title: Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study.
abstract: Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m2. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m2in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m2of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.
authors.affiliation: Division of Pediatric Stem Cell Transplant and Regenerative Medicine, Lucile Packard Children's Hospital, Stanford University, Palo Alto, California. Electronic address: ssoni1@stanford.edu.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Soni
authors.affiliation: Division of Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdel-Azim
authors.affiliation: Division of Pediatric Hematology-Oncology, Primary Children's Medical Center, University of Utah, Salt Lake City, Utah.
authors.forename: Meghann
authors.initials: M
authors.lastname: McManus
authors.affiliation: Pediatric Blood and Marrow Transplant Program, Doernbecher Children's Hospital, Oregon Health and Sciences University, Portland, Oregon.
authors.forename: Eneida
authors.initials: E
authors.lastname: Nemecek
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
authors.forename: Ann
authors.initials: A
authors.lastname: Woolfrey
authors.affiliation: The Children's Hospital, TriStar Centennial and Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Haydar
authors.initials: H
authors.lastname: Frangoul
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D019172:Transplantation Conditioning / Q000379:methods*; D014916:Whole-Body Irradiation / Q000379:methods*
chemical_list: D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D000077866:Clofarabine
keywords: Clofarabine; Hematopoietic stem cell transplantation; Nonmyeloablative