Disease Overview
Treatment Overview
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Note: Juvenile myelomonocytic leukemia (JMML) was classified as a myelodysplastic syndrome (MDS) under the French-American-British scheme.[1] The World Health Organization classification removed JMML from MDS, placing it in the new category Myelodysplastic/Myeloproliferative Diseases (MDS/MPD).[1-3]

JMML (also known as juvenile chronic myelomonocytic leukemia) is a rare hematopoietic malignancy of childhood accounting for 2% of all childhood leukemias.[4] A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia, a disease noted only occasionally in children. In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:[5,6]

Major criteria (all three required)

• No Philadelphia chromosome or BCR/ABL fusion gene.
• Peripheral blood monocytosis is greater than 1 × 10⁹/L.
• Fewer than 20% blasts (including promonocytes) in the blood and bone marrow.

Minor criteria (two or more required)

• Fetal hemoglobin (Hb F) increased for age.
• Immature granulocytes in the peripheral blood.
• White blood cell count is greater than 1 × 10⁹/L.
• Clonal chromosomal abnormality (e.g., monosomy 7).
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.

The clinical features of JMML at the time of initial presentation may include the following:[5-8]

• Constitutional symptoms (e.g., malaise, pallor, and fever) or evidence of an infection.
• Symptoms of bronchitis or tonsillitis (in approximately 50% of cases).
• Bleeding diathesis.
• Maculopapular skin rashes (in 40%–50% of cases).
• Lymphadenopathy (in approximately 75% of cases).
• Hepatosplenomegaly (in most cases).

The clinical and laboratory features of JMML can closely mimic a variety of infectious diseases, including those caused by the Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, histoplasma, mycobacteria, and toxoplasma. Laboratory testing can distinguish whether JMML or infectious diseases have affected the clinical and hematologic findings.[5,6,9-11]

JMML typically presents in young children (median age approximately 1 year) and occurs more commonly in boys (male to female ratio approximately 2.5:1). The cause for JMML is not known.[6] Children with neurofibromatosis type 1 (NF1) are at increased risk for developing JMML, and up to 14% of cases of JMML occur in children with NF1.[8,12]

Morphologically, the peripheral blood picture in this disease shows leukocytosis, anemia, and frequently, thrombocytopenia.[6-8,13,14] The median reported white blood cell count varies from 25 × 10⁹/L to 35 × 10⁹/L. In 5% to 10% of children with JMML, however, it is greater than 100 × 10⁹/L. The leukocytosis is comprised of neutrophils, promyelocytes, myelocytes, and monocytes. Blasts, including promonocytes, usually account for less than 5% of the white blood cells and always for less than 20%. Nucleated red blood cells are seen frequently. Thrombocytopenia is typical and may be severe.[6-8,13,14] Bone marrow findings include the following:[6,8,13,14]

• Hypercellularity with granulocytic proliferation.
• Hypercellularity with erythroid precursors (in some patients).
• Monocytes comprising 5% to 10% of marrow cells (30% or more in some patients).
• Minimal dysplasia.
• Reduced numbers of megakaryocytes.

A distinctive characteristic of JMML leukemia cells is their spontaneous proliferation in vitro without the addition of exogenous stimuli, an ability that results from the leukemia cells being hypersensitive to GM-CSF.[15,16] No Philadelphia chromosome or BCR/ABL fusion gene exists. Although cytogenetic abnormalities, including monosomy 7, occur in 30% to 40% of patients, none is specific for JMML.[6,14,17] In JMML associated with NF1, loss of the normal NF1 allele is common, and loss of heterozygosity for NF1 has been observed in some patients with JMML who lack the NF1 phenotype.[17] This genetic alteration results in a loss of neurofibromin, a protein that is involved in the regulation of the ras family of oncogenes.[17] Point mutations in ras have been reported to occur in the leukemic cells of 20% of patients with JMML.[6,18]

The median survival times for JMML vary from approximately 10 months to more than 4 years, depending partly on the type of therapy chosen.[7,8,19] Prognosis is related to age at the time of diagnosis. The prognosis is better in children younger than 1 year at the time of diagnosis. Children older than 2 years at the time of diagnosis have a much worse prognosis.[6,7] A low platelet count and a high Hb F level have been associated with a worse prognosis.[8,13] Approximately 10% to 20% of cases may evolve to acute leukemia.[7,8]

No consistently effective therapy is available for JMML. Historically, more than 90% of patients have died despite the use of chemotherapy.[20] Patients appeared to follow three distinct clinical courses:

1. Rapidly progressive disease and early demise.
2. Transiently stable disease followed by progression and death.
3. Clinical improvement that lasted for as long as 9 years before progression or, rarely, long-term survival.

