Abstract
Background
Juvenile myelomonocytic leukemia (JMML) is very rare and aggressive disease of infancy and childhood. This disorder is characterized by features of both myeloproliferative and myelodysplastic disorders. Allogeneic stem cell transplant is the only curative option available for this disease. The median survival time of children who do not receive an allograft can be as short as 10 to 12 months. Recent studies have highlighted the importance of epigenetic aberrations (aberrant DNA methylation) in JMML. Hence, azacytidine an epigenetic modifier can be good potential therapeutic option in these group of patients. There are very few cases reported in literature. Rarity of this disease makes prospective randomized trials with this agent difficult. Here we report favorable outcome for three patients diagnosed with this fatal condition.
Case Series
Three patients diagnosed JMML as per WHO 2016 Criteria since March 2017 were enrolled in this study after obtaining informed consent. Details of baseline patient characteristics are shown in table 1. All the patients received azacytidine at 75mg/m2/ day for seven consecutive days every 28 days. All the patients have refused option of allogenic stem cell transplant and hence they are planned to be kept on same protocol till progression. Two children are continuing treatment. First patient enrolled in this study has completed 13 cycles. Second patient discontinued treatment after completion of 5 cycles of azacytidine (parental preference). Third patient in this study has completed 9 cycles. Bone marrow aspiration and cytogenetic evaluation was planned after 6 cycles of azacytidine.
Results
All the children enrolled in this study are maintaining stable course and are free from transfusion requirement. The second patient who discontinued therapy after 5 cycles of azacytidine is also doing well as per telephonic confirmation with parents and is free from any transfusion requirement at 14 months since he was enrolled in study. At a median follow up of 13 months since the date of diagnosis, all three children are surviving (Range 10-16 months) which is already higher than median overall survival reported for patients not receiving stem cell transplant. No patient has shown evidence of clinical progressive disease as per response criteria of JMML International Symposium (December 2013). As per these criteria one patient had clinical complete remission, another patient had clinical partial remission with progressive genetic disease and the patient who lost to follow up is considered to have clinically stable disease (since we could not complete assessment for this patient). Table 2 summarizes response to treatment for different parameters assessed. We documented a new cytogenetic abnormality (appearance of 20 q deletion) in one patient which was not documented at baseline. Therapy was well tolerated and no major toxicities (grade III-IV) were documented except episode of febrile neutropenia in one patient requiring hospitalization. Other adverse events included thrombocytopenia in between cycles but none were grade III-IV after initial platelet response.
Discussion and conclusion
Though the sample size is small, results are encouraging. To note all patients in our study had platelet count less than 33 thousand and two patients had haemoglobin F percentage higher than that for age which are poor prognostic clinical variable as reported by EWOG-MDS study group. Our results are similar to those reported by EWOG MDS study group which comprised of nine treatment naive patients. Azacytidine was used for bridge to transplant in this group. However, in resource poor setting like India where most families cannot afford transplant it would be prudent to evaluate if azacytidine can prolong survival or alter the natural history of this fatal disease. Long term study with more number of patients are required to know whether azacytidine can be a suitable alternative in patients where stem cell transplant is not an option.
No relevant conflicts of interest to declare.
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