Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study.
Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosomal fragility, progressive marrow failure, and cancer predisposition. Hematopoietic cell transplantation (HCT) is curative for FA-related marrow failure or leukemia, but both radiation exposure during transplant and graft-versus-host disease (GVHD) may increase risk of later malignancies of the head and neck and anogenital area. In this study, we tested a radiation-free conditioning regimen with a T-cell-depleted graft to eliminate radiation exposure and minimize early and late toxicities of transplant. Forty-five patients (median age, 8.2 years; range 4.3-44) with FA underwent HCT between June 2009 and May 2014. The preparative regimen included busulfan, cyclophosphamide, fludarabine, and rabbit anti-thymocyte globulin. Busulfan levels were monitored to avoid excess toxicity. All grafts were CD34-selected/T-cell-depleted using the CliniMacs CD34 columns (Miltenyi). Thirty-four patients (75.6%) with marrow failure and 11 (24.4%) with myelodysplastic syndrome underwent HCT using matched unrelated (n = 25, 55.5%), mismatched unrelated (n = 14, 31.1%), or mismatched related donors (n = 6, 13.4%). One year probabilities of overall and disease-free survival for the entire cohort, including patients with myeloid malignancy and those receiving mismatched related/haploidentical grafts, were 80% (±6%) and 77.7% (±6.2%), respectively (median follow-up 41 months). All young children (<10 years of age) undergoing HCT for marrow failure using low-dose busulfan-containing regimen survived. No patients developed acute grade 3-4 GVHD. Sequential reduction of busulfan dose was successfully achieved per study design. Our results show excellent outcomes in patients with FA undergoing alternative donor HCT without radiation exposure. The study is registered to www.clinicaltrials.gov as #NCT01082133.
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Parinda A
0000-0001-9971-8597
PA
Mehta
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Stella M
SM
Davies
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Thomas
T
Leemhuis
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Kasiani
K
Myers
Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.|Division of Pediatric Hematology-Oncology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY.
Nancy A
0000-0003-1417-1823
NA
Kernan
Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.|Division of Pediatric Hematology-Oncology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY.
Susan E
SE
Prockop
Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.|Division of Pediatric Hematology-Oncology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY.
Andromachi
A
Scaradavou
Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.|Division of Pediatric Hematology-Oncology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY.
Richard J
RJ
O'Reilly
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA.
David A
DA
Williams
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA.
Leslie
L
Lehmann
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
Eva
0000-0003-3874-0007
E
Guinan
Children's Hospital of Wisconsin, Milwaukee, WI; and.
David
0000-0001-5714-0002
D
Margolis
Fred Hutchinson Cancer Research Center, Seattle, WA.
K Scott
KS
Baker
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Adam
A
Lane
Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering, New York, NY.|Division of Pediatric Hematology-Oncology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY.
Farid
F
Boulad
D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002066:Busulfan / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use; D005199:Fanconi Anemia / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011446:Prospective Studies; D035781:Siblings; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000961:Antilymphocyte Serum; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; C512542:thymoglobulin; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine