HFE Genotype Is of Donor Origin and Does Not Correlate with Iron Overload Present in Patients after Allogeneic Stem Cell Transplantation.
Authors: Eisfeld Ann-Kathrin , Burkhardt Ralph , Teupser Daniel , Schroeder Sabine , Krahl Rainer , Junghans Andrea , Edel Elvira , Doehring Christa , Thiery Joachim , Niederwieser Dietger W. , Al-Ali Haifa K. 
Published: October 2019

Abstract
Introduction: A substantial proportion of European populations (10–40%) are heterozygous carriers (het) and 0.1–0.3% homozygos (homo) for the hemochromatosis gene (HFE). Patients (pts) with hematologic malignancies often receive multiple blood transfusions (BT). 228 pts undergoing allogeneic stem cell transplantation (SCT) at the University of Leipzig and their donors were screened for HFE. Furthermore, HFE genotype after SCT and body iron stores were correlated with BT and GVHD.
Pts and methods: 228 pts (125 m/103 f; median age 46 years) transplanted from Jan, 2001-May, 2004 and their donors [related, n=72 (31.6%); unrelated, n=156 (68.4%)] were screened for HFE. Diagnosis was acute leukemia and MDS in 126 (55%), chronic leukaemia in 51 (23%), lymphoma in 23 (10%), aplastic anemia in 5 (2%), and others in 23 (10%) pts. The majority of pts (n=120; 52.6%) received 12 gray TBI and Cyclophosphamid 120 mg/kg as preparative regimen. ATG 15 mg/kg for 3 days was given to recipients of unrelated SCT. 108 ( 47.4%) pts received Fludarabin 30 mg/m2 for 3 days and 2 gray TBI. 93 pts [36 (38.7%) had a related and 57 (61.3%) an unrelated donor] surviving SCT at least 4 months were further assessed. HFE analysis was performed before and after SCT by PCR techniques using LightCycler, Roche. Serum (s.) iron, transferrin, and ferritin were measured according to IFCC recommendations. Normal iron, transferrin, and ferritin values were 9.5–29.9 μmol/l, 1.9–3.6 g/l, 30–400 ng/ml respectively.
Results: Before SCT, HFE mutations were found in 83 (36.4%) pts. 77 pts were het (52 for H63D, 16 for C282Y, 3 for S65C, 6 compound). 6 pts were homo for HFE (5 for H63D and 1 for C282Y). No correlation was found between HFE type and diagnosis. Similarly, mutations were demonstrated in 88 (38.6%) donors. 84 donors were het (50 for H63D, 18 for C282Y, 9 for S65C, 7compound). 4 donors were homo (2 for H63D, 2 for C282Y). After SCT, all 93 (100%) pts for whom data are available expressed donor HFE. Median s. iron, transferrin, and ferritin were 20 μmol/l (range 3.8 – 64.3 ), 1.7 g/l (0.6 – 3), and 952 ng/ml (32.7– 6832.4) respectively. 83 (89.2%) pts showed excess body iron. Median number (no.) of BT was 22 units (range 0–109). In multivariate analysis, median ferritin strongly correlated with the no.of BT (p<0.0001), older age (p=0.0001), and acute leukemia (p=0.0003). Body iron stores did not correlate with HFE genotype prior to or after SCT. Interestingly, acute GVHD of the liver grade I-III present in 8 (8.6%) and isolated SGPT/SGOT elevations seen in 51 (54.8%) pts tended to correlate with iron stores (p=0.06, p=0.1 respectively).
Conclusions: 1)Mutations of the HFE were detected in a substantial proportion of donors and pts 2)HFE was always of donor origin after SCT 3)The majority of surviving pts after SCT have markedly increased body iron stores correlating with the no.of BT 4)There seems to be a correlation between iron stores and hepatic GVHD and abnormal liver function after SCT. The influence of iron stores on short- and long-term morbidity and mortality after SCT needs further study. 5)The effect of removal of excess iron by phlebotomy after SCT on GVHD and liver function is currently being assessed.