Treatment Options Under Clinical Evaluation

Children with Down syndrome have an increased risk of leukemia with a ratio of acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML predominates and exhibits a distinctive biology.[1-8]

In addition to increased risk for AML during the first 3 years of life, neonates with Down syndrome may also develop a transient myeloproliferative disorder (TMD) (also termed transient leukemia). This disorder mimics congenital AML, but typically improves spontaneously within the first 3 months of life, though TMD can remit as late as 20 months.[9] Although TMD is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 20% of affected infants.[9,10] Infants with progressive organomegaly, visceral effusions, preterm delivery, bleeding diatheses, failure of spontaneous remission, and laboratory evidence of progressive liver dysfunction, and very high white blood cell count are at particularly high risk for early mortality.[10,11] Therapeutic intervention is warranted in patients in whom severe hydrops or organ failure is apparent. Several treatment approaches have been used, including exchange transfusion, leukopheresis, and low-dose cytarabine.[12]

The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of TMD but then develop AML, has been reported to be 16 months with a range of 1 to 30 months.[9,13] Thus, most infants with Down syndrome and TMD who later develop AML will do so within the first 3 years of life. Patients with Down syndrome who develop AML with an antecedent TMD have superiorly event-free survival (EFS) (91% ± 5%) compared to such children without having TMD (70% ± 4%) at 5 years.[11] While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk for developing subsequent AML.[10]

For children with Down syndrome who develop AML, outcome is generally favorable.[14] The prognosis is particularly good (EFS exceeding 80%) in children aged 4 years or younger at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.[15] Appropriate therapy for these children is less intensive than current AML therapy, and hematopoietic stem cell transplant is not indicated in first remission.[3,13,15-18]

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• The Children's Oncology Group (COG) is conducting a non-randomized study (AAML0431) of the treatment of newly diagnosed AML or myelodysplastic syndromes (MDS) in children younger than 4 years with Down syndrome. The main goal of the study is to increase survival while reducing toxicity. The treatment reduces the amount of intrathecal chemotherapy and the cumulative dose of anthracycline compared to the prior COG and Children's Cancer Group (CCG) Down syndrome AML study treatment plans and moves the Capizzi II intensification to earlier in the regimen. The planned study will not include the small number (5%–10%) of Down syndrome patients aged 4 years and older at diagnosis, since these patients had an inferior outcome (28% EFS at 6 years) on CCG-2891.[17] These children are eligible for the COG study (AAML0531) but will not receive stem cell transplant or be randomized to receive gemtuzumab ozogamicin.

References

1. Ravindranath Y: Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment. Pediatr Blood Cancer 44 (1): 1-7, 2005.  [PUBMED Abstract]
   
   
2. Ross JA, Spector LG, Robison LL, et al.: Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 44 (1): 8-12, 2005.  [PUBMED Abstract]
   
   
3. 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.  [PUBMED Abstract]
   
   
4. Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005.  [PUBMED Abstract]
   
   
5. Massey GV: Transient leukemia in newborns with Down syndrome. Pediatr Blood Cancer 44 (1): 29-32, 2005.  [PUBMED Abstract]
   
   
6. Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44 (1): 33-9, 2005.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. Jubinsky PT: Megakaryopoiesis and thrombocytosis. Pediatr Blood Cancer 44 (1): 45-6, 2005.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. Al-Kasim F, Doyle JJ, Massey GV, et al.: Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study. J Pediatr Hematol Oncol 24 (1): 9-13, 2002.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. Craze JL, Harrison G, Wheatley K, et al.: Improved outcome of acute myeloid leukaemia in Down's syndrome. Arch Dis Child 81 (1): 32-7, 1999.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005.  [PUBMED Abstract]
    
    

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