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Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)     
Last Modified: 08/22/2007
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Juvenile Myelomonocytic Leukemia

Treatment options under clinical evaluation

Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia (JCML), 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. Few approaches other than hematopoietic stem cell transplantation (HSCT) have resulted in long-term survival for JMML.[2,3] Children with neurofibromatosis 1 (NF1) and Noonan syndrome are at increased risk for developing JMML [4,5] and up to 14% of cases of JMML occur in children with NF1.[6] Approximately 85% of JMML cases harbor 1 of 3 mutually exclusive mutations leading to activated ras signaling, including direct oncogenic ras mutations, NF1 inactivating mutations or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations.[7,8]

Historically, more than 90% of patients with juvenile myelomonocytic leukemia died despite the use of chemotherapy.[9] Patients appeared to follow 3 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. A retrospective review from the United Kingdom described 31 children (19 with JMML and 12 with monosomy 7) in which chemotherapy (nonintensive and intensive) and marrow-ablative therapy with marrow reconstitution from a sibling or unrelated HLA-matched donor was used. The projected 5-year survival rate was 5% in patients with JMML and 40% in those with monosomy 7.[10]

Based on the observation that the characteristic in vitro granulocyte-macrophage colony-stimulating factor hypersensitivity of JMML cells could be inhibited by clinically achievable concentrations of cis-retinoic acid (C-RA), 12 patients with JMML were evaluated in a pilot study using C-RA.[11] Of 10 evaluable patients, responses were as follows: 2 complete responses, 3 partial responses, one minimal response, 4 progressive disease. Toxicity was minimal. Responses were relatively slow, and most children who experienced progressive disease did so within a few weeks of C-RA treatment.

HSCT offers the best chance of cure for JMML.[2,12-14] A summary of the outcomes of 91 patients with JMML treated with HSCT in 16 different reports is as follows: 38 patients (41%) were still alive at the time of reporting, including 30 (50%) of the 60 patients who received grafts from HLA-matched or one-antigen mismatched familial donors, 2 of 12 (17%) with mismatched donors, and 6 of 19 (32%) with matched unrelated donors.[1] 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.[15] 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.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site 1.

  • The Children's Oncology Group trial AAML0122 tested the role of the farnesyl transferase inhibitor R115777 (Zarnestra, Tipifarnib). This study has been completed, but results have not yet been reported.


References

  1. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.  [PUBMED Abstract]

  2. Sanders JE, Buckner CD, Thomas ED, et al.: Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia. Blood 71 (4): 1144-6, 1988.  [PUBMED Abstract]

  3. Bunin N, Saunders F, Leahey A, et al.: Alternative donor bone marrow transplantation for children with juvenile myelomonocytic leukemia. J Pediatr Hematol Oncol 21 (6): 479-85, 1999 Nov-Dec.  [PUBMED Abstract]

  4. 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]

  5. 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]

  6. 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]

  7. 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]

  8. 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]

  9. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.  [PUBMED Abstract]

  10. Passmore SJ, Hann IM, Stiller CA, et al.: Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 85 (7): 1742-50, 1995.  [PUBMED Abstract]

  11. 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]

  12. 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]

  13. 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]

  14. Starý J, Locatelli F, Niemeyer CM, et al.: Stem cell transplantation for aplastic anemia and myelodysplastic syndrome. Bone Marrow Transplant 35 (Suppl 1): S13-6, 2005.  [PUBMED Abstract]

  15. 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]


Table of Links

1http://www.cancer.gov/clinicaltrials