title: Hematopoietic stem cell mobilization for gene therapy: superior mobilization by the combination of granulocyte-colony stimulating factor plus plerixafor in patients with β-thalassemia major.
abstract: Successful stem cell gene therapy requires high numbers of genetically engineered hematopoietic stem cells collected using optimal mobilization strategies. Here we focus on stem cell mobilization strategies for thalassemia and present the results of a plerixafor-based mobilization trial with emphasis on the remobilization with granulocyte-colony stimulating factor (G-CSF)+plerixafor in those patients who had previously failed mobilization. Plerixafor rapidly mobilized CD34(+) cells without inducing hyperleukocytosis; however, 35% of patients failed to reach the target cell dose of ≥6×10(6) CD34(+) cells/kg. Four subjects who failed on either plerixafor or G-CSF were remobilized with G-CSF+plerixafor. The combination proved highly synergistic; the target cell dose was readily reached and the per-apheresis yield was significantly increased over initial mobilization, ultimately resulting in single-apheresis collections, despite a more than 50% reduction of the dose of G-CSF in splenectomized patients to avoid hyperleukocytosis. The total stem and progenitor cells mobilized in G-CSF+plerixafor patients were higher than in patients treated by plerixafor alone. Importantly, the G-CSF+plerixafor-mobilized cells displayed a primitive stem cell phenotype and higher clonogenic capacity over plerixafor-mobilized cells. G-CSF+plerixafor represents the optimal strategy when very high yields of stem cells or a single apheresis is required. The high yields and the favorable transplantation features render the G-CSF+plerixafor-mobilized cells the optimal CD34(+) cell source for stem cell gene therapy applications.
authors.affiliation: 1 Hematology-BMT Unit, Gene and Cell Therapy Center, George Papanicolaou Hospital , Thessaloniki 57010, Greece .
authors.forename: Evangelia
authors.initials: E
authors.lastname: Yannaki
authors.forename: Garyfalia
authors.initials: G
authors.lastname: Karponi
authors.forename: Fani
authors.initials: F
authors.lastname: Zervou
authors.forename: Varnavas
authors.initials: V
authors.lastname: Constantinou
authors.forename: Asimina
authors.initials: A
authors.lastname: Bouinta
authors.forename: Varvara
authors.initials: V
authors.lastname: Tachynopoulou
authors.forename: Konstantina
authors.initials: K
authors.lastname: Kotta
authors.forename: Erica
authors.initials: E
authors.lastname: Jonlin
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.forename: George
authors.initials: G
authors.lastname: Stamatoyannopoulos
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D001596:Benzylamines; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D000080027:Cyclams; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008297:Male; D010641:Phenotype; D016896:Treatment Outcome; D055815:Young Adult; D017086:beta-Thalassemia / Q000235:genetics / Q000628:therapy
chemical_list: D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor