Bone Marrow Transplantation (2016) 51, 938–944 © 2016 Macmillan Publishers Limited All rights reserved 0268-3369/16 www.nature.com/bmt ORIGINAL ARTICLE Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors P Anur1, DN Friedman1, C Sklar1, K Oeffinger1,2, M Castiel3, J Kearney4, B Singh3, SE Prockop1, NA Kernan1, A Scaradavou1, R Kobos1, K Curran1, J Ruggiero1, N Zakak1,RJO’Reilly1 and F Boulad1,5 Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least 1 year post HSCT. Patients underwent either a TBI- (N = 18) or busulfan- (N = 4) based cytoreduction followed by T-cell-depleted transplants from alternative donors. Twenty patients were alive at time of the study with a 5- and 10-year overall survival of 100 and 84% and no evidence of chronic GvHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, 4 (22%) developed hypothyroidism, 7 (39%) had insulin resistance and 5 (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism and gonadal dysfunction after busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes. Bone Marrow Transplantation (2016) 51, 938–944; doi:10.1038/bmt.2016.32; published online 21 March 2016 INTRODUCTION patients with FA post transplant has been limited.4 Herein we Fanconi anemia (FA) is an inherited bone marrow failure report the late effects and long-term health among 22 patients syndrome characterized by chromosome fragility, constitutional with FA following HSCT at Memorial Sloan Kettering Cancer Center abnormalities and cancer susceptibility. Bone marrow failure can (MSK) with a median follow-up of 7.45 years. This represents lead to marrow aplasia with severe aplastic anemia (SAA), one of the largest reports of late effects in patients with FA myelodysplastic syndrome (MDS) and/or AML. Allogeneic hema- undergoing HSCT. topoietic stem cell transplantation (HSCT) is the only curative option for the hematological manifestations of this disease. In the past decade, cytoreductive regimens including fludarabine and PATIENTS AND METHODS T-cell-depleted grafts have improved the overall survival (OS) in FA We performed a single-institutional, retrospective review of long-term after allogeneic transplants from alternative donors.1,2 Long-term outcomes of patients with FA who underwent HCST at MSK from March survival rates in this group now range from 50 to 70%.1,2 Although 1999 to December 2012. Data collection was approved by the MSK HSCT can restore long-term hematopoiesis and cure the Institutional Review Board/Privacy Board. Clinical and laboratory data were abstracted from the MSK medical records. hematologic complications of patients with FA, these patients do not always recover to complete health. The inherent defective DNA repair in somatic lineages predisposes them to cancers and Patient characteristics an increased susceptibility to complications of HSCT, affecting Thirty-eight patients with a diagnosis of FA, confirmed by diepoxybutane their long-term survival. Indeed, in addition to long-term testing, received an allogeneic HSCT from alternative donors during this complications of HSCT, patients with FA may have disease- time period. Among these 38 patients, 22 patients who underwent first 4 specific complications such as endocrinopathies and increased transplantation from an alternative donor and survived 1 year post risks for squamous cell carcinoma (SCC). In order to improve transplant were eligible for inclusion in this study. Patient characteristics are summarized in Table 1. Age at transplant ranged from 5.4–35.6 years overall outcomes and further increase survival rates, it is necessary (median: 12.1 years): 8 patients were younger than 10 years of age; to better understand the long-term complications in patients with 8 patients were between 10 and 17 years; and 6 patients were older than FA following HSCT. 18 years of age at the time of transplant. Hematologic diagnoses at the Late effects after HSCT and recommendations for follow-up time of HSCT were SAA (N = 11), MDS (N = 6) and AML (N = 5). All patients have been reported in pediatric patients.3 However, the data for with MDS and AML were transplanted with active disease and without 1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Department of Psychiatry, Memorial Sloan Kettering Cancer Center, New York, NY, USA and 5Department of Pediatrics, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA. Correspondence: Dr F Boulad, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. E-mail: [email protected] Received 18 June 2015; revised 29 January 2016; accepted 1 February 2016; published online 21 March 2016 Late