Alter, Blanche P.

Abstract We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Abstract Abstract 4213 INTRODUCTION Fanconi Anemia (FA) is a primarily autosomal recessive disorder with a defective DNA repair pathway associated with mutations in any of 13 genes. The majority of patients reported in the literature have one or multiple congenital anomalies, including low birth weight, short stature, café au lait spots, abnormal radii and/or thumbs, structural renal abnormalities, microcephaly, and deafness, among others. About 25% of reported patients had few or none of these findings. The hazard of severe aplastic anemia peaks at 10 years of age, and patients have very high risks of acute myeloid leukemia and specific solid tumors, such as head and neck and gynecologic squamous cell carcinomas. Only six patients have been reported who were diagnosed between 40 and 50 years of age. However, patients may present as adults with neoplasms, or remain asymptomatic and undiagnosed. METHODS We report the diagnosis of FA in the oldest known patient, an asymptomatic 55 year old woman (Case 2), identified only because she was a potential stem cell donor for her 42 year old sister (Case 1) with severe aplastic anemia. RESULTS Case 1 had a history of thrombocytopenia at 26, and anemia and thrombocytopenia during pregnancy; physical exam was normal except for a slightly deformed thumb; blood lymphocyte chromosome aberrations were increased with both diepoxybutane (DEB) and mitomycin C (MMC). The patient died following an HLA-matched bone marrow transplant from a non-FA brother. Case 2, the other of two siblings of Case 1 who were HLA matches, had higher than normal chromosome breakage in blood (3 cells with multiple radials with MMC) but not in the FA range; skin fibroblasts were diagnostic of FA, confirming hematopoietic somatic mosaicism. She had a normal appearance, a history of hypothyroidism and mitral valve prolapse, five pregnancies with five children (one miscarriage, one set of twins), a near normal blood count (Hb 13.3 g/dl, MCV 99 fl, WBC 3500/ul, and platelets 139,000/ul), and was a regular blood donor. Bone marrow cellularity and morphology were normal, but cytogenetics showed a small clone (46,XX,add(11)(q23)[6]/46,XX[14]). Complementation analysis of Case 1 indicated group A (FA-A), and molecular analysis identified two mutations in the FANCA gene. One mutation, p.S1208S (c.3624C>T) was a splice site mutation occurring in exon 36 and has been previously described. The second mutation was a novel nonsense mutation in exon 23, p.S674X (c.2021C>A). Five siblings had normal breakage results; four were heterozygous for the nonsense mutation and one was negative for both mutations. Case 2, with mosaicism for FA, had the familial splice mutation in both blood and fibroblasts, and the familial nonsense mutation in fibroblasts, but was skewed heavily toward wild-type in blood. cDNA studies confirmed that the predicted splice mutation created an alternate splice site resulting in multiple transcripts, including exon skipping, which varied in different tissues. The molecular mechanism for the loss of the nonsense mutation in the blood is most likely due to back mutation at a hot spot, which occurred in a hematopoietic stem cell which then had a selective growth advantage. CONCLUSIONS Reversion of one FANCA mutation probably occurred in a hematopoietic stem cell which was selected for and repopulated the peripheral blood. A plausible explanation for the lack of FA clinical features is the leaky splice mutation which may provide sufficient levels of protein for normal function in DNA repair. Family members should be tested for FA by chromosome breakage analysis in blood (and/or fibroblasts to identify those who may be mosaics). Those who have FA are at risk of syndrome-specific solid tumors, as well as aplastic anemia, myelodysplastic syndrome, and leukemia, if a non-gene corrected hematopoietic stem cell were to emerge. Even if asymptomatic, they should not be used as stem cell transplant donors for siblings with FA, because they may fail to repopulate the recipient marrow. FA is undoubtedly underdiagnosed in adults at this time. Disclosures: No relevant conflicts of interest to declare.