, 1996 (abstr 3440) 26. Kojima S, Sako M, Kato K, et al: An effective chemotherapeutic regimen for acute myeloid leukemia and myelodysplastic syndrome in children with Down’s syndrome. Leukemia 14:786–791, 2000[CrossRef][Medline]
27. Taub JW, Matherly LH, Stout ML, et al: Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: A contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 87:3395–3403, 1996 28. Taub JW, Stout ML, Buck SA, et al: Myeloblasts from Down syndrome children with acute myeloid leukemia have increased in vitro sensitivity to cytosine arabinoside and daunorubicin. Leukemia 11:1594–1595, 1997[CrossRef][Medline]
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33. Zwaan CM, Kaspers GJ, Pieters R, et al: Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 99:245–251, 2002 34. Busciglio J, Yankner BA: Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378:776–779, 1995[CrossRef][Medline]
35. Bar-Peled O, Korkotian E, Segal M, et al: Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenic-Cu/Zn superoxide dismutase neurons. Proc Natl Acad Sci USA 93:8530–8535, 1996 36. Arbuzova S, Hutchin T, Cuckle H: Mitochondrial dysfunction and Down’s syndrome. Bioessays 24:681–684, 2002[CrossRef][Medline] 37. Licastro F, Mocchegiani E, Masi M, et al: Modulation of the neuroendocrine system and immune functions by zinc supplementation in children with Down’s syndrome. J Trace Elem Electrolytes Health Dis 7:237–239, 1993[Medline] 38. Romano C, Pettinato R, Ragusa L, et al: Is there a relationship between zinc and the peculiar comorbidities of Down syndrome? Downs Syndr Res Pract 8:25–28, 2002[Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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75% event-free survival [EFS] for DS-AML), raised concern for increased mortality with intensification of therapy. This high responsiveness to chemotherapy of AML in those with DS is especially remarkable, given that phenotypically it has the features of megakaryocytic leukemia (AMkL) and is often preceded by a history of myelodysplastic syndrome, both considered poor prognostic predictors of AML in individuals without DS.
