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
| Autor: | Osnat Bohana-Kashtan, Margaret M. Showel, Martin S. Tallman, Jessica K. Altman, Abi Vainstein-Haras, James M. Foran, Avichai Shimoni, Arnon Aharon, Michal Abraham, Yaron Pereg, Shaul Kadosh, Arnon Nagler, Ella Sorani, Yishai Ofran, Galia Oberkovitz, Naveen Pemmaraju, Amnon Peled, Ahmed AlRawi, Emil Samara, Geoffrey L. Uy, Tzipi Lustig, Michael Andreeff, Irit Glicko-Kabir, Stephen Shaw, Jorge E. Cortes, Carlos E. Bueso-Ramos, Adam Foley-Comer, Gautam Borthakur, John F. DiPersio, Jacob M. Rowe |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Receptors CXCR4 Acute myelogenous leukemia (AML) medicine.medical_treatment Bone Marrow Cells Gastroenterology Drug Administration Schedule 03 medical and health sciences Myelogenous 0302 clinical medicine Refractory Recurrence Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans 030212 general & internal medicine Aged Chemotherapy CXCR4 antagonist business.industry Remission Induction Cytarabine Middle Aged medicine.disease Hematopoietic Stem Cell Mobilization Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Female Bone marrow business Peptides medicine.drug |
| Zdroj: | CancerReferences. 127(8) |
| ISSN: | 1097-0142 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text