A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

Abstract

In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

Conflict of interest statement

Conflict-of-interest disclosure: H.L. received honoraria from Agios; research funding from Bristol-Myers Squibb and Karyopharm; and was the Principal Investigator of clinic trials for Novartis and Arog. M.J.T. received honoraria from UptoDate; is a member of consultancy/advisory board/monitoring committees for AbbVie, AstraZeneca, Celgene, Janssen, and Roche/Genentech; and received research funding from AbbVie (institution), Merck (institution), Pharmacyclics (institution), TG Therapeutics (institution), and Gilead Sciences (institution). J.S. received research funding from AbbVie and Bristol-Myers Squibb; and has a consulting or advisory role with Bristol-Myers Squibb, AstraZeneca, and Merck. W.S. received honoraria from UpToDate and Research to Practice; and has a consulting or advisory role with Agios, Astellas, Daiichi, Kite, and Pfizer. O.O. has a consulting or advisory role with AbbVie and Celgene; and received research funding from Celgene (institution), Incyte (institution), AstraZeneca (institution), Astex Pharmaceuticals (institution), NS Pharma (institution), AbbVie (institution), Gilead Sciences (institution), Janssen Oncology (institution), Oncotherapy (institution), Agios (institution), and CTI (institution). The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

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Graphical abstract

Figure 1.

Gene mutations and response to treatment. Patients had next-generation sequencing performed on pretreatment bone marrow samples, and pathogenic variants were identified. *Genes associated with response, P < .05.