Malignancies and Outcome in Patients with Ataxia-Telangiectasia: Results From the French National Registry for Primary Immune Deficiencies.

Ataxia-Telangiectasia (A-T) is rare inherited condition characterized by progressive neurological impairment, oculocutaneous telangiectasias, susceptibility to infections and predisposition to cancer. A-T is due to bi-allelic mutations in the ATM gene located on chromosome 11q23. ATM encodes a multifunction serine-threonine kinase involved detection and repair of DNA double-strand breaks, and regulation of cell-cycle check-points and apoptosis. A-T patients present an increased susceptibility to antimitotic chemotherapy and radiation.. Cancer is a major contributor to morbidity and mortality in A-T and ATM mutation analysis suggests a correlation between the presence of bi-allelic loss-of–function mutations and earlier onset of cancer, mainly hematological malignancies (R. Micol et al., manuscript submitted). Here we analyze the prevalence, histological subtype and outcome in A-T patients presenting with malignancies.

Two-hundred and fifty A-T patients born between 1954 and 2005 and included in the registry held by the French National Reference Center for Primary Immune Deficiencies (CEREDIH, manuscript submitted) were retrospectively analyzed. Clinical and histological data was extracted from the CEREDIH database.

Fifty-five patients (22% of the entire A-T cohort) presented with malignancies. Mean age at diagnosis of malignancy was 14.4 years (SD 9.8). Forty-nine patients (89%) presented with hematological malignancies and 6 (10.9%) with adenocarcinoma (3 mammary gland, 2 gastric, 1 thyroid). Hematological malignancies occurred earlier than carcinomas (mean 11.8 vs. 33.7 years respectively, p<001). High-grade Non-hodgkin lymphoma (NHL) was the most frequent hematological malignancy (31 patients, 56.3%) followed by Hodgkin's lymphoma (HL, 9 cases, 16.3%), acute lymphoblastic leukemia (ALL, 7 cases, 12,7%) and T-cell prolymphocytic leukaemia (T-PLL, 2 cases, 3.6%). Among NHL, 20 were of B-cell phenotype, including 4 cases of Burkitt's lymphoma. Three NHL were of T-cell phenotype and in 8 cases the phenotype was not available. Information on tumor staging was available for 18 NHL. Seventeen NHL were disseminated (Ann Arbor stage III/IV). Extranodal involvement was present in 14 NHL, absent in one case and unknown in 16. Six NHL (all B-cell) were EBV(+), 2 EBV(-) and in 23 cases the information was missing. Thirteen out of 14 NHL patients for whom treatment information was available received chemotherapy. Information on dosage was available for 11 patients. Five of them received a reduced dose. Three patients with ALL received chemotherapy including 1 who also received radiotherapy as part of conditioning for allogeneic HSCT. Of the 3 patients with carcinoma for whom information was available, 1 received chemotherapy only, one radiotherapy only and one both. Toxicity was recorded for 8 NHL patients (no toxicity in 2, hematological in 2, other in 4). Treatment response was recorded in 9 NHL patients (CR in 3, PR in 3 and no response in 3). Cause of death was recorded in 10 NHL patients: 7 patients died from tumor progression, 1 from infection and 2 from other causes. Mean survival after diagnosis of malignancy was 1.3 years for all histological subtypes. Comparison according to type of response to treatment showed that patients undergoing a major response had a longer survival than patients with minor or no response (mean survival 4.14 years for the former vs. 0.28 years for the latter, p<0.05).

Malignancy is a major contributor to morbidity and mortality in A-T, occurring in 22% of the present cohort. Hematological malignancies, mainly high grade B-cell NHL, are the most frequent cancers observed (56.3% of the observed malignancies and 12.4% of the patients in the cohort). EBV is associated with a noticeable proportion of high grade B-cell lymphomas, implying a possible contribution of the underlying immune deficiency in the pathogenesis of NHL during A-T. Tolerance to treatment including radiotherapy is variable. Despite poor overall survival, several patients underwent prolonged remissions and experienced improved survival. These results underscore the need to treat A-T patients with malignancies providing proper supportive care, including prevention and treatment of infections and mucositis. Further analysis of ATM mutations is required to determine if tolerance and response to treatment is correlated with the genotype.

No relevant conflicts of interest to declare.