Alternative donor hematopoietic cell transplantation for Fanconi anemia

Abstract

• With no prior opportunistic infections/transfusions, 5-year survival after alternative donor HCT with TBI 300 cGy, CY, FLU, and ATG was 94%. • Today, most FA patients with standard risk disease are cured of their bone marrow failure by HCT even without an HLA-matched sibling donor.Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell-depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976. (Blood. 2015;125(24):3798-3804)

Somatic, hematologic phenotype, long‐term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology–Oncology)

“…Differently from other analyses suggesting that malformations affected the outcome [10,11], in our study, in agreement with other surveys [12,13] somatic phenotype did not impact on survival suggesting that hematological evolution is a heavier determinant of outcome.…”

“…Tight monitoring of patients may help to intercept the right timing when consistent decline of hematopoiesis appears but before evolution and other comorbidities like severe fungal infections or hemorrhages occur. The choice of doing a HSCT from HLA MUD donor should be individually weighted, on above elements and also on the best available high resolution HLA matched donor and can be supported by the recent new conditioning and GvHD prevention regimens that enabled very good outcomes [13,21]. In summary, this large comprehensive study provides an updated and accurate evaluation of the general outcome of a large cohort of FA patients.…”

“…Eleven patients (11.3%) were identified because of a family history of FA, i.e., were diagnosed after an affected sibling. Of the 86 neodiagnoses, 21 patients (24.4%) did not have any somatic malformations but only hematological anomalies at diagnosis [13], or hematological anomalies with low stature and facial features [8].…”

Case series of Fanconi anemia in Hevi pediatric hospital-Duhok

“…1,2 The first description of FA cases associated with developmental defects was by the Swiss pediatrician Guido Fanconi in 1927. 3 Biallelic mutations in 1 of 17 genes (called FA complementation groups A through Q) involved in DNA repair processes are causes of FA.…”

“…3 Biallelic mutations in 1 of 17 genes (called FA complementation groups A through Q) involved in DNA repair processes are causes of FA. 2,4 The fundamental cause is genomic instability resulting from the lack in the reproduction dependent DNA cross-link repair pathway usually referred to as the FA/BRCA pathway.…”