Current Clinical Trials

Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia, is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias.[1] A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia. Children with neurofibromatosis 1 (NF1) and Noonan syndrome are at increased risk for developing JMML [2,3] and up to 14% of cases of JMML occur in children with NF1.[4] Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated ras signaling, including direct oncogenic ras mutations (approximately 20%) [5,6], NF1 inactivating mutations (approximately 15% to 25%) [7], or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%).[8,9]

Historically, more than 90% of patients with JMML died despite the use of chemotherapy.[10] Patients appeared to follow three distinct clinical courses: (1) rapidly progressive disease and early demise; (2) transiently stable disease followed by progression and death; and (3) clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival. Children older than 2 years and high blood fetal hemoglobin (HbF) levels at diagnosis are predictors of poor outcome.[4,11]

The role of conventional anti-leukemia in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML.[12] Among the agents that have shown anti-leukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and 6-mercaptopurine), and isotretinoin.[12,13] Acute myeloid leukemia (AML) induction chemotherapy can induce remissions in children with JMML, but resistant disease is much more common for JMML than for de novo AML and the role of AML-type therapy in the treatment of JMML is not clear.[14]

HSCT offers the best chance of cure for JMML.[15-17] A report from the European Working Group on Childhood MDS notes a 55% and 49% 5-year event-free survival for a large group of children with JMML transplanted with HLA-identical matched family donors or unrelated donors, respectively.[16] Of note is that the transplant took place without any prior cytoreductive therapy except for that given as part of the myeloblative preparative regimen, which included busulphan, cyclophosphamide, and melphalan. Disease recurrence is the primary cause of treatment failure for children with JMML following HSCT and occurs in 30%–40% of cases. [15-17]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with juvenile myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.  [PUBMED Abstract]
   
   
2. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.  [PUBMED Abstract]
   
   
3. Choong K, Freedman MH, Chitayat D, et al.: Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol 21 (6): 523-7, 1999 Nov-Dec.  [PUBMED Abstract]
   
   
4. Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997.  [PUBMED Abstract]
   
   
5. Flotho C, Valcamonica S, Mach-Pascual S, et al.: RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13 (1): 32-7, 1999.  [PUBMED Abstract]
   
   
6. Miyauchi J, Asada M, Sasaki M, et al.: Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 83 (8): 2248-54, 1994.  [PUBMED Abstract]
   
   
7. Side LE, Emanuel PD, Taylor B, et al.: Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 92 (1): 267-72, 1998.  [PUBMED Abstract]
   
   
8. Tartaglia M, Niemeyer CM, Fragale A, et al.: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34 (2): 148-50, 2003.  [PUBMED Abstract]
   
   
9. Loh ML, Vattikuti S, Schubbert S, et al.: Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103 (6): 2325-31, 2004.  [PUBMED Abstract]
   
   
10. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.  [PUBMED Abstract]
    
    
11. Passmore SJ, Chessells JM, Kempski H, et al.: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 121 (5): 758-67, 2003.  [PUBMED Abstract]
    
    
12. Bergstraesser E, Hasle H, Rogge T, et al.: Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: a retrospective analysis and definition of response criteria. Pediatr Blood Cancer 49 (5): 629-33, 2007.  [PUBMED Abstract]
    
    
13. Castleberry RP, Emanuel PD, Zuckerman KS, et al.: A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 331 (25): 1680-4, 1994.  [PUBMED Abstract]
    
    
14. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002.  [PUBMED Abstract]
    
    
15. Smith FO, King R, Nelson G, et al.: Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116 (3): 716-24, 2002.  [PUBMED Abstract]
    
    
16. Locatelli F, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 105 (1): 410-9, 2005.  [PUBMED Abstract]
    
    
17. Yusuf U, Frangoul HA, Gooley TA, et al.: Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant 33 (8): 805-14, 2004.  [PUBMED Abstract]
    
    

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