Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study

Abstract

Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST). The natural history of FA is well characterised; hazard rates in the other syndromes have not yet been quantified. An open cohort was established at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to December, 2007 were followed up to December, 2008. Diagnoses were confirmed with standard tests. Age-associated risks of adverse events were calculated. Most patients in each syndrome survived to young adulthood. Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients. The NCI cohort provides the first direct quantitative comparison of timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that both FA and DC are major cancer susceptibility syndromes. The IBMFS, historically considered paediatric disorders, have important management implications for physicians treating adult patients.

Fig 1

Cumulative incidence and annual hazard rate of competing adverse events by age in patients with Fanconi Anaemia (FA) or Dyskeratosis congenita (DC). Adverse events are severe bone marrow failure (BMF, blue), leukaemia (AML, black), or solid tumours (ST, red). A and D, NCI FA cohort, N = 66. B and E, combined results of the NCI FA cohort with three previously published cohorts: NAS, North American Survey, N = 145; GEFA, German Fanconi Anaemia Registry, N = 181; ISFAR, Israeli Fanconi Anaemia Registry, N = 66 (Rosenberg et al, 2003, 2007; Tamary et al, 2009). C and F, NCI DC cohort, N = 50. A–C, cumulative incidence by age (cumulative percentage experiencing each event as initial cause of failure) and 95% confidence intervals (CI) (shaded areas). D–F, annual hazard rates (incidence rate per year among subjects who are still susceptible) and 95% CI (shaded areas).

Fig 2

Cumulative incidence and annual hazard rate of myelodysplastic syndrome by age in patients with Fanconi Anaemia (FA) or Dyskeratosis congenita (DC). A and D, NCI FA cohort. B and E, combined results of the NCI FA cohort with the three previously published cohorts. C and F, NCI DC cohort. A–C, cumulative incidence by age and 95% CIs. D–F, annual hazard rates and 95% confidence intervals. B and E, red, ISFAR; blue, NAS; purple, GEFA; green NCI; black, combined FA.

Fig 3

Survival curves according to syndrome. A, probability of overall survival. B, probability of survival free of cancer. C, probability of survival free of severe bone marrow failure. Green, Fanconi anaemia; red, dyskeratosis congenita; blue, Diamond-Blackfan anaemia; maroon, Shwachman-Diamond syndrome. Numbers in each syndrome are provided in Table I.

Fig 4

Survival curves according to genotype within FA and DC. A and D, probability of overall survival. B and E, probability of survival free of cancer. C and F, probability of survival free of severe bone marrow failure. A–C, FA genotypes. Green, FANCA; red, FANCC; blue, BRCA2 (FANCD1); maroon, Other or unknown. D–F, DC genotypes. Green, DKC1; red, TERC; blue, TERT; maroon, TINF2; black, unknown. Numbers in each genotype are provided in Table III.