effects in patients with FA after HSCT P Anur et al 939 GvHD prophylaxis included tacrolimus or cyclosporine. G-CSF was started Table 1. Patients characteristics on Day +7 for all patients to promote engraftment. T-cell depletion, single- dose TBI, PBSC collection and supportive care methods were previously N =22 described.2 Neutrophil engraftment, primary graft failure, chimerism, MDS, fi 2 Gender AML and GvHD were de ned as previously described. Female 14 Male 8 Long-term follow-up care All 22 patients were seen for comprehensive long-term follow-up in the FA Complementation group MSK Pediatric Survivorship/long-term follow-up (LTFU) clinic, which follows A11patients who have survived at least 1 year after completion of therapy. C2 Patients received risk-based comprehensive care according to COG LTFU D2 1 Guidelines6 either annually or biannually. All FA patients also underwent G3 annual head and neck cancer screening exams, and adult female patients Other—unknown 5 underwent gynecologic evaluation. Female patients also received three doses of quadrivalent human papilloma virus vaccine (HPV) after immune Age at HSCT (years) Median 12.1 reconstitution. Range 5.4–35.6 Patients were evaluated by physical exam and laboratory evaluation at each visit. All patients had a serum ferritin measurement drawn at the Hematologic diagnosis initial visit, before transplant, and periodically after transplant with at least SAA 11 one measurement at one year post-transplant follow-up. Liver iron – MDS 6 concentration was measured using T2*-MRI (normal range: 0.17 1.8 mg/g AML 5 dry weight of liver) using a 1.5 T magnetic resonance imaging (MRI) machine. MRI measurement of liver iron concentration was based on Prior treatment imaging of proton transverse relaxation rates (T2*) within the liver. Thyroid Androgens 15 function was evaluated using thyroid-stimulating hormone and free T4. 420 red blood cell transfusions 7 Glucose homeostasis was measured using fasting or 2 h postprandial glucose and insulin levels. Blood glucose levels were classified according to 7 Conditioning regimen American Diabetic Association recommendations. Insulin resistance was TBI/Flu/Cy 18 defined by homeostasis model assessment-estimated insulin resistance Dose of TBI (450 cGy) (HOMA-IR) Index, where HOMA-IR = {[fasting insulin (μU/mL)] × [fasting Bu/Flu/Cy 4 glucose (mgL/dL)}/405; with the denominator of 405 serving as a normalizing factor. HOMA-IR values above 2.6 (75th percentile) were 8 Donor N (%) considered diagnostic of insulin resistance. Gonadal function was Unrelated matched 9 evaluated by levels of follicle-stimulating hormone (FSH) and luteinizing Unrelated mismatched 5 hormone; early-morning testosterone was measured in males to assess Related mismatched 8 Leydig cell function and clinical information on menstrual regularity was abstracted on postpubertal females. Elevated FSH levels (415 mIU/mL) Follow-up (years) were consistent with ovarian dysfunction or male germ cell dysfunction. Median 7.4 Ovarian failure was defined as ovarian dysfunction requiring hormone TBI cohort 9.1 replacement therapy, or elevated FSH levels (415 mIU/mL) with pubertal Bu cohort 2.8 arrest or clinical amenorrhea. Leydig cell dysfunction was defined as Range 2.3–15.3 elevated luteinizing hormone levels (415 mIU/mL) with low morning testosterone levels (o250 ng/dL) in a sexually mature male. Abbreviations: Bu = Busulfan; Cy = cyclophosphamide; FA = Fanconi anemia; FLU = fludarabine; HSCT = hematopoietic stem cell transplantation; MDS = myelodysplastic syndrome; SAA = severe aplastic anemia. Statistical analysis Patient demographic data are reported as range, mean and median values. Survival rates were calculated using Kaplan–Meier method, censoring at time of last contact using SPSS (IBM, Armonk, NY, USA). For Student’s t-test, a P-value of o0.05 was considered significant. Disease-free survival pretransplant chemotherapy. Fifteen patients (68%) had received fi androgens and 7 patients received 420 blood transfusions prior to was de ned as survival with absence/resolution of hematologic disease transplantation. (SAA, MDS or AML). Transplant characteristics RESULTS Patients and donors were HLA typed for HLA-A, -B, -C, DRB1 and DQB1 Transplant outcome using high-resolution typing. Unrelated donors (N = 14) were matched The median follow-up for the 22 patients included in this study (N = 9) or mismatched (N = 5) at one antigen (N = 1) or greater than one – antigen (N = 4; A,DQ – C,DQ – B,C – B-C). Related donors (N = 8) were was 7.45 years (range: 2.28 15.33 years).