Improved hematopoietic stem cell mobilization for gene therapy using single agent motixafortide in sickle cell disease Free

While the development and approval of gene therapies (GT) for sickle cell disease (SCD) has transformed treatment options for patients, a critical limitation remains in the ability to obtain sufficient autologous hematopoietic stem cells (HSCs) for ex vivo manufacture of a drug product. Currently, HSC mobilization for SCD is limited to single agent plerixafor (P), a CXCR4 antagonist, since G-CSF is associated with an increased risk of vaso-occlusive events (VOEs) and death. While P is both safe and effective for mobilizing HSCs, many patients require repeated collection cycles and sometimes fail to collect sufficient cells for manufacture. In clinical trials approximately 2/3 SCD patients required more than one collection cycle, prolonging the pre-transplant period. Motixafortide (M) is a long-acting CXCR4 inhibitor that is FDA approved in combination with G-CSF to mobilize HSCs for autologous transplant in multiple myeloma. Single agent M has been used to successfully mobilize HSCs in healthy allogeneic donors (PMCID: PMC10500469).

These reported results prompted interest in using M to mobilize HSCs for people with SCD who had a poor response to P for GT. In this context, we report the use of M at 5 centers in 10 patients, comprising 15 total collection cycles. Ages ranged from 14-50 years and include 6 females. Each cycle incorporated ≥2 consecutive apheresis days. M (1.25 mg/kg) was given 6-13 hours before apheresis in 11 cycles while in 4 cycles it was given only prior to the first session. Apheresis was performed according to institutional standards with collected cells intended for commercial GT manufacture. Seven of 10 patients had previously failed to mobilize and/or collect sufficient HSCs after at least one cycle of P (range 1-3 cycles) with a median P-mobilized PB CD34+ count of 21.5 cells/µl, range 9.5–95). Daily M resulted in a median PB CD34+ cell count of 79.5 cells/μl (range 19-243,11 cycles), while single-dose M followed by two apheresis sessions yielded 104.5 cells/µl (range 38-175). Six of 7 patients obtained sufficient cells for manufacture; 1 patient failed to mobilize with either agent. The median total number of CD34+ cells collected/day with P was 2.6 x 10⁶/kg compared to 6.8 x 10⁶/kg with M. M was used first line in 3 patients with preexisting clinical concerns precluding multiple collection cycles. Two of these 3 patients received a single M dose/cycle achieving a median PB CD34 count of 125.5 cells/ul (range 15-304) and collected a median of 5.6 x 10⁶/kg/day (range 3.8 -27.4). The third patient received daily M, achieving PB CD34+ cells/µl of 224 (day 1) and 137 (day 2) cells/µl, with corresponding daily collections of 9.5 and 9.6 x 10⁶/kg CD34+ cells. Comparison of M administered as a single dose/session versus daily dosing demonstrated a decline in Day 2 PB CD34+ cell count of 73.7% and 21.1%, respectively. Manufacture and/or infusion of a GT product is ongoing for 10 patients with one patient already successfully transplanted with appropriate engraftment.

The most common adverse events were induration at the injection site (92%), pruritus with rash or hives (88%), and local or generalized pain (62%, narcotics used in 41%). There were 2 instances of lip swelling and fever, but no cases of anaphylaxis. Two patients required prolonged hospitalization for pain management, one attributed to VOE. To mitigate known local injection site and potential systemic reactions to M, all patients received prophylactic H-1 and H-2 antagonists and acetaminophen, with 82% receiving additional montelukast. Corticosteroids were used prophylactically in 25% and as treatment in 1 patient.These results support further study and consideration of M for HSC mobilization in SCD and highlight its potential role for patients who fail to mobilize adequately with P alone. Notably, currently approved GT products require nearly twice the number of HSCs for manufacture compared with the clinical trials, underscoring the urgent need for alternative mobilizing strategies to address this challenge. The ability to collect 2 or 3-fold more stem cells in select patients with SCD can help accelerate the expansion of these transformative therapies. Ongoing clinical trials of M in SCD are examining safety, mobilization efficacy, optimal dose timing, and editing potential (NCT06442761; NCT05618301). Additional studies are warranted to determine the ideal prophylactic medication regimen.