Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study

Blood. 2017 Apr 20;129(16):2308-2315. doi: 10.1182/blood-2016-09-743112. Epub 2017 Feb 8.

Abstract

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antilymphocyte Serum / therapeutic use
  • Bone Marrow / drug effects
  • Bone Marrow / immunology
  • Bone Marrow / pathology
  • Busulfan / therapeutic use
  • Child
  • Child, Preschool
  • Cyclophosphamide / therapeutic use
  • Fanconi Anemia / immunology
  • Fanconi Anemia / pathology
  • Fanconi Anemia / therapy*
  • Female
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / pathology
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Lymphocyte Depletion
  • Male
  • Myeloablative Agonists / therapeutic use*
  • Myelodysplastic Syndromes / immunology
  • Myelodysplastic Syndromes / pathology
  • Myelodysplastic Syndromes / therapy*
  • Prospective Studies
  • Siblings
  • Survival Analysis
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Transplantation Conditioning / methods*
  • Transplantation, Homologous
  • Treatment Outcome
  • Unrelated Donors
  • Vidarabine / analogs & derivatives
  • Vidarabine / therapeutic use

Substances

  • Antilymphocyte Serum
  • Myeloablative Agonists
  • Cyclophosphamide
  • thymoglobulin
  • Vidarabine
  • Busulfan
  • fludarabine

Associated data

  • ClinicalTrials.gov/NCT01082133
  • ClinicalTrials.gov/NCT01082133