Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cells that can be harvested for transduction or gene editing. We therefore performed a phase I dose-escalation ...study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34
cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and ten were on hydroxyurea. Of eight patients who achieved a CD34
cell concentration >30 cells/μL, six were on hydroxyurea. There was no clear dose response to increasing plerixafor dosage. There was a low rate of serious adverse events; two patients developed vaso-occlusive crises, at the doses of 80 μg/kg and 240 μg/kg. Hydroxyurea may have contributed to the limited CD34
mobilization by affecting baseline peripheral blood CD34 counts, which correlated strongly with peak peripheral blood CD34 counts. Plerixafor administration did not induce significant increases in the fraction of activated neutrophils, monocytes, or platelets. However, increased neutrophils positive for activated β2 integrin and Mac-1 were associated with serious adverse events. In summary, plerixafor was well tolerated but did not achieve consistent CD34
cell mobilization in this cohort of patients, most of whom were being actively treated with hydroxyurea and only one was chronically transfused. The study will continue with escalation of the dose of plerixafor and modification of hydroxyurea administration.
.
▪
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.
Display omitted
No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Load filters
No result was selected!
Please select the results that you wish to export.
The search was successfully saved.
Editing
The search could not be saved.
Saved searches can be viewed in the list My searches.
The changes made to the saved search were saved successfully.
Save search
Shelf entry
No result was selected!
Adding material to shelf was successful.
Adding material to shelf was partly successful.
Adding material to shelf failed completely.
It was not necessary to add the material to the shelf.
Please select the results that you want to put on shelf!
On shelf the following records have been successfully added:
On shelf the following records have been successfully added:
PDF
