Safe and efficient peripheral blood stem cell collection in patients with sickle cell disease using plerixafor.

Hematopoietic stem cell (HSC) gene therapy is potentially curative for sickle cell disease (SCD); however, options for HSC collection are limited in this population, and investigation of the collection, efficiency, and safety of peripheral blood (PB) mobilization with plerixafor from start to finish is needed. Here we describe consistent, safe, and sufficient PB HSC collection and processing after plerixafor mobilization from the greatest number of participants reported to date and the first twoinstitutional study. Our data suggest plerixafor mobilized HSC in SCD are enriched for long-term engrafting HSC, which is not true of HSC from SCD bone marrow (BM), supporting a paradigm shift in the optimal HSC source for patients with SCD. This open-label phase I study was sponsored by the National Heart, Lung and Blood Institute at the National Institutes of Health (NIH) and was conducted at the NIH Clinical Center and St. Jude Children’s Research Hospital (SJCRH) (clinicaltrials.gov identifier: NCT03226691). All participants provided written informed consent for a protocol approved by each institution’s Institutional Review Board. Hydroxyurea (HU) was stopped at least two weeks prior to mobilization, and all participants received red blood cell exchange the day prior to mobilization and collection to target <30% sickle hemoglobin (HbS). Participants received a single subcutaneous dose (240 mg/kg) of plerixafor (Mozobil, Sanofi, Bridgewater, NJ, USA) 4 hours (h) before leukapheresis. Participants in the NIH cohort also received 325 mg aspirin. If the minimum target CD34 cell dose of 1.5x10 cells/kg (goal target 2.0x10 cells/kg) was not obtained, a second subcutaneous dose (240 mg/kg) of plerixafor was administered the next day followed by repeat collection. Blood samples were drawn before and 2 h after plerixafor administration, as well as at the start and end of apheresis. Participants were observed on an inpatient basis for at least 24 h after apheresis and received outpatient follow up 3-10 days after discharge. Other methods are described in Online Supplementary Text 1. Fifteen participants with SCD (HbSS n=13, HbSC n=1, HbSβ n=1) were enrolled at SJCRH (n=3) or NIH (n=12) between July 2017 and February 2019. Median age was 29 years (20-50 years) and 47% were male (n=7). Mean hemoglobin (Hb) was 9.2 gm/dL (7.3-13.6 gm/dL), with an average %HbS preand post-exchange transfusion of 57.9% (18.1-87.1%) and 27.0% (15.1-37.7%), respectively. Most participants were on HU prior to study entry (n=11); remaining participants were maintained on regular exchange transfusions (n=5, one participant was on both HU and exchange transfusion). HU was stopped a median of 17 days prior to mobilization and collection (range 15-34 days). The most common SCD-related complications prior to study entry were iron overload (n=11), vaso-oclusive crisis (VOC) (n=10), and acute chest syndrome (n=7). Median baseline CD34 cell count was 7.3 cells/mL (1.0-41.0 cells/mL) (Figure 1A). Median CD34 cell counts varied substantially after plerixafor administration, averaging 38.5 cells/mL (3.0-152.0 cells/mL) at 2 h, 52.0 cells/mL (9.0-183.0 cells/mL) at 4 h/start of apheresis, and 21.0 cells/mL (2.0-129.0 cells/mL) at the completion of apheresis (Figure 1A and B). Two participants did not achieve the minimum CD34 target and underwent a second procedure the following day (Figure 1C). One of these participants achieved the