BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study

Gautam Borthakur, Yishai Ofran, Martin S. Tallman, James Foran, Geoffrey L. Uy, John F. DiPersio, Margaret M. Showel, Avichai Shimoni, Arnon Nagler, Jacob M. Rowe, Jessica K. Altman, Michal Abraham, Amnon Peled, Stephen Shaw, Osnat Bohana-Kashtan, Ella Sorani, Yaron Pereg, Adam Foley-Comer, Galia Oberkovitz, Tzipi M. LustigIrit Glicko-Kabir, Arnon Aharon, Abi Vainstein-Haras, Shaul E. Kadosh, Emil Samara, Ahmed N. Al-Rawi, Naveen Pemmaraju, Carlos Bueso-Ramos, Jorge E. Cortes, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML. Methods: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23). Results: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts. Conclusions: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.

Original languageEnglish
Pages (from-to)1246-1259
Number of pages14
JournalCancer
Volume127
Issue number8
DOIs
StatePublished - Apr 15 2021

Keywords

  • BL-8040
  • CXCR4
  • acute myelogenous leukemia (AML)
  • cytarabine

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