@article{6f9139e19d69401788501ed613c0b265,
title = "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",
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.",
keywords = "BL-8040, CXCR4, acute myelogenous leukemia (AML), cytarabine",
author = "Gautam Borthakur and Yishai Ofran and Tallman, \{Martin S.\} and James Foran and Uy, \{Geoffrey L.\} and DiPersio, \{John F.\} and Showel, \{Margaret M.\} and Avichai Shimoni and Arnon Nagler and Rowe, \{Jacob M.\} and Altman, \{Jessica K.\} and Michal Abraham and Amnon Peled and Stephen Shaw and Osnat Bohana-Kashtan and Ella Sorani and Yaron Pereg and Adam Foley-Comer and Galia Oberkovitz and Lustig, \{Tzipi M.\} and Irit Glicko-Kabir and Arnon Aharon and Abi Vainstein-Haras and Kadosh, \{Shaul E.\} and Emil Samara and Al-Rawi, \{Ahmed N.\} and Naveen Pemmaraju and Carlos Bueso-Ramos and Cortes, \{Jorge E.\} and Michael Andreeff",
note = "Funding Information: This work was supported by BioLineRx Ltd. Funding Information: Gautam Borthakur reports grants and research support from GlaxoSmithKline, Janssen Scientific Affairs, Eli Lilly, Bristol‐Myers Squibb, Cyclacel, AstraZeneca, Incyte, Bayer Healthcare, Agensys, AbbVie, Oncoceutics, BioLineRx Ltd, Novartis, XBiotech, Eisai, TetraLogic Pharmaceuticals, Strategia Therapeutics, Polaris, Arvinas, Merck, Cantargia AB, PTC Therapeutics, Selvita, BioTheryX, MedImmune, and Mundipharma‐EDO GmbH, outside the submitted work; and personal fees from PTC Therapeutics, BioLineRx Ltd, Argenx, and BioTheryX, outside the submitted work; and other support from BioLineRx Ltd, during the course of the study. Martin S. Tallman reports research funding from AbbVie, Amgen, ADC Therapeutics, BioSight, Cellerant, Glycomimetics, Orsenix, and Rafael, outside the submitted work; personal fees from AbbVie, Amgen, BioLineRx Ltd, Daiichi‐Sankyo, Delta Fly Pharma, Jazz Pharma, KAHR, Nohla, Novartis, Oncolyze, Orsenix, Rigel, Roche, and Tetraphase, outside the submitted work; and royalties from . James Foran reports personal fees from Revolution Medicine, Novartis, Servier, Pfizer Inc, and Bristol‐Myers Squibb, outside the submitted work; and institutional research funding from AbbVie, BioLineRx Ltd, Boehringer Ingelheim, Actinium, Aprea, Aptose, H3Biosciences, Kura Oncology, Tolero, Trillium, Xencor, Takeda/Millennium, and Xencor, outside the submitted work. Geoffrey L. Uy reports personal fees from Astellas, Curis, GlaxoSmithKline, Jazz Pharma, Pfizer Inc, and Roche/Genentech, outside the submitted work. John F. DiPersio reports personal fees from Arch, Rivervest, Biokine, Amphivena, Bluebird, Celgene, Incyte, NeoImuneTech, and Macrogenics, outside the submitted work; research support from BioLineRx Ltd, Amphivena, and Magenta, outside the submitted work; nonfinancial research support from BioLineRx Ltd, outside the submitted work; and ownership investments in Magenta and WUGEN. Jacob M. Rowe reports personal fees from BioSight and Pluristem, outside the submitted work, and serves on the data‐monitoring committee of BioLineRx Ltd. Jessica K. Altman reports personal fees from AbbVie, Astellas, Daiichi‐Sankyo, Theradex, Agios, Novartis, and BioSight, outside the submitted work, and serves on the data‐monitoring committee of Glycomimetics. Michal Abraham is an employee Biokine. Amnon Peled: is a consultant for Biokine. Stephen Shaw, Ella Sorani, Adam Foley‐Comer, Galia Oberkovitz, Tzipi M. Lustig, Irit Glicko‐Kabir, Arnon Aharon, and Abi Vainstein‐Haras are or were employed by BioLineRx Ltd. Osnat Bohana‐Kashtan is an employee of BioLineRx Ltd and reports a patent issued (Methods of selecting treatment for CXCr4‐associated cancer) to BioLineRx Ltd. Yaron Pereg is an employee of BioLineRx Ltd and reports patents pending (US20160082071 and US20190046602) to BioLineRx Ltd. Shaul E. Kadosh is an employee of StatExcellence. Emil Samara is an employee of PharmaPolaris International Inc. Ahmed N. Al‐Rawi reports personal fees from PeerView, Prime Oncology, Novartis, Cancer Expert Now, Agios, the France Foundation, Theradex, AbbVie, and Astellas, outside the submitted work; travel and accommodation reimbursement from Daiichi‐Sankyo for advisory board service, outside the submitted work, and serves on the data‐monitoring committee of Glycomimetics. Naveen Pemmaraju reports personal fees from Pacylex Pharmaceuticals, Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Diagnostics, and Blueprint Oncology, outside the submitted work; and research funding/clinical trials support from Stemline Therapeutics, Novartis, AbbVie, MustangBio, Samus, Cellectis, Plexxikon, Daiichi‐Sankyo, Affymetrix, and the SagerStrong Foundation, outside the submitted work. Jorge E. Cortes reports institutional research support from Astellas, Daiichi‐Sankyo, Bristol‐Myers Squid, Novartis, Pfizer Inc, Takeda, Merus, Forma, and Amphivena, outside the submitted work; and personal fees from Novartis, Pfizer Inc, Biopath Holdings, Daiichi‐Sankyo, and Takeda, outside the submitted work. Michael Andreeff reports research support from the National Cancer Institute, the US Food and Drug Administration, the Leukemia Society of America, the Cancer Prevention and Research Institute of Texas, the MD Anderson Moon Shots Program, Amgen Inc, AstraZeneca, Daiichi‐Sankyo, Glycomimetics, and BioLineRx Ltd, outside the submitted work, and personal fees from Amgen Inc, AstraZeneca, Oncoceutics, Aptose, and Daiichi‐Sankyo, outside the submitted work. The remaining authors made no disclosures. UpToDate Publisher Copyright: {\textcopyright} 2020 American Cancer Society",
year = "2021",
month = apr,
day = "15",
doi = "10.1002/cncr.33338",
language = "English",
volume = "127",
pages = "1246--1259",
journal = "Cancer",
issn = "0008-543X",
number = "8",
}