Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

Bristol Myers Squibb Princeton NJ

Bristol Myers Squibb San Francisco CA

Celgene Corporation a Bristol Myers Squibb company Uxbridge United Kingdom

Department of Paediatric Hematology and Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Pathology Böblingen Hospital Sindelfingen Germany

Department of Pediatric Hematology and Immunology Centre Hospitalier Universitaire Paris France

Department of Pediatric Hematology and Oncology IRCCS Ospedale Pediatrico Bambino Gesù Rome Italy; and

Department of Pediatric Hematology and Oncology Münster University Children's Hospital Münster Germany

Department of Pediatric Sciences Istituto Giannina Gaslini Istituto di Ricovero e Cura a Carattere Scientifico Genoa Italy

Department of Pediatrics Sapienza University of Rome Rome Italy

Department of Pediatrics Universitätsklinikum Frankfurt Frankfurt Germany

Division of Haematology Kinderspital Zürich Zürich Switzerland

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical Center University of Freiburg Freiburg Germany

Faculty of Biosciences Heidelberg University Heidelberg Germany

Formerly Bristol Myers Squibb Princeton NJ

German Cancer Consortium Site Frankfurt Frankfurt Germany

German Cancer Research Center Heidelberg Germany

Hematology Oncology Prinses Máxima Center for Pediatric Oncology Hematology Utrecht The Netherlands

Pediatric Hematology and Oncology Institut de Recerca Hospital Sant Joan de Deu de Barcelona Barcelona Spain

Pediatric Hematology Oncology Fondazione IRCCS Policlinico San Matteo Pavia Italy

Pediatrics and Pediatric Oncology Hôpital de la Timone Marseilles France

Translational Cancer Epigenomics Section Division of Translational Medical Oncology German Cancer Research Center Heidelberg Germany

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Phenotypic profiling of CD34+ cells by advanced flow cytometry improves diagnosis of juvenile myelomonocytic leukemia

Second allogeneic stem cell transplantation can rescue a significant proportion of patients with JMML relapsing after first allograft

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ClinicalTrials.gov
NCT02447666