Targeting SAMHD1 with hydroxyurea in first‐line cytarabine‐based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT‐AML trial

Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-CTP levels through targeted inhibition of SAMHD1.In this phase-1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients.Nine patients were enrolled and received at least two courses of ara-C (1g/m2 /2 h b.i.d. d1-5, i.e. a total of 10/m2 g per course), hydroxyurea (1-2 g d1-5), and daunorubicin (60 mg/m2 d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex-vivo drug sensitivity assays were performed.The most common grade 3/4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; P = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukemic bone-marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (P = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow-cytometry or RT-qPCR) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well tolerated, and median time to neutrophil recovery >1.0×109 /L and to platelet recovery >50×109 /L after start of cycle one was 19 days and 22 days, respectively. Six of nine patients underwent hematopoietic stem-cell transplantation. With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in CR2.Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML-therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study. This article is protected by copyright. All rights reserved.