Safety and efficacy of plerixafor dose escalation for the mobilization of cd34+ hematopoietic progenitor cells in patients with sickle cell disease: Interim results

Farid Boulad, Tsiporah Shore, Koen van Besien, Caterina P. Minniti, Mihaela Barbu-Stevanovic, Sylvie Wiener Fedus, Fabiana Perna, June Greenberg, Danielle Guarneri, Vijay Nandi, Audrey Mauguen, Karina Yazdanbakhsh, Michel Sadelain, Patricia A. Shi

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)770-777
Number of pages8
JournalHaematologica
Volume103
Issue number5
DOIs
StatePublished - Apr 30 2018

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Hydroxyurea
Sickle Cell Anemia
Hematopoietic Stem Cells
Safety
Neutrophils
Integrins
Genetic Therapy
Monocytes
Blood Cells
Blood Platelets
JM 3100

ASJC Scopus subject areas

  • Hematology

Cite this

Safety and efficacy of plerixafor dose escalation for the mobilization of cd34+ hematopoietic progenitor cells in patients with sickle cell disease : Interim results. / Boulad, Farid; Shore, Tsiporah; van Besien, Koen; Minniti, Caterina P.; Barbu-Stevanovic, Mihaela; Fedus, Sylvie Wiener; Perna, Fabiana; Greenberg, June; Guarneri, Danielle; Nandi, Vijay; Mauguen, Audrey; Yazdanbakhsh, Karina; Sadelain, Michel; Shi, Patricia A.

In: Haematologica, Vol. 103, No. 5, 30.04.2018, p. 770-777.

Research output: Contribution to journalArticle

Boulad, F, Shore, T, van Besien, K, Minniti, CP, Barbu-Stevanovic, M, Fedus, SW, Perna, F, Greenberg, J, Guarneri, D, Nandi, V, Mauguen, A, Yazdanbakhsh, K, Sadelain, M & Shi, PA 2018, 'Safety and efficacy of plerixafor dose escalation for the mobilization of cd34+ hematopoietic progenitor cells in patients with sickle cell disease: Interim results', Haematologica, vol. 103, no. 5, pp. 770-777. https://doi.org/10.3324/haematol.2017.187047
Boulad, Farid ; Shore, Tsiporah ; van Besien, Koen ; Minniti, Caterina P. ; Barbu-Stevanovic, Mihaela ; Fedus, Sylvie Wiener ; Perna, Fabiana ; Greenberg, June ; Guarneri, Danielle ; Nandi, Vijay ; Mauguen, Audrey ; Yazdanbakhsh, Karina ; Sadelain, Michel ; Shi, Patricia A. / Safety and efficacy of plerixafor dose escalation for the mobilization of cd34+ hematopoietic progenitor cells in patients with sickle cell disease : Interim results. In: Haematologica. 2018 ; Vol. 103, No. 5. pp. 770-777.
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AU - Boulad, Farid

AU - Shore, Tsiporah

AU - van Besien, Koen

AU - Minniti, Caterina P.

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.

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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.

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