title: Clofarabine and busulfan conditioning facilitates engraftment and provides significant antitumor activity in nonremission hematologic malignancies.
abstract: Patients with hematologic malignancies not in remission before allogeneic hematopoietic stem cell transplantation (HSCT) have a poor prognosis. To improve the antitumor activity of conditioning, we combined clofarabine with myeloablative doses of busulfan in a phase 1/2 study in nonremission hematologic malignancies. Forty-six patients were enrolled, including 31 patients with nonremission acute myelogenous leukemia (AML). Patients had a median age of 53 years, with a median comorbidity index of 3. Donors were unrelated, HLA mismatched, or both in 59% of patients. Common grade III to IV nonhematologic toxicities included transient transaminitis (50%), mucositis (24%), hand-foot syndrome (13%), transient hypoxia (13%), nausea/vomiting (9%), and diarrhea (9%). All patients engrafted. Complete remission was achieved in 80% of all patients by day +30 and in 100% of AML patients without prior hematopoietic stem cell transplantation. Two-year nonrelapse mortality for all patients was 31%, and overall survival was 28%. In AML, the overall survival was 48% at 1 year and 35% at 2 years. These data suggest that clofarabine combined with myeloablative doses of busulfan is well tolerated, secures engraftment, and possesses significant antitumor activity, particularly in nonremission AML. This study is registered at www.ClinicalTrials.gov under identifier NCT00556452.
authors.affiliation: Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: John
authors.initials: J
authors.lastname: Magenau
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tobai
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Edward
authors.initials: E
authors.lastname: Peres
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.forename: Carrie
authors.initials: C
authors.lastname: Kitko
authors.forename: Sung
authors.initials: S
authors.lastname: Choi
authors.forename: Gregory
authors.initials: G
authors.lastname: Yanik
authors.forename: David
authors.initials: D
authors.lastname: Frame
authors.forename: Andrew
authors.initials: A
authors.lastname: Harris
authors.forename: Harry
authors.initials: H
authors.lastname: Erba
authors.forename: Lisa
authors.initials: L
authors.lastname: Kujawski
authors.forename: Kojo
authors.initials: K
authors.lastname: Elenitoba-Johnson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sanks
authors.forename: Dawn
authors.initials: D
authors.lastname: Jones
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.forename: James
authors.initials: J
authors.lastname: Ferrara
authors.forename: John
authors.initials: J
authors.lastname: Levine
authors.forename: Shin
authors.initials: S
authors.lastname: Mineishi
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects; D002675:Child, Preschool; D000077866:Clofarabine; D018572:Disease-Free Survival; D006085:Graft Survival / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000401:mortality* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D015996:Survival Rate; D013997:Time Factors; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D019653:Myeloablative Agonists; D000077866:Clofarabine; D002066:Busulfan