Azacitidine (Vidaza((R))) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015)

Background Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor.Objective We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation.Methods Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment.Results Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m(2) was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML.Conclusions Azacitidine 75 mg/m(2) prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML.Clinical Trial RegistrationEudraCT 2010-022235-10.

Automated summary

This study aimed to evaluate the safety, pharmacokinetics, and efficacy of azacitidine in children with relapsed MDS/JMML prior to a second hematopoietic stem cell transplantation. The results showed no response in patients with MDS, but 83% achieved stable disease, and the overall response rate in the JMML cohort was 75%. The study suggests that azacitidine is a safe and efficacious option for relapsed JMML.