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Predictors of outcomes in hematopoietic cell transplantation for Fanconi anemia
Cancio, M., Troullioud Lucas, A. G., Bierings, M., Klein, E., de Witte, M. A., Smiers, F. J., Bresters, D., Boelens, J. J., Smetsers, S. E.
Bone marrow transplantation. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) remains the only cure for the hematologic manifestations of Fanconi anemia (FA). We performed retrospective predictor analyses for HCT outcomes in FA for pediatric and young adult patients transplanted between 2007 and 2020 across three large referral institutions. Eighty-nine patients, 70 with bone marrow failure +/- cytogenetic abnormalities, 19 with MDS/AML, were included. Five-year overall survival (OS) was 83.2% and event-free survival (EFS) was 74%. Age ≥19, HLA mismatch and year of HCT were multivariable predictors (MVPs) for OS, EFS and treatment-related mortality (TRM). In the pediatric group, TCD was a borderline MVP (P = 0.059) with 5-year OS of 73.0% in TCD vs. 100% for T-replete HCT. The cumulative incidence of day 100 grade II-IV aGvHD and 5-year cGvHD were 5.6% and 4.6%, respectively. Relapse in the MDS/AML subgroup occurred in 4 patients (16%). Graft failure was seen in 9 patients (TCD 6/37 [16%]; T-replete 3/52 [5.7%]). Six patients developed malignancy after HCT. Survival chances after HCT for FA are excellent and associated with high engrafted survival and low toxicity. Age ≥19, HLA mismatch, year of transplant and 'TCD in the <19 years group' (although borderline) were found to be negative predictors for survival.
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[Stem Cell Transplantations for Patients with Fanconi Anemia: An Israeli Tertiary Center Experience]
Even-Or, E., Zaidman, I., Najajreh, M., Avni, B., Grisariu, S., Stepensky, P.
Harefuah. 2023;162(1):9-14
Abstract
INTRODUCTION Fanconi anemia (FA) is a rare genetic syndrome characterized by increased chromosomal breakage, congenital anomalies, bone marrow failure and an increased tendency to develop malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure and the hematologic malignancies these patients develop. Given the sensitivity of FA patients to chemotherapy and radiation, as to the clinical symptoms of graft versus host disease (GvHD), HSCT in these patients is challenging. Since the mid-nineties, HSCT for FA patients is performed in our center by using the fludarabine based reduced-intensity protocol. AIMS To summarize the results of HSCT for patients with FA using a fludarabine based reduced-intensity conditioning regimen at the Hadassah Medical Center. METHODS This retrospective research is based on the collection and analysis of clinical and laboratory data from the medical records of patients. RESULTS Since June 1996 up till February 2020, 39 patients with FA underwent 43 HSCTs with a fludarabine based protocol at the Hadassah Medical Center. Four patients required a second transplant due to primary engraftment failure. Nine patients (23%) suffered from acute GvHD, four of them severe. Eight patients (20%) developed chronic GvHD, two with an extensive and debilitating disease. Thirty-three (85%) of the patients survived and six died, five shortly after the transplant, and one twenty years later from malignancy. CONCLUSIONS Our results show high survival rates with low rates of engraftment failure and reasonable rates of GvHD. DISCUSSION As of today, there is an effective and safe treatment for patients with FA who require HSCT by using a fludarabine-based reduced-intensity conditioning regimen, with high survival rates and few complications.
