title: Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia.
abstract: The prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33-71) at 1 year and 38% (95% CI: 18-46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26-64) at 1 year and 29% (95% CI: 13-48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1-24) at 1 year and 12% (95% CI: 3-19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174.
authors: Hematology Department, Centre Hospitalier et Universitaire (CHU) de Nantes, France mohamad.mohty@inserm.fr.|Centre d'Investigation Clinique en Cancérologie (CI2C), CHU de Nantes, France.|Centre de Recherche Saint-Antoine, INSERM, UMRS 938, France.|Université Pierre et Marie Curie, Paris, France.|Hematology Department, AP-HP, Université Paris 6, Hôpital Saint Antoine, France.
authors: Mohamad
authors: M
authors: Mohty
authors: Hematology Department, Centre Hospitalier et Universitaire (CHU) de Nantes, France.|Centre de Recherche Saint-Antoine, INSERM, UMRS 938, France.|Université Pierre et Marie Curie, Paris, France.|Hematology Department, AP-HP, Université Paris 6, Hôpital Saint Antoine, France.
authors: Florent
authors: F
authors: Malard
authors: Unité de Transplantation et de Thérapie Cellulaire (U2T), Institut Paoli-Calmettes, Marseille, France.
authors: Didier
authors: D
authors: Blaise
authors: Hematology Department, CHU Haut-Lévêque, Bordeaux, France.
authors: Noel
authors: N
authors: Milpied
authors: Service de Greffe de Moelle, AP-HP, Université Paris 7, Hôpital Saint Louis, France.
authors: Gérard
authors: G
authors: Socié
authors: Hematology Department, IUCT Oncopole, Toulouse, France.
authors: Anne
authors: A
authors: Huynh
authors: Institut d'hématologie de Basse Normandie, CHU, Côte de Nacre 14000 Caen, France.
authors: Oumédaly
authors: O
authors: Reman
authors: CHU de Lille, LIRIC INSERM U995, Université Lille 2, France.
authors: Ibrahim
authors: I
authors: Yakoub-Agha
authors: Unité de Transplantation et de Thérapie Cellulaire (U2T), Institut Paoli-Calmettes, Marseille, France.
authors: Sabine
authors: S
authors: Furst
authors: Hematology Department, Centre Hospitalier et Universitaire (CHU) de Nantes, France.
authors: Thierry
authors: T
authors: Guillaume
authors: Hematology Department, CHU Haut-Lévêque, Bordeaux, France.
authors: Resa
authors: R
authors: Tabrizi
authors: Hematology Department, CHU Haut-Lévêque, Bordeaux, France.
authors: Stéphane
authors: S
authors: Vigouroux
authors: Hematology Department, Centre Hospitalier et Universitaire (CHU) de Nantes, France.
authors: Pierre
authors: P
authors: Peterlin
authors: Unité de Transplantation et de Thérapie Cellulaire (U2T), Institut Paoli-Calmettes, Marseille, France.
authors: Jean
authors: J
authors: El-Cheikh
authors: Hematology Department, Centre Hospitalier et Universitaire (CHU) de Nantes, France.|Centre d'Investigation Clinique en Cancérologie (CI2C), CHU de Nantes, France.
authors: Philippe
authors: P
authors: Moreau
authors: Hematology Department, AP-HP, Université Paris 6, Hôpital Saint Antoine, France.
authors: Myriam
authors: M
authors: Labopin
authors: Hematology Department, Centre Hospitalier et Universitaire (CHU) de Nantes, France.|Centre d'Investigation Clinique en Cancérologie (CI2C), CHU de Nantes, France.
authors: Patrice
authors: P
authors: Chevallier
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage; D000077866:Clofarabine; D003561:Cytarabine / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D019233:Retreatment; D016019:Survival Analysis; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D003561:Cytarabine; D000077866:Clofarabine