1. Academic Validation
  2. The high-affinity CXCR4 antagonist BKT140 is safe and induces a robust mobilization of human CD34+ cells in patients with multiple myeloma

The high-affinity CXCR4 antagonist BKT140 is safe and induces a robust mobilization of human CD34+ cells in patients with multiple myeloma

  • Clin Cancer Res. 2014 Jan 15;20(2):469-79. doi: 10.1158/1078-0432.CCR-13-1302.
Amnon Peled 1 Michal Abraham Irit Avivi Jacob M Rowe Katia Beider Hanna Wald Lena Tiomkin Lena Ribakovsky Yossi Riback Yaron Ramati Sigal Aviel Eithan Galun Howard Laurence Shaw Orly Eizenberg Izhar Hardan Avichai Shimoni Arnon Nagler
Affiliations

Affiliation

  • 1 Authors' Affiliations: Hematology Division and BMT, Chaim Sheba Medical Center and Tel Aviv University, Tel-Hashomer; Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jerusalem; Biokine Therapeutics Ltd., Science Park, Ness Ziona; and Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center and Technion, Haifa, Israel.
Abstract

Purpose: CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.

Experimental design: Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m(2) cyclophosphamide (day 0), followed by granulocyte colony-stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.

Results: BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34(+) cells (20.6 ± 6.9 × 10(6)/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 10(6) CD34(+) cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).

Conclusions: When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34(+) cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment.

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