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Fanconi anemia phenotypic and transplant outcomes' associations in Iranian patients
Ansari, F., Behfar, M., Naji, P., Darvish, Z., Rostami, T., Mohseni, R., Alimoghaddam, K., Salajegheh, P., Ahadi, B., Mardani, M., et al
Health science reports. 2023;6(4):e1180
Abstract
OBJECTIVES Fanconi anemia (FA) is a rare, heterogeneous, inherited disorder. Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis. This study reports the outcomes of FA-HSCT patients and identifies factors, including clinical phenotype. Our team examined more than 95% of Iranian FA patients during the last decade. STUDY DESIGN One hundred and six FA patients (age range: 2-41) who underwent HSCT from March 2007 to February 2018 were enrolled. Clinical characteristics of genetic disease, pre-HSCT findings, HSCT indication, and long-term follow-up evaluated and recorded. Data were analyzed using SPSS 19.0. RESULTS The mean follow-up period for survivors was 36 months (range, 1-101). The 3-year overall survival (OS) and disease-free survival were 72.2% and 71.2%, respectively. The 3-year OS rate for patients with limited and extensive malformations was 78.8% and 56.6%, respectively (p = 0.025). Acute graft versus host disease incidence was 60.52% for patients with limited malformations versus 70% for patients with extensive ones (p = 0.49). Chronic graft versus host disease incidence for these two groups was 9.21% and 10%, respectively (p = 0.91). CONCLUSIONS OS was not associated with each of the malformations singly; however, it was lower in the extensive group. The younger age of patients at the HSCT time leads to a higher OS. The differences in FA patients' outcomes and the various genotypes were probably related. These data provide a powerful tool for further studies on genotype-phenotype association with HSCT results.
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[Diagnosis status and genetic characteristics analysis of Fanconi anemia in China]
Li, N., Hu, D. X., Qin, X., Zhu, Y. P., Zhou, M., He, L., Chang, L. X., Xu, X. J., Dai, Y., Cao, X. Y., et al
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2023;61(10):889-895
Abstract
Objective: To analyze the clinical and molecular diagnostic status of Fanconi anemia (FA) in China. Methods: The General situation, clinical manifestations and chromosome breakage test and genetic test results of 107 pediatric FA cases registered in the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) and the Chinese Children Blood and Marrow Transplantation Registry Group (CCBMTRG) from August 2009 to January 2022 were analyzed retrospectively. Children with FANCA gene variants were divided into mild and severe groups based on the type of variant, and Wilcoxon-test was used to compare the phenotypic differences between groups. Results: Of the 176 registered FA patients, 69 (39.2%) cases were excluded due to lack of definitive genetic diagnosis results, and the remaining 107 children from 15 hospitals were included in the study, including 70 males and 37 females. The age at transplantation treatment were 6 (4, 9) years. The enrolled children were involved in 10 pathogenic genes, including 89 cases of FANCA gene, 7 cases of FANCG gene, 3 cases of FANCB gene, 2 cases of FANCE gene and 1 case each of FANCC, FANCD1, FANCD2, FANCF, FANCJ, and FANCN gene. Compound heterozygous or homozygous of loss-of-function variants account for 69.2% (72/104). Loss-of-function variants account for 79.2% (141/178) in FANCA gene variants, and 20.8% (37/178) were large exon deletions. Fifty-five children (51.4%) had chromosome breakage test records, with a positive rate of 81.8% (45/55). There were 172 congenital malformations in 80 children.Café-au-Lait spots (16.3%, 28/172), thumb deformities (16.3%,28/172), polydactyly (13.9%, 24/172), and short stature (12.2%, 21/172) were the most common congenital malformations in Chinese children with FA. No significant difference was found in the number of congenital malformations between children with severe (50 cases) and mild FANCA variants (26 cases) (Z=-1.33, P=0.185). Conclusions: FANCA gene is the main pathogenic gene in children with FA, where the detection of its exon deletion should be strengthened clinically. There were no phenotypic differences among children with different types of FANCA variants. Chromosome break test is helpful to determine the pathogenicity of variants, but its accuracy needs to be improved.
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5.
