TY - JOUR
T1 - Safety and efficacy of plerixafor dose escalation for the mobilization of cd34 + hematopoietic progenitor cells in patients with sickle cell disease
T2 - Interim results
AU - Boulad, Farid
AU - Shore, Tsiporah
AU - van Besien, Koen
AU - Minniti, Caterina
AU - Barbu-Stevanovic, Mihaela
AU - Fedus, Sylvie Wiener
AU - Perna, Fabiana
AU - Greenberg, June
AU - Guarneri, Danielle
AU - Nandi, Vijay
AU - Mauguen, Audrey
AU - Yazdanbakhsh, Karina
AU - Sadelain, Michel
AU - Shi, Patricia A.
N1 - Funding Information:
The authors would like to thank our study subjects for their participation; the Doris Duke Charitable Foundation for a 2011 Innovation in Clinical Research Award for trial support (to PAS and MS); Sanofi-Genzyme for provision of plerixafor; Jena Simon for referring one study patient; W. Beau Mitchell for assistance with platelet activation studies; and Henny Billett, Narla Mohandas, and Beth Shaz for departmental support.
PY - 2018/4/30
Y1 - 2018/4/30
N2 - 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. Clinicaltrials.gov identifier: NCT02193191.
AB - 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. Clinicaltrials.gov identifier: NCT02193191.
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U2 - 10.3324/haematol.2017.187047
DO - 10.3324/haematol.2017.187047
M3 - Article
C2 - 29419425
AN - SCOPUS:85046348539
VL - 103
SP - 770
EP - 777
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 5
ER -