Hematopoietic stem cell mobilization for allogeneic stem cell transplantation by motixafortide, a novel CXCR4 inhibitor

Zachary D. Crees, Michael P. Rettig, Asad Bashey, Steven M. Devine, Samantha Jaglowski, Fei Wan, Amy Zhou, Melinda Harding, Abi Vainstein-Haras, Ella Sorani, Irit Gliko-Kabir, Brenda J. Grossman, Peter Westervelt, John F. DiPersio, Geoffrey L. Uy

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Granulocyte colony-stimulating factor (G-CSF) is the most common agent used for mobilizing peripheral blood (PB) hematopoietic stem and progenitor cells (HSPCs) for allogeneic hematopoietic cell transplantation (allo-HCT). However, G-CSF mobilization often requires multiple leukapheresis procedures (LPs) and injections.1,2 G-CSF is also associated with bone pain, rare but life-threatening splenic rupture, and vaso-occlusive complications in patients with sickle-cell disease.1,3-5 CXCR4 and SDF-1/CXCL12 interactions are crucial for HSPC retention within the bone marrow niche.6-8 Plerixafor (AMD3100), is a low-affinity (Ki: 652 nM), short-acting CXCR4 inhibitor (CXCR4i) previously shown to mobilize PB HSPCs for HCT.9-11 In these studies, up to 34% of allogeneic donors (allo-donors) mobilized with single-agent plerixafor failed to collect >2 × 106 CD34+ cells per kg with 1 injection and 1 LP; whereas 10% required ≥3 injections, ≥3 LPs, and G-CSF rescue.11-14 Therefore, development of rapid and reliable HSPC mobilization regimens remains an unmet need. Motixafortide (BL-8040) is a novel 14-residue, cyclic, synthetic peptide CXCR4i with high affinity (Ki 0.32 nM) and slow receptor dissociation rate, previously shown to induce rapid (onset, 0.5-2 hours) and sustained (duration, >48 hours) HSPC mobilization.15 To our knowledge, the authors report the first trial evaluating motixafortide mobilization of allo-donors for HCT. A multicenter, open-label, single-arm, 2-part, phase 2 study (NCT02639559) was conducted with institutional review board approval and written informed consent from all participants. Donors were aged between 18 and 70 years, with an Eastern Cooperative Oncology Group performance status from 0 to 1. Recipients were aged between 18 and 75 years, with and Eastern Cooperative Oncology Group performance status from 0 to 2, undergoing allo-HCT for hematologic malignancy (Table 1). Part-1 included HLA-identical (5/6 or 6/6 HLA-matched) sibling donors. Part-2 included HLA–matched sibling or haploidentical donors. Motixafortide was administered via subcutaneous injection at 1.0 mg/kg in part-1 and 1.25 mg/kg in part-2. The rationale for motixafortide dosing strategy in this study was based on data from 3 prior clinical trials (NCT01010880, NCT02073019, and NCT01838395), in which motixafortide alone or in combination with other mobilizing agents (chemotherapy ± G-CSF) was administered at doses of 0.5 or 1.5 mg/kg in healthy volunteers, patients with multiple myeloma, and patients with acute myeloid leukemia with an acceptable toxicity profile and a dose-dependent increase in CD34+ cell mobilization at the 1.0 and 1.25 mg/kg dose range. The primary end point was efficacy of 1 motixafortide injection to mobilize ≥2 × 106 CD34+ cells per kg (recipient weight) in ≤2 LPs. First LP (≥3 blood volumes) began from 180 to 270 minutes after motixafortide administration. Second LP (if needed) began 24 hours after motixafortide administration. If ≥2.0 × 106 CD34+ cells per kg were collected within 2 LPs, mobilization was complete (supplemental Figure 1).

Original languageEnglish
Pages (from-to)5210-5214
Number of pages5
JournalBlood Advances
Volume7
Issue number18
DOIs
StatePublished - Sep 26 2023

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