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O.Steinberg-Shemer et al.
between the age of the first event of MDS and the age of the first event of leukemia; however, both MDS and leukemia were diagnosed significantly earlier relative to solid tumors (P=0.001 and P<0.001, respectively) (Figure 2A). Seven patients developed two cancers, three patients developed three cancers, and two patients developed four cancers.
Figure 2. Cumulative incidence (CI) by age for adverse events in patient with Fanconi anemia (FA). (A) CI by age of first cancer. Myelodysplastic syndrome (MDS) – blue; leukemia – red; solid tumors – green. MDS and leukemia events both appeared significantly earlier than solid tumors (P=0.001 and P<0.001, respectively). No significant difference was found between the age of first event of MDS versus leukemia; (B) CI of HSCT. (C) CI of solid tumors for patient who underwent hematopoietic stem cell transplantation (HSCT) (blue) or did not have a transplant (red). No significant difference was found between the groups.
Hematopoietic stem cell transplantation
Approximately half of the patients with FA in the reg- istry (n=59) underwent a HSCT; seven of the patients underwent a second transplant. The median age for the first transplant was 9.3 years (range: 0.45-30.8) (Figure 2B). Indication for HSCT was MDS/leukemia in 15 patients; the rest (n=44) were transplanted due to BMF. 25% were transplanted in the 1990s, 39% in the years 2000-2009, and 36% between 2010-2017. No association was found between a history of HSCT and incidence of solid tumor or age of first cancer (Figure 2C). Solid tumors were reported in six non-transplanted patients and in four trans- planted patients, of which two were transplanted due to MDS/leukemia and the other two due to BMF. Among the four transplanted patients, the median time from trans- plant until solid tumor diagnosis was 10 years (range: 2.5- 18). The five patients with at least three events of cancer had no previous HSCT.
Survival
Currently 65 of the 111 patients (59%) in the cohort are alive with a median age of 16.5 years (range: 0.8-37). Forty-three patients have died, and three were lost to fol- low-up. The median age of death was 11 years (range: 0.1- 49). Causes of death were mostly cancer related (23 patients; 53%) or transplant-related (11 patients; 25%). 64% of transplanted patients are alive, and 56% of non- transplanted patients are alive and no significant (NS) dif- ference was found in the age of death between transplant- ed and non-transplanted patients. The 5-year survival of the post-HSCT cohort was 44%, and 10-year post-HSCT survival was 27%. Among the transplanted patients, 78% of those transplanted due to BMF are alive, while only 27% of those transplanted for MDS/leukemia are alive.
Genotype
Genetic analysis was performed on 94 patients (85% of the cohort), of which 88 patients (94% tested) reached a genetic diagnosis. The majority were found to have muta- tions in the FANCA gene, followed by mutations in FANCG, FANCC, FANCJ, and FANCD1 (Figure 3). The six undiagnosed patients had an incomplete genetic analysis performed. Of these, two siblings were found to have a heterozygous mutation in FANCC (Table 4).
Table 2. Congenital anomalies of patients with Fanconi anemia in Israel.
A
B
C
Anomaly
Any anomaly
Café-au-lait spots
Renal structure
CNS structure
Hearing loss
Congenital heart disease Male genitourinary
Radial ray Gastrointestinal structure Spine
Cleft lip/palate
N=111
100 (90.1%)
58 (52.3%) 44 (39.6%) 21 (18.9%) 20 (18%) 18 (16.2%) 18 (16.2%) 18 (16.2%) 9 (8.1%)
6 (5.4%)
2 (1.8%)
Anomalies as reported in patient charts. CNS: central nervous system.
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