T-cell depleted allogeneic hematopoietic stem cell transplant for the treatment of Fanconi anemia and MDS/AML
Satty, A. M., Klein, E., Mauguen, A., Kunvarjee, B., Boelens, J. J., Cancio, M., Curran, K. J., Kernan, N. A., Prockop, S. E., Scaradavou, A., et al
Bone marrow transplantation. 2023
Abstract
The only curative approach for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising in patients with Fanconi anemia (FA) is allogeneic hematopoietic stem cell transplantation (HCT); however, HCT approaches are inconsistent and limited data on outcomes exist. We retrospectively evaluated outcomes of thirty patients with FA and MDS/AML who underwent first allogeneic HCT with a T-cell depleted (TCD) graft at our institution. Patients were transplanted on successive protocols with stepwise changes in cytoreduction and GVHD prophylaxis. All but two patients (93%) experienced durable hematopoietic engraftment. With median follow-up of 8.7 years, 5-year OS was 66.8% and DFS 53.8%. No significant differences in survival were found in patients with high-risk prognostic features (age ≥20 years, AML diagnosis, alternative donor graft) or when stratified by conditioning regimen. The 5-year cumulative incidences of relapse and NRM were 24.3% and 21.9%, respectively. NRM was higher in patients ≥20 years at HCT but did not otherwise differ. We herein demonstrate promising outcomes following allogeneic HCT for patients with FA and MDS/AML using TCD grafts, particularly in a cohort of high-risk patients with 50% ≥20 years and a majority receiving mismatched grafts. Future prospective studies are needed to compare this approach with other HCT platforms.
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Gonadal function in pediatric Fanconi anemia patients treated with hematopoietic stem cell transplant
Koo, J., Grom-Mansencal, I., Howell, J. C., Rios, J. M., Mehta, P. A., Davies, S. M., Myers, K. C.
Haematologica. 2023
Abstract
Gonadal dysfunction and reduced fertility are clinical manifestations well described in patients with Fanconi anemia (FA) and following hematopoietic stem cell transplantation (HSCT). It is difficult to differentiate gonadal dysfunction from the primary disease itself or from HSCT procedures. Therefore, it is important to manage expectations about gonadal failure and infertility for all patients with FA, regardless of HSCT status. We performed a retrospective analysis of 98 pediatric patients with FA who were transplanted between July 1990 to June 2020 to evaluate the incidence of gonadal dysfunction in female and male patients with FA. New onset premature ovarian insufficiency (POI) was diagnosed in a total of 30 (52.6%) patients. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were increased in patients diagnosed with POI. Anti-Mullerian Hormone (AMH) levels declined in POI patients after HSCT (r2 = 0.21, p = 0.001). Twenty (48.8%) male patients were diagnosed with testicular failure. FSH levels increased after HSCT even in patients without testicular failure (r2=0.17, p=0.005). Inhibin B levels decreased over time after HSCT in patients with testicular failure (r2 = 0.14, p = 0.001). These data indicate brisk decline in already impaired gonadal function in transplanted children with FA.
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7.
Outcomes in Hematopoietic Stem Cell Transplantation for Congenital Amegakaryocytic Thrombocytopenia
Cancio, M., Hebert, K., Kim, S., Aljurf, M., Olson, T., Anderson, E., Burroughs, L., Vatsayan, A., Myers, K., Hashem, H., et al
Transplantation and cellular therapy. 2022;28(2):101.e1-101.e6
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Abstract
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, inherited bone marrow failure syndrome. Hematopoietic stem cell transplantation (HSCT) is considered a curative treatment option, but existing descriptions of patient and transplant characteristics and outcomes after related and unrelated donor HSCT are sparse. We describe outcomes after HSCT for congenital amegakaryocytic thrombocytopenia (CAMT; n = 86) from 2000 to 2018. We conducted an analysis of data collected by the Center for International Blood and Marrow Transplant Research on patients with CAMT receiving therapeutic allogeneic HSCT. The predominant donor type was HLA-matched or mismatched unrelated donors (n = 58, 67%). The remaining included HLA-matched sibling (n = 23, 27%) and HLA-mismatched relative (n = 5, 6%). The predominant graft types were bone marrow (n = 53, 62%) and cord blood (n = 25, 29%). The median age at transplantation was 3 years, with 82 of 86 patients being transplanted aged ≤10 years. The 5-year graft failure-free and overall survival were 83% (95% confidence interval [CI], 74-90) and 86% (95% CI, 78-93), respectively. An examination for risk factors confirmed mortality was higher after HLA-mismatched relative and mismatched unrelated donor HSCT compared to HLA-matched sibling and matched unrelated donor HSCT (hazard ratio 3.52, P = .04; 75% versus 93%). The 1-year incidence of graft failure was 19% after HLA-mismatched HSCT (n = 32) compared to 7% after HLA-matched HSCT (n = 54, P = .15). Day-100 grade II-IV acute graft-versus-host disease was 13%, 26%, and 30% after HLA-matched sibling, HLA-matched and mismatched unrelated donor HSCT. The 5-year incidence of chronic graft-versus-host disease was 33% with 24 of 28 patients having received grafts from HLA-matched (n = 13) and mismatched unrelated (n = 11) donors. Although HLA-matched donors are preferred, HLA-mismatched donors also extend survival for CAMT.
