Safety and Efficacy Trial of Escalation of Plerixafor for Mobilization of CD34+ Hematopoietic Progenitor Cells (HPCs) for Globin Gene Transfer in Patients with Sickle Cell Disease

There is presently no curative therapy for SCD other than allogeneic hematopoietic progenitor cell (HPC) transplantation. Incoming trials of autologous gene therapy approaches in patients with sickle cell disease (SCD) include the need of HPCs for gene transduction. However, the use of G-CSF for mobilization of HPCs is contraindicated in this patient population, having resulted in sickle crises and death in some patients.

Plerixafor is an inhibitor of the CXCR4 chemokine receptor on HPCs and blocks binding of its ligand, stromal cell-derived factor-1α (SDF-1α). It is FDA-approved at doses of 240 μg/kg subcutaneously in combination with G-CSF for autologous HPC mobilization in non- Hodgkin lymphoma and multiple myeloma patients.

We designed a multi center 3+3, phase 1 study of dose escalation of plerixafor for mobilization of HPC in patients with SCD. The primary goal of this trial is to evaluate the safety of, and the optimal dose for the mobilization of HPCs with plerixafor alone. The desired optimal peripheral blood CD34 concentration was set at > 30 cells/μl. Plerixafor was supplied by Sanofi following their approval of the protocol. Because of the ethical considerations, and the risks associated with the mobilization of patients with SCD, the protocol was submitted to, and approved by the FDA; IND 122657. It was registered with ClinicalTrials.gov; identifier: NCT02193191.

Fourteen patients with SCD were entered on the study to date, and 13 patients were evaluable. Patients' age was 21-41 years (median 30 years). Patients had a history of SCD complications including vaso-occlusive crises, acute chest syndrome, osteomyelitis, cerebral aneurysm, retinal ischemia, and skin ulcers. Nine patients were on, and 4 patients were off hydroxyurea at the time of accrual on study.

Six patients were treated at the first dose level of 80 μg/Kg, three patients at the second dose level of 160 μg/Kg, and to date, four patients at the third dose level of 240 μg/Kg. Two patients developed adverse events of vaso-occlusive crisis, 2 and 4 days following completion of plerixafor at the first and third dose level respectively, requiring increasing the first and third dose cohorts to 6 patients.

White blood cell counts (WBC), absolute neutrophil counts (ANC), absolute lymphocyte counts (ALC) (x 10^9/L), CD34+ and CD34+CD38- cell counts were measured at the following time points: 0, 6-12 and 20-24 hours post-treatment with Plerixafor, which allowed to identify the optimal CD34 peak time in SCD patients.

The results of peak WBC, ANC and ALC, and fold increase for these counts, as well as CD34+ concentrations (cells/μl), and number of patients achieving a CD34+count > 30 cells/μl are shown in Table 1 for patients at the 3 dose levels. There was a 1.8-2.8 fold increase in WBC and 1.0-2.2 fold increase in ANC at the 3 dose levels, and CD34 concentrations were: 7-132 cells/μl, 27-251 cells/μl and 19-95 cells/μl for the 3 respective dose levels. There were no significant variations in the levels of hemoglobin and platelets.

In summary, this is the first trial on the use of plerixafor for HPC mobilization in patients with SCD. Our data in 13 patients support the safety of plerixafor administration at doses of 80, 160 μg/Kg, and 240 μg/Kg, which is especially significant, in view of the prior toxicity associated with G-CSF in this patient population. Plerixafor increased WBC, ANC and ALC to acceptable levels (1.8-2.8 fold), and allowed the mobilization of high numbers of CD34+ cells for 8 of 13 patients treated at the 3 dose levels. This study will allow us to define the optimal conditions for effective globin gene transfer after optimization of lentivirus-mediated globin gene transfer with the TNS9.3.55 vector in an upcoming trial.

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