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

Amnon Peled, 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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/m2 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 × 106/kg), which were obtained through a single apheresis. All transplanted patients received ~5.3 × 106 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. Clin Cancer Res; 20(2); 469-79.

Original languageAmerican English
Pages (from-to)469-479
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number2
DOIs
StatePublished - 15 Jan 2014

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