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Etiologies of hearing loss in Fanconi Anemia
Karempelis, P., Greenlund, L., Gruhl, R., Dorrity, J., Wagner, J., Roby, B.
International journal of pediatric otorhinolaryngology. 2022;155:111068
Abstract
OBJECTIVES We aim to describe types of hearing loss associated with Fanconi anemia patients who underwent a bone marrow transplant (BMT) to identify possible etiologies of hearing loss. Additionally, we hope to investigate hearing loss early in life as a potential predictor of needing a BMT surgery. Fanconi anemia is a rare autosomal recessive disease that is the most common inherited bone marrow failure syndrome, characterized by bone marrow failure and multiple congenital anomalies, including hearing loss. This is the largest study to date reviewing types of hearing loss in patients with Fanconi anemia, specifically in those who have undergone BMTs. METHODS A retrospective chart review of patients diagnosed with Fanconi anemia at a single institution, tertiary, referral-based children's hospital with a bone marrow transplant team specializing in Fanconi anemia was conducted from 4/19/1976 to 10/19/2015. History, physical examination, audiometry, and imaging findings were reviewed in patients with and without history of bone marrow transplant. Patient hearing levels, as measured by pure tone audiometry at 500 Hz, 1, 2, and 4 kHz, were evaluated. Patients were grouped by transplant status and results and were assessed to determine type and degree of hearing loss. Statistical analysis was performed to compare the likelihood of bone marrow transplant procedures in Fanconi anemia patients with normal and abnormal hearing. RESULTS There were 252 patients with Fanconi anemia identified via diagnosis search in institutional electronic medical records using CPT codes and cross referencing with the Fanconi Anemia database, 58 of whom had available audiometric data. Of the 58 Fanconi anemia patients with available audiograms, 21 (36%) had abnormal audiograms; 37 patients had normal audiograms. Twenty out of 21 (95%) patients who had abnormal audiograms had undergone bone marrow transplants. Thirty-one of 37 (84%) patients with normal audiograms had received bone marrow transplants. Statistical analysis showed that patients with hearing loss were more likely to require a BMT in the future (OR = 3.87, p = 0.05). Of the patients with abnormal audiograms and a bone marrow transplant (n = 20), 14 (70%) had conductive hearing loss, 5 (25%) had mixed hearing loss, and 1 patient (5%) had sensorineural hearing loss. 13 of 20 patients (65%) had bilateral hearing loss and eight of 20 (40%) had unilateral hearing loss. Of those patients with conductive hearing loss (n = 15), the most common etiologies were Eustachian tube dysfunction (47%), external auditory canal stenosis (33%), and abnormal middle ear anatomy (13%). CONCLUSIONS Hearing loss is a common finding in Fanconi anemia patients who have undergone BMTs with conductive hearing loss being the most common audiologic manifestation in our cohort of patients. This demonstrates the necessity of frequent hearing screenings in this population and close collaboration with audiology throughout patient care. Our study indicates that hearing status early in life may be a predictor of needing a bone marrow transplant in the future. Further studies should explore the long-term impact of BMT surgery on hearing status.
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Two decades of stem cell transplantation in patients with Fanconi anemia: Analysis of factors affecting transplant outcomes
Fink, O., Even-Or, E., Avni, B., Grisariu, S., Zaidman, I., Schejter, Y. D., NaserEddin, A., Najajreh, M., Stepensky, P.
