CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS A 20-year perspective on the International Fanconi Anemia Registry (IFAR)

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellu-lar hypersensitivity to DNA cross-linking agents and cancer predisposition. Re-cent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility pro-teins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a signifi-cant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a pro-spectively collected database of FA pa-tients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 sub-jects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neo-plasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were non-hematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28 % cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a signifi-cantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCC muta-tions (P .007) and hematopoietic stem cell transplantation (P <.0001) define a poor-risk subgroup. The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of out-come and aid clinicians with decisions regarding major therapeutic modalities