Page 18 - Haematologica-5

Editorials
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ing employed in an ongoing HSC gene therapy trial was recently recognized to result in suboptimal yields of high purity HSC at the end of collection and processing, along with substantial pain after each harvest, and most subjects required two or three harvests to yield sufficient cell doses for manufacturing.5,6
In this issue of the Journal, two groups of investigators report their results using a third approach to HSC collec- tion in SCD through mobilization with an inhibitor of the CXCR4 chemokine receptor, plerixafor. Boulad et al. per- formed a dose escalation study of plerixafor among a total of 15 SCD patients at steady state.7 Ten of the patients were receiving concomitant treatment with hydroxyurea. Only a minority of patients in each cohort achieved the target of ≥30 CD34+ cells/μL at 12 h after the plerixafor injection: three out six at a dose of 80 μg/kg, one out of three at a dose of 160 μg/kg, and two out of six at a dose of 240 μg/kg. Two patients (15%) experienced a vaso-occlusive crisis during the study period – one each at 80 and 240 μg/kg. None of the patients underwent leuka- pheresis, thus attribution of these adverse events could be narrowed to plerixafor. On the other hand, Lagresle- Peyrou et al. reported the outcomes of three patients who received plerixafor at a dose of 240 μg/kg.8 All three patients received at least 2 months of red cell exchange transfusion to target a sickle hemoglobin (HbS) near 30% while hydroxyurea was discontinued. The peak CD34+ cell count reached >75 cells/μL at as early as 3 h after the injection. All three patients also underwent leukapheresis of 15 to 21 L, with a resulting total CD34+ cell yield of 4.5 to 5.8 x 106 cells/kg and a purity of 80% to 95%. No pain, vaso-occlusive crises, or sickle-related events were observed in these three patients.
While the number of patients is relatively small in both studies, important lessons relevant to autologous HSC mobilization and collection in SCD with plerixafor can be gleaned. The first lesson regards preparation of the patients. Specifically, stopping hydroxyurea and utilizing red cell transfusions, simple or exchange, to target a HbS of 30% were likely key factors in the successful mobiliza- tion of the series reported by Lagresle-Peyrou et al. Conversely, the absence of these measures in the study by Boulad et al. may explain why the majority of their patients failed to reach the target CD34+ concentration. This is consistent with prior work demonstrating a lower CD34+ cell content in the marrow of SCD patients on hydroxyurea when compared to those not on the drug.3 Discontinuation of hydroxyurea combined with sched- uled red cell transfusion to keep the HbS near 30% may also have improved purity, which was 80% to 95% in the study by Lagresle-Peyrou et al., while helping to mini- mize the risk of sickle cell-related adverse events while hydroxyurea treatment was interrupted. Secondly, leuko- cyte and neutrophil counts increased 2- to 3-fold just hours after a single injection of plerixafor, even at the lowest dose of 80 μg/kg tested. Although increases of a similar magnitude also occurred with filgrastim, the adverse events seen with filgrastim may have been relat- ed to the prolonged duration of 5 to 6 days from filgras- tim that led to the high rates of adverse events in the ear-
lier reports. We will need more patients to ascertain the contribution of leukocytosis alone and/or the duration of leukocytosis in developing sickle-related complications. Thirdly, only three patients underwent leukapheresis and though adverse events appear acceptable, expanded accrual could capture additional side effects. Furthermore, if patients with SCD do not meet the goal and need addi- tional mobilization and collection, there could be cumu- lative side effects. Finally, the peak of mobilization of CD34+ cells appeared to be much earlier, at 3-6 hours. This observation is distinct from that in healthy donors, in whom the peak is observed at 6-12 hours.9 Perhaps the chronically hyperproliferative marrow in SCD partly explains this early release of HSC; there could be other factors at play. Regardless, this observation suggests that for optimal collection, apheresis should be started within 4-6 hours of dosing.
As clinical applications of gene transfer and gene editing strategies are being implemented in SCD, obtaining ade- quate numbers of HSC safely from patients could be the ‘bottleneck’, preventing broad dissemination of these exciting approaches. The early results provide optimism that mobilization with plerixafor could be a safer and more efficacious alternative for HSC collection to either filgras- tim mobilization or bone marrow harvesting, and provide general confidence for the further development of these promising approaches to a one-time cure for SCD.
©2017 NIH (National Institutes of Health)
References
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haematologica | 2018; 103(5)