Clinical transplantation. 2022;:e14835
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Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for the hematological complications of patients with Fanconi anemia (FA). Over the last two decades, HSCT outcomes have improved dramatically following the development of regimens tailored for FA patients. In this study, we analyzed genetic, clinical, and transplant data of 41 patients with FA who underwent HSCT at Hadassah Medical Center between November 1996 and September 2020. Overall survival (OS) was 82.9% with a median follow-up time of 2.11-years (95% CI, .48-16.56). Thirteen patients (31.7%) developed acute graft-versus-host disease (GVHD), three of them with grades 3-4. Nine patients developed chronic GVHD, five had extensive disease. Twelve patients (29.3%) developed stable mixed-chimerism with complete resolution of bone marrow failure; none of them had acute nor chronic GVHD. Significantly higher GVHD rates were observed in transplants from peripheral blood stem cell grafts as compared to other stem cell sources (p = .002 for acute and p = .004 for chronic GVHD). Outcome parameters were comparable between HSCT from matched-sibling (n = 20) to other donors (n = 21), including survival rates (p = .1), time to engraftment (p = .69 and p = .14 for neutrophil and platelet engraftment time, respectively), chimerism status (p = .36 and p = .83 for full-donor and mixed chimerism, respectively), and GVHD prevalence (p = 1). Our results demonstrate the vast improvements in HSCT outcomes of patients with FA, narrowing the gap between matched-sibling versus alternative donor transplantations. Our data identify factors that may significantly affect transplant outcomes such as graft source and chimerism status. This article is protected by copyright. All rights reserved.
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Radiation-free Reduced-intensity Hematopoietic Stem Cell Transplantation with In-Vivo T-cell Depletion from Matched Related and Unrelated Donors for Fanconi Anemia: Prognostic Factor Analysis
Kiumarsi, A., Mousavi, S. A., Kasaeian, A., Rostami, T., Rad, S., Ghavamzadeh, A., Mousavi, S. A.
Experimental hematology. 2022
Abstract
OBJECTIVES Fanconi anemia (FA) is a rare and complex genetic disorder, clinically characterized by bone marrow failure, congenital defects, and cancer predisposition. Hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis after the occurrence of marrow failure or clonal hematopoietic abnormality. However, radiation exposure during transplant may increase the risk of later malignancies. In this retrospective study, we analyzed the results of HSCT with a radiation-free, busulfan-based conditioning regimen in FA patients. METHODS A total of 122 patients (median age, 8 years; range 2-18 years) with FA who underwent HSCT between January 2008 and January 2020 were enrolled in this study and followed up to the end of 2020. The preparative regimen included busulfan (0.2 mg/kg/day; day -9 to -6), cyclophosphamide (15 mg/kg/day; day -5 to -2), and in-vivo T-cell depletion with rabbit anti-thymocyte globulin. All patients received graft-versus-host disease (GvHD) prophylaxis with cyclosporine combined with methotrexate. We used Kaplan-Meier method, log-rank test, and Cox proportional hazards (PH) models to analyze the survival of the patients. RESULTS Peripheral blood, bone marrow and cord blood hematopoietic stem cells were used in 84 (68.9%), 31 (25.4%) and 7 (5.7%) patients, respectively. Donors were matched sibling in 48 (39.3%), matched other relative in 56 (45.9%), and matched unrelated in 18 (14.8%) patients. With a median follow up time of 24.25 months, graft rejection only occurred in one patient. The 1 and 5-year overall survival was 84.14% (95% CI: 76.02-89.70) and 82.16% (95% CI, 73.01-88.45), respectively. Among documented patient characteristics before transplant, presence of cardiopulmonary, genitourinary, central nervous system and limb malformations significantly impacted survival rates. CONCLUSION Our results show excellent outcomes in patients with FA undergoing HSCT with a radiation-free, busulfan-based conditioning regimen. It would be desirable that future studies will be aimed at optimizing the outcome of HSCT in FA patients.