A recent retrospective review described 60 children with JMML treated with chemotherapy (nonintensive and intensive) and/or bone marrow transplantation (BMT) using sibling or unrelated human leukocyte antigen (HLA)-matched donor marrow or autologous marrow. The median survival was 4.4 years.[7][Level of evidence: 3iiiA]

BMT seems to offer the best chance of cure for JMML.[4,8,19-22] A summary of the outcome of 91 patients with JMML treated with BMT in 16 different reports is as follows: 38 patients (41%) were still alive at the time of reporting, including 30 of the 60 (50%) patients who received grafts from HLA-matched or 1-antigen mismatched familial donors, 2 of 12 (17%) with mismatched donors, and 6 of 19 (32%) with matched unrelated donors.[4]

In a retrospective study investigating the role of BMT for chronic myelomonocytic leukemia (CMML), 43 children with CMML and given BMT were evaluated. In 25 cases, the donor was a HLA-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 cases a matched unrelated donor. Conditioning regimens consisted of total-body radiation therapy and chemotherapy in 22 patients, whereas busulfan with other cytotoxic drugs were used in the remaining patients. Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. Probabilities of transplant-related mortality for children transplanted from HLA-identical/one-antigen-disparate relatives or from matched unrelated donors/mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%; the 5-year event-free survival (EFS) rate was 31%. The authors of this study concluded that children with CMML and an HLA-compatible relative should be transplanted as early as possible.[19][Level of evidence: 3iiiDii]

In a more recent retrospective review from Japan, the records of 27 children with JMML who underwent allogeneic hematopoietic stem cell transplantation (SCT) were examined to determine the role of different variables that potentially influence outcome. The source of grafts was HLA-identical siblings in 12 cases, HLA-matched unrelated individuals in 10 cases, and HLA-mismatched donors in five cases. Total-body radiation therapy was used in 18 cases. At 4 years after SCT, EFS and overall survival (OS) were 54.2% (+/- 11.2% standard error [SE]) and 57.9% (+/- 11.0% [SE]), respectively. Six patients died of relapse and three died of complications. Patients with abnormal karyotypes showed a significantly lower OS than those with normal karyotypes (P < .001). Patients younger than 1 year showed a significantly higher OS than those older than 1 year. Other variables studied were not associated with OS. A multivariate analysis of these factors indicated that the abnormal karyotype was the only significant risk factor for lower OS.[23][Level of evidence: 3iiiA] Five of 10 patients with JMML responded to the oral administration of 13-cis retinoic acid (i.e., two complete responses, three partial responses); median duration of response was 37 months. Treatment with retinoic acid was associated with a decrease in spontaneous colony formation and in GM-CSF hypersensitivity.[24]

Molecular-targeting therapies currently under evaluation include the use of farnesyltransferase inhibitors that prevent ras protein maturation, which may result in increased tumor cell apoptosis and inhibition of tumor cell growth.[16,25]

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. Vardiman JW: Myelodysplastic/myeloproliferative diseases: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 47-8. 
   
   
2. Emanuel PD: Myelodysplasia and myeloproliferative disorders in childhood: an update. Br J Haematol 105 (4): 852-63, 1999.  [PUBMED Abstract]
   
   
3. Hasle H, Niemeyer CM, Chessells JM, et al.: A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17 (2): 277-82, 2003.  [PUBMED Abstract]
   
   
4. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.  [PUBMED Abstract]
   
   
5. Niemeyer CM, Fenu S, Hasle H, et al.: Response: differentiating myelomonocytic leukemia from infectious disease. Blood 91(1): 365-367. 
   
   
6. Vardiman JW, Pierre R, Imbert M, et al.: Juvenile myelomonocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 55-7. 
   
   
7. Luna-Fineman S, Shannon KM, Atwater SK, et al.: Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93 (2): 459-66, 1999.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. Lorenzana A, Lyons H, Sawaf H, et al.: Human herpesvirus 6 infection mimicking juvenile myelomonocytic leukemia in an infant. J Pediatr Hematol Oncol 24 (2): 136-41, 2002.  [PUBMED Abstract]
   
   
10. Luna-Fineman S, Shannon KM, Lange BJ: Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood 85 (8): 1985-99, 1995.  [PUBMED Abstract]
    
    
11. Pinkel D: Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 91 (1): 365-7, 1998.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. 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]
    
    
14. Hess JL, Zutter MM, Castleberry RP, et al.: Juvenile chronic myelogenous leukemia. Am J Clin Pathol 105 (2): 238-48, 1996.  [PUBMED Abstract]
    
    
15. Emanuel PD, Bates LJ, Castleberry RP, et al.: Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77 (5): 925-9, 1991.  [PUBMED Abstract]
    
    
16. Emanuel PD, Snyder RC, Wiley T, et al.: Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors. Blood 95 (2): 639-45, 2000.  [PUBMED Abstract]
    
    
17. 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]
    
    
18. 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]
    
    
19. Locatelli F, Niemeyer C, Angelucci E, et al.: Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol 15 (2): 566-73, 1997.  [PUBMED Abstract]
    
    
20. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.  [PUBMED Abstract]
    
    
21. 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]
    
    
22. 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]
    
    
23. Manabe A, Okamura J, Yumura-Yagi K, et al.: Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia 16 (4): 645-9, 2002.  [PUBMED Abstract]
    
    
24. 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]
    
    
25. Rowinsky EK, Windle JJ, Von Hoff DD: Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 17 (11): 3631-52, 1999.  [PUBMED Abstract]
    
    

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