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]
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.[4,9,20,21,22,23] 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]