Improved collection of hematopoietic stem cells and progenitors from Fanconi anemia patients for gene therapy purposes

Abstract

Anèmia de Fanconi; Mozobil; Teràpia gènica

Anemia de Fanconi; Mozobil; Terapia génica

Fanconi anemia; Mozobil; Gene therapy

Difficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols.

This work was supported by grants from the European Commission’s Seventh Framework Program (HEALTH-F5-2012-305421 to the EUROFANCOLEN Consortium, J.A.B., J. Sevilla, C.D.-d.-H., J. Soulier, and J. Surralles), Ministerio de Sanidad, Servicios Sociales e Igualdad (EC11/060 and EC11/550 to C.D.-d.-H., J. Sevilla, J.A.B., and J. Surralles), Ministerio de Economía, Comercio y Competitividad and Fondo Europeo de Desarrollo Regional (SAF2015-68073-R, RTI2018-097125-B-I00 to P.R. and RTI2018-098419-B-I00 to J. Surralles), Fondo de Investigaciones Sanitarias at the Instituto de Salud Carlos III (RD12/0019/0023 to J.C.S.), and Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid (AvanCell Project; B2017/BMD3692). CIBERER is an initiative of the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional. J. Surralles is supported by ICREA Academia and FARF.