Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up

Abstract

The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone marrow failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone marrow failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone marrow failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone marrow failure and specific cancers. clinicaltrials.gov Identifier: 00027274.

Trial registration: ClinicalTrials.gov NCT00027274.

Figure 1.

Complications in patients in the NCI inherited bone marrow failure syndromes cohort. (A–D) Cumulative incidence (top panels) and annual hazard rates (bottom panels) of competing adverse events by age in patients with (A) Diamond-Blackfan anemia (DBA), (B) Dyskeratosis congenita (DC), (C) Fanconi anemia (FA) and (D) Shwachman-Diamond syndrome (SDS). Adverse events are severe bone marrow failure leading to hematopoietic cell transplantation or death (HCT or death, blue), acute leukemia (red), or solid tumors (ST, black). Top panels, cumulative incidence of experiencing each event as the initial cause of failure (observed, stair-step lines) and 95% confidence intervals (shaded areas). Bottom panels, annual hazard rates (modeled, smooth curves), i.e., % per year who develop a given event type among subjects who are still susceptible, and 95% confidence intervals (shaded areas).

Figure 2.

Cumulative incidence and annual hazard rates of myelodysplastic syndrome (MDS) by age. Patients with (A) Diamond-Blackfan anemia (DBA), (B) Dyskeratosis congenita (DC), (C) Fanconi anemia (FA) and (D) Shwachman-Diamond syndrome (SDS). Top panels show observed (stair-step lines) and modeled (smooth curves) cumulative incidence curves. Bottom panels show hazard rates (smooth curves) as described in Figure 1. MDS is not considered a competing risk.

Figure 3.

Survival curves for patients in the NCI IBMFS cohort, showing proportion alive by age in years. (A) Diamond-Blackfan anemia (DBA), (B) Dyskeratosis congenita (DC), (C) Fanconi anemia (FA) and (D) Shwachman-Diamond syndrome (SDS). Tick marks represent patients who were still alive at the time of analysis. Observed survival (stair-step lines) and smoothed survival (smooth curves) are shown; shaded areas show 95% confidence intervals for the smoothed curves.

Figure 4.

Cumulative incidence of solid tumors by age in non-transplanted and transplanted patients. Non-transplanted, blue and transplanted, red. (A) Fanconi anemia (FA), including one patient with FANCD1/BRCA2 who developed a brain tumor at age 32 months, 21 months following a stem cell transplant. The rate ratio for transplanted/non-transplanted is 3.5 (95% CI 1.2 – 9.2). (B) FA, excluding the patient with FANCD1/BRCA2. The rate ratio is 3 (95% CI 0.97 – 8.2). (C) Dyskeratosis congenita (DC). The rate ratio is 5.7 (95% CI 1.1 – 20.3).