A Radiation-Free Regimen for Patients With Fanconi Anemia and Related Conditions?

Authors’ Perspective

Lead author Parinda Mehta, MD, and senior author Farid Boulad, MD: “Our results show a clear and critical need for improvement in outcomes for adult patients with Fanconi anemia (FA) and those transplanted for [FA-related] myelodysplastic syndromes or leukemia. Alternative donor hematopoietic cell transplantation (HCT) can be successfully performed in patients with FA by using a chemotherapy-based conditioning regimen and T-cell depleted grafts, thereby avoiding radiation and preventing graft-versus-host disease. … These results encourage physicians to use alternative donor transplants in the absence of a matched sibling donor, when HCT is indicated.”


For patients with Fanconi anemia (FA)-related marrow failure or leukemia, hematopoietic cell transplantation (HCT) is a curative option; however, the radiation exposure during transplant and risk for graft-versus-host disease (GVHD) may increase subsequent risk of head and neck and anogenital malignancies in these patients.

In a prospective, single-arm, multicenter phase II study, Parinda A. Mehta, MD, from the Division of Bone Marrow Transplantation and Immune Deficiency at the Cincinnati Children’s Hospital Medical Center in Ohio, and co-authors evaluated a radiation-free conditioning regimen with a T-cell depleted graft, finding that patients experienced one- and three-year survival rates of 80 percent. No patients, the authors reported, developed grade 3/4 GVHD.

The study, published in Blood, enrolled 45 patients (median age = 8.2 years; range = 4.3-44 years) with FA, most of whom were children (n=40) who underwent HCT at five centers (Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital, Fred Hutchinson Cancer Research Center/Seattle Children Hospital, Children’s Hospital of Wisconsin, and Memorial Sloan Kettering Cancer Center) between June 2009 and May 2014.

Thirty-four patients (75.6%) had severe marrow failure and 11 (24.4%) had myelodysplastic syndromes (MDS). Of these patients:

  • 5% (n=25) underwent HCT using matched unrelated donors
  • 1% (n=14) underwent HCT using mismatched unrelated donors
  • 4% (n=6) underwent HCT using mismatched related donors

The radiation-free regimen consisted of busulfan, cyclophosphamide 10 mg/kg, fludarabine 35 mg/m2, and rabbit anti-thymocyte globulin 2.5 mg/kg. The first 25 patients received busulfan 0.81 mg/kg, and the dose was reduced to 0.60 mg/kg for the remaining patient population. “Engraftment was not compromised by this dose reduction, and toxicity, in particular mucositis and hyperbilirubinemia, was significantly reduced,” the authors noted.

At day 100, the cumulative incidence of acute GVHD was 6.7 percent. Patients had a median time to an absolute neutrophil count of ≥0.5×109/L of 9 days (range = 7-15 days), a median time to CD4 count recovery (>200×109/L) of 6.6 months (range = 2.6-13 months), and a median time to normal T-cell function of 7.5 months (range = 3.7-25.5 months).

After a median follow-up of 41 months (range = 17.4-76.8 months), disease-free survival at one- and three- years was 77.8 percent, with no late events reported. Younger patients had longer survival, Dr. Mehta and co-authors reported, with an overall survival rate of 92.3 percent in patients <10 years of age, compared with 63.2 percent in patients ≥10 years of age (p=0.02).

At the time of publication, 35 patients were alive. Deaths were related to MDS (n=1), relapsed MDS (n=1), infections (n=5), multi-organ failure (n=2), and severe pulmonary hypertension (n=1).

“The majority of patients enrolled in this study were children, and outcomes were excellent for them,” the authors concluded. “It is clear, however, that outcomes in the five adult patients were unsatisfactory, with only one [adult patient] surviving.”

The study is limited by its small patient population and short follow-up.

Source: Mehta PA, Davies SM, Leemhuis T, et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood. 2017 February 8. [Epub ahead of print]

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