A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML Journal Article

Authors: Fathi, A. T.; Erba, H. P.; Lancet, J. E.; Stein, E. M.; Ravandi, F.; Faderl, S.; Walter, R. B.; Advani, A. S.; DeAngelo, D. J.; Kovacsovics, T. J.; Jillella, A.; Bixby, D.; Levy, M. Y.; O’Meara, M. M.; Ho, P. A.; Voellinger, J.; Stein, A. S.
Article Title: A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML
Abstract: Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 mg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity. © 2018 by The American Society of Hematology.
Journal Title: Blood
Volume: 132
Issue: 11
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-09-13
Start Page: 1125
End Page: 1133
Language: English
DOI: 10.1182/blood-2018-03-841171
PROVIDER: scopus
PUBMED: 30045838
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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  1. Eytan Moshe Stein
    110 Stein