Response to up-front azacitidine in juvenile myelomonocytic leukemia (JMML): Interim analysis of the prospective European multicenter study AZA-JMML-001

Background: JMML is a chemotherapy‐resistant neoplasia of early childhood. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the only curative therapy, being able to cure approximately 50% of these children. Relapse is the major cause of treatment failure, with chemotherapy prior to HSCT being notably unsuccessful. Novel therapies controlling JMML prior to HSCT are urgently needed. Aims: We conducted a phase 2, multicenter, open‐label study to evaluate pharmacodynamics, safety, and antileukemia activity of azacitidine monotherapy prior to HSCT in patients with newly diagnosed JMML. Methods: Azacitidine was administered at 75 mg/m 2 /day intravenously on Days 1–7 of a 28‐day cycle for 3 to 6 cycles. The primary endpoint was the number of patients achieving clinical complete remission or clinical partial remission (cPR) at Cycle 3 Day 28 (C3D28); secondary endpoints included overall survival following HSCT. Results: Between September 2015 and November 2017, 18 JMML patients (13 PTPN11 ‐, 3 NRAS ‐, 1 KRAS ‐, 1 NF1‐mutated), aged 0.2–7.0 years, were enrolled in the study. Median (range) white blood cell (WBC) count, platelet count, and spleen size were: 19.7 (4.3–59.0) × 10 9 /L, 28 (7–85) × 10 9 /L, and 4 (2–14) cm below the costal margin, respectively. DNA methylation class (Lipka et al. Nat Comm . 2017;8:2126; n = 18) was high, intermediate, or low in 11, 5, and 2 patients, respectively. Sixteen patients completed 3 cycles of therapy and 5 of them completed 6 cycles. Two patients discontinued treatment before completing 3 cycles due to disease progression. Six patients (33%) experienced ≥1 grade 3 or 4 manageable adverse event, consistent with the known azacitidine safety profile. Eleven patients (61%) achieved cPR at C3D28 and 7 had progressive disease either at C3D28 or prior. Importantly, 8 of the 15 patients who needed platelet transfusions before or shortly after treatment initiation did not require transfusions at the time of HSCT. Seven of these 8 platelet responders had normalized their platelet count (≥130 × 10 9 /L). Palpable spleen size decreased in 11 responders by a median of 3.5 cm after 3 cycles and ranged from 0 to 2 cm below the costal margin after 6 cycles. Seventeen patients received allo‐HSCT from a human leukocyte antigen‐compatible related or unrelated donor following a busulfan‐ (n = 15) or treosulfan‐based (n = 2) preparative regimen after a median of 57 days (36–112) from last azacitidine dose. Fourteen out of 16 transplanted patients were leukemia‐free at median follow‐up of 15.6 months (0.8–22.5) after HSCT. Two children (both high‐methylation class) given HSCT relapsed after the allograft. Sixteen of the 18 patients were alive at a median follow‐up of 22.2 months (14.2–33.1). One patient who discontinued treatment before Cycle 3 died from disease progression, and 1 non‐responder child died from graft failure. Summary/Conclusion: This study showed azacitidine monotherapy was well tolerated in children with newly diagnosed JMML. Although the long‐term advantage of azacitidine therapy remains to be fully assessed, both decrease in spleen size and significant platelet responses observed demonstrate that the drug was effective in JMML and provided clinical benefit to patients with JMML in this study. This clinical trial has shown that azacitidine therapy prior to HSCT may be considered for patients with JMML.