Pilot and Feasibility Trial of Plerixafor for Hematopoietic Stem Cell (HSC) Mobilization in Patients With Sickle Cell Disease Pilot and Feasibility Trial of Plerixafor for Hematopoietic Stem Cell (HSC) Mobilization in Patients With Sickle Cell Disease

Sickle cell disease (SCD) is one of the most common genetic diseases in the world. In North America, an estimated 2600 babies are born with SCD each year1, and approximately 70,000 to 100,000 individuals of all ages are affected in the United States2. The clinical manifestations of SCD include acute events, such as recurrent debilitating painful crises, as well as life-threatening pulmonary, cardiovascular, renal, and neurologic complications. The only established curative treatment for SCD patients is allogeneic hematopoietic stem cell transplant (HSCT). Unfortunately, access to this intervention is limited by availability of suitable matched donors, and HSCT is associated with significant morbidity and mortality. For patients who cannot undergo HSCT, treatment of SCD has been limited to one FDA-approved medication, hydroxyurea, and supportive symptomatic care. After decades with very few novel therapeutic options for SCD patients, autologous cell-based genetic therapies, including lentiviral-based gene therapy as well as gene editing, now offer the possibility of innovative curative approaches for patients lacking a matched donor for hematopoietic stem cell transplantation. Gene therapy for sickle cell disease is increasingly promising, and there are currently open clinical trials at several centers that employ a gene addition strategy. Options for autologous HSC collection include bone marrow harvest or peripheral blood HSC mobilization. Bone marrow (BM) harvest is an invasive procedure requiring anesthesia, which is associated with sickle cell-related morbidities, and may not achieve goal CD34+ cell dose, necessitating repeated procedures scheduled over multiple months. In most gene therapy trials, HSCs are obtained through peripheral collection after mobilization with granulocyte colony-stimulating factor (G-CSF) followed by peripheral blood (PB) apheresis. However, this approach is contraindicated in SCD because G-CSF has been reported to cause severe adverse effects in sickle cell patients. Even with doses sometimes smaller than standard, G-CSF has been shown to result in vaso-occlusive crises, severe acute chest syndrome, and in one report, massive splenomegaly and death. Alternative options for mobilization are needed. Plerixafor has been compared to G-CSF in a sickle cell mouse model, and results showed effective mobilization of HSC subsets, without neutrophil or endothelial activation, and with lower total WBC and neutrophil counts compared to G-CSF-treated mice. Plerixafor use has not yet been documented in sickle cell patients. One other trial is currently open to test plerixafor in SCD patients (NCT02193191) but no results have yet been reported. Based on pre-clinical data, the mechanism of action of plerixafor, as well strategies the investigator will employ to mitigate risk, the investigator anticipates that it will be well-tolerated in the SCD patient population.