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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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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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Does Mixed Chimerism After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients With Fanconi Anemia Impact on Outcome?
Ayas, M., Siddiqui, K., Al-Jefri, A., Al-Ahmari, A., Ghemlas, I., Al-Saedi, H., Al-Anazi, A., Khan, S., El-Solh, H., Al-Seraihi, A.
Transplantation and cellular therapy. 2021;27(3):257.e1-257.e6
Abstract
Fanconi anemia (FA) cells are characterized by genomic instability, which places FA patients at risk for malignancies such as leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT). Mixed chimerism (MC) in FA patients might have a unique implication because the persistent existence of FA cells might give rise to a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome according to chimerism status. Patients with FA who had evidence of progressive bone marrow failure and were blood products-transfusion dependent (packed red blood cells, platelets, or both) were included in the study. Those who had myelodysplasia (MDS) or an abnormal clone or evidence of leukemia were excluded. All but 3 patients had normal renal and cardiac function at the time of transplantation. In total, 160 patients with FA underwent allogeneic HCT at our center from January 1995 to December 2017; mean age at HCT was 8.4. Chimerism data at last follow-up visit were available on 97 patients who are the subjects of this analysis (no day +100 chimerism data on one of them). On day +100, 46 patients (47.9%) had full chimerism (FC) and 50 (52.1%) had MC, whereas at last follow-up 50 (51.5%) exhibited FC and the remaining 47 (48.5%) had MC. Cumulative incidence of all grades acute graft-versus-host disease (GVHD) was 13.4% and that of grade III to IV GVHD was 4.1%. Chronic GVHD was seen in eight (8.0%) patients. Incidence of severe acute GVHD (grade = III) and that of chronic GVHD were not significantly associated with FC or MC measured at day +100 (P values = .347 and .254, respectively), nor at the last follow-up. Graft failure occurred in 2 patients; both from the MC at day +100 group. No graft failures occurred in the FC at day +100 group (P value = 1.00). At a median follow-up of 83.8 months (95% confidence interval, 51.0-116.6; range, 19.3-181.1 months) the cumulative probability of overall survival (OS) at 5 years was 95.7% ± 2.1%. Mean follow-up time in our cohort was 90.7 months. Five-year overall survival was not significantly associated with FC or MC evaluated at day +100 (95.7% ± 3.0% versus 95.6% ± 3.1%, P value = .908) nor at the last follow-up (96.0% ± 2.8% versus 95.4% ± 3.2%, P value = .925). No patient in either group developed MDS/leukemia during the follow-up period. We conclude that mixed chimerism in patients with FA appears to have no adverse effect on outcome in our follow-up period. A longer follow-up period is needed, however, to confirm the validity of this statement.
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Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis
Yabe, M., Morio, T., Tabuchi, K., Tomizawa, D., Hasegawa, D., Ishida, H., Yoshida, N., Koike, T., Takahashi, Y., Koh, K., et al
International journal of hematology. 2020
Abstract
We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients [aplastic anemia (AA), n?=?118; myelodysplastic syndrome (MDS), n?=?30; acute leukemia, n?=?15] who underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (=?18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II-IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.
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Population frequency of Fanconi pathway gene variants and their association with survival after hematopoietic cell transplant for severe aplastic anemia
McReynolds, L. J., Wang, Y., Thompson, A. S., Ballew, B. J., Kim, J., Alter, B. P., Hicks, B., Zhu, B., Jones, K., Spellman, S. R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Severe aplastic anemia (SAA) is most frequently immune mediated, however, rare inherited bone marrow failure syndromes, such as Fanconi anemia (FA), may be causal, and can present as aplastic anemia (AA). FA is primarily an autosomal recessive disorder caused by having two pathogenic variants in a single FA/BRCA DNA repair pathway gene. Patients with SAA often undergo genetic testing during clinical evaluation that may identify single deleterious alleles in FA pathway genes. We quantified the rate of germline single deleterious alleles in 22 FA genes using both a general population database (3234 variants/125,748 exomes) and in a cohort of patients with SAA undergoing hematopoietic cell transplant (HCT) (21 variants/730 patients). The variants were classified as deleterious using in silico tools (REVEL, MetaSVM, VEP) and database resources (ClinVar, LOVD-FA). We found similar rates of single deleterious alleles in an FA genes in both groups (2.6 and 2.9%). The presence of a single deleterious variant in a gene for FA in SAA HCT recipients did not affect the overall survival after HCT (HR=0.85, 95% CI=0.37-1.95, p=0.71), or post-HCT cancer risk (p=0.52). Our results show that the identification of a germline monoallelic deleterious variant in an FA gene, in a patient with idiopathic SAA does not influence the outcome of HCT. Our findings suggest that there is no need for special treatment considerations for patients with SAA and a single deleterious FA allele identified on genetic testing.
