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

Kirk E. Cahill, Yasmin H. Karimi, Theodore G. Karrison, Nitin Jain, Margaret Green, Howard Weiner, Noreen Fulton, Sabah Kadri, Lucy A. Godley, Andrew S. Artz, Hongtao Liu, Michael J. Thirman, Michelle M. Le Beau, Megan E. McNerney, Jeremy Segal, Richard A. Larson, Wendy Stock, Olatoyosi Odenike*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)599-606
Number of pages8
JournalBlood Advances
Volume4
Issue number4
DOIs
StatePublished - Feb 25 2020
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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    Cahill, K. E., Karimi, Y. H., Karrison, T. G., Jain, N., Green, M., Weiner, H., Fulton, N., Kadri, S., Godley, L. A., Artz, A. S., Liu, H., Thirman, M. J., Le Beau, M. M., McNerney, M. E., Segal, J., Larson, R. A., Stock, W., & Odenike, O. (2020). A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia. Blood Advances, 4(4), 599-606. https://doi.org/10.1182/bloodadvances.2019000795