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

Amir T. Fathi, Harry P. Erba, Jeffrey E. Lancet, Eytan M. Stein, Farhad Ravandi, Stefan Faderl, Roland B. Walter, Anjali S. Advani, Daniel J. DeAngelo, Tibor J. Kovacsovics, Anand Jillella, Dale Bixby, Moshe Y. Levy, Megan M. O’Meara, Phoenix A. Ho, Jenna Voellinger and Anthony S. Stein

Key Points

  • Vadastuximab talirine, a CD33-targeted antibody-drug conjugate, is active in combination with HMAs in frontline AML.

  • The addition of vadastuximab talirine to HMAs led to high remission rates and protracted myelosuppression in older patients.

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 μg/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.

  • Submitted March 28, 2018.
  • Accepted July 11, 2018.
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