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.

Cellular Composition and 5hmC Signature Predict the Treatment Response of AML Patients to Azacitidine Combined with Chemotherapy

“…Study Subjects: Detailed phase 1 trial design methods for this study had been reported. [6] The study population included patients age ≥ 18 years with high-risk AML and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. AML was defined by the 2008 criteria of the World Health Organization (WHO).…”

“…The results of this trial have been previously published. [6] To identify gene expression programs that may confer sensitivity to AZA-HiDAC-Mito treatment, we collected mononuclear cells from bone marrow (BM) and/or peripheral blood (PB) prior to AZA treatment (Day 0) and performed RNA-seq. Twenty-eight patients had pre-treatment material available for RNA-seq.…”

NPM1 exon 5 mutations in acute myeloid leukemia: Implications in diagnosis and minimal residual monitoring

“…They were initially treated on the SWOG S1203 protocol [ 7 ] with idarubicin, cytarabine, and vorinostat with primary refractory disease. Second line of therapy was on protocol [ 8 ] with azacitidine, cytarabine, and mitoxantrone with residual disease followed by a hematopoietic stem and progenitor cell transplant before relapsing. They received two cycles of hypomethylating agent‐based therapies before dying of refractory disease.…”

Clinical and molecular response of AML harboring non-canonical FLT3 N676K driver mutations to contemporary FLT3 inhibitors

“…The study was approved by the Institutional Review Board and conducted according to the Declaration of Helsinki. Our practice utilizes a validated 1213 gene next-generation sequencing (NGS) panel that has been previously described (6)(7)(8). NGS is employed at presentation and at subsequent time points to assess response or disease status.…”