Juvenile Myelomonocytic Leukemia
Note: Juvenile myelomonocytic leukemia (JMML) was classified as a myelodysplastic syndrome (MDS) under the French-American-British scheme. The World Health Organization classification removed JMML from MDS, placing it in the new category Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN).[1-3]
JMML (also known as juvenile chronic myelomonocytic leukemia) is a rare hematopoietic malignancy of childhood accounting for 2% of all childhood leukemias. 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:[5-7]
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.
- 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 the following:
- Those caused by the Epstein-Barr virus.
- Human herpesvirus 6.
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.[6,7] 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.[9,13]
Morphologically, the peripheral blood picture in this disease shows leukocytosis, anemia, and frequently, thrombocytopenia.[6-9,14,15] 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.[6-9,14,15] Bone marrow findings include the following:[6,7,9,14,15]
- 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.[16,17] 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.[6,15,18] 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. This genetic alteration results in a loss of neurofibromin, a protein that is involved in the regulation of the ras family of oncogenes. Point mutations in ras have been reported to occur in the leukemic cells of 20% of patients with JMML.[6,19]
The median survival times for JMML vary from approximately 10 months to more than 4 years, depending partly on the type of therapy chosen.[8,9,20] 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.[6,8] A low platelet count and a high Hb F level have been associated with a worse prognosis.[9,14] Approximately 10% to 20% of cases may evolve to acute leukemia.[8,9]Treatment Overview
No consistently effective therapy is available for JMML. Historically, more than 90% of patients have died despite the use of chemotherapy. Patients appeared to follow three distinct clinical courses:
- Rapidly progressive disease and early demise.
- Transiently stable disease followed by progression and death.
- 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.[Level of evidence: 3iiiA]
BMT seems to offer the best chance of cure for JMML.[4,9,20-23] 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.
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.[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.[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.
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.[17,26]Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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
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