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Chromosomal Aberrations and Survival after Unrelated Donor Hematopoietic Stem Cell Transplant in Patients with Fanconi Anemia
Wang, Y., Zhou, W., Alter, B. P., Wang, T., Spellman, S. R., Haagenson, M., Yeager, M., Lee, S. J., Chanock, S. J., Savage, S. A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism (SNP) arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991-2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research. For survival analyses, we used the Kaplan-Meier estimator to calculate the survival probabilities and the exact log-rank test to compare the survival differences across groups. Chromosomal aberrations were detected in 16 patients (22%); most frequent were: clonal copy-loss in chromosome 7 (9.6%), clonal copy-gains in the long arm (q) of chromosome 1 (chr1q+; 8.2%), and clonal or complete copy-gains in the q arm of chromosome 3 (chr3q+; 8.2%). Seven patients (9.6%) had alterations in 3 or more chromosomes. Poor post-HCT overall survival (OS) was noted in patients with chr3q+ (p=0.04), or those with abnormalities in ≥3 chromosomes (p=0.03). The 1-yr OS=0% vs. 45% in patients with either alteration versus its absence. No statistically significant differences in OS were noted in patients carrying deletions in chr7 (1-year OS=29% vs. 42%, respectively, log-rank p=0.74). The study is limited by the small sample size. A larger, prospective study is warranted to validate our findings in light of recent improvement in transplant modalities and outcomes.
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Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology)
Svahn, J., Bagnasco, F., Cappelli, E., Onofrillo, D., Caruso, S., Corsolini, F., De Rocco, D., Savoia, A., Longoni, D., Pillon, M., et al
American Journal of Hematology. 2016;91(7):666-71
Abstract
We analyzed 97 Fanconi anemia patients from a clinic/biological database for genotype, somatic, and hematologic phenotype, adverse hematological events, solid tumors, and treatment. Seventy-two patients belonged to complementation group A. Eighty percent of patients presented with mild/moderate somatic phenotype and most with cytopenia. No correlation was seen between somatic/hematologic phenotype and number of missense mutations of FANCA alleles. Over follow-up, 33% of patients improved or maintained mild/moderate cytopenia or normal blood count, whereas remaining worsened cytopenia. Eleven patients developed a hematological adverse event (MDS, AML, pathological cytogenetics) and three developed solid tumors. 10 years cumulative risk of death of the whole cohort was 25.6% with median follow-up 5.8 years. In patients eligible to hematopoietic stem cell transplantation because of moderate cytopenia, mortality was significantly higher in subjects transplanted from matched unrelated donor over nontransplanted subjects, whereas there was no significant difference between matched sibling donor transplants and nontransplanted patients. In patients eligible to transplant because of severe cytopenia and clonal disease, mortality risk was not significantly different in transplanted from matched unrelated versus matched sibling donor versus nontransplanted subjects. The decision to transplant should rely on various elements including, type of donor, HLA matching, patient comorbidities, impairment, and clonal evolution of hematopoiesis. Am. J. Hematol. 91:666-671, 2016. © 2016 Wiley Periodicals, Inc. Copyright © 2016 Wiley Periodicals, Inc.