Iron Overload Strongly Correlates with Acute Graft-Versus-Host-Disease of the Liver and Treatment Related Mortality after Allogeneic Hematopoetic Cell Transplantation (HCT).
Authors: Eisfeld Ann-Kathrin , Burkhardt Ralph , Teupser Daniel , Schroeder Sabine , Krahl Rainer , Junghans Andrea , Edel Elvira , Doehring Christa , Liebert Uwe G. , Niederwieser Dietger W. , Al-Ali Haifa K. 
Published: April 2020

Risk factors for morbidity and treatment related mortality (TRM) following HCT have been well defined in retrospective analysis and prospective validations. These include disease-, recipient- and donor-specific characteristics, but not treatment related factors. Considering that patients undergoing HCT usually receive multiple blood transfusions (BT) and that mutations of the HFE gene are common in the European population, we asked the question if iron overload and HFE mutations were risk factors for complications following HCT.

Patients and methods: From January 2001 to December 2004, 265 consecutive patients (142 m/123 f; median age 47 y) received HCT at the University of Leipzig. Patients suffered from acute leukaemia (n=113; 43%), chronic leukaemia (n=75; 28%), lymphoma (n=37; 14%), multiple myeloma (n=21; 8%), and others (n=19; 7%). Preparative regimen consisted of Cyclophosphamid 120 mg/kg and 12 Gy TBI in 145 (55%) patients. The remaining 120 (45%) patients were conditioned with Fludarabin 30 mg/m2/day for 3 days and 2 Gy TBI. HCT was performed from matched related donors in 85 (32%) and matched unrelated donors (MUD) in 180 (68%) patients. Patients and donors were screened for mutant HFE genes by PCR using LightCycler, Roche. Serum ferritin (reference values 30–400 ng/ml) was measured at a median of 1 month after HCT. At the time of measurement, patients had to be in good clinical condition with normal C-reactive protein.

Results: Elevated iron stores were present in 86% of patients (median ferritin 1697 ng/ml). At a median of 25 (range 7–55) months after HCT, 92 (35%) patients have died from relapse (n= 27; 29%) or TRM (n= 65; 71%). TRM occurred at a median of 4 months after HCT. Median ferritin in patients who died (measured at a median of 3 months prior to death) and in surviving patients were 3815 and 1146 ng/ml respectively (p&lt;0.0001). The median number of BT at HCT in the 2 groups were 34, and 16 unit respectively (p&lt;0.0001). MUD, CMV-serological status and the gender of the donor did not correlate with TRM. In multivariate analysis, ferritin and BT strongly correlated with TRM (p&lt;0.0001). Mutant HFE genes were found in 98 (37%) patients prior to HCT [heterozygous (het; n=82, 84%), compound (n=9; 9%), homozygous (homo; n=7; 7%). Similarly, 99 (37%) donors showed mutant HFE genes [het, n=86 (87%), compound, n=8 (8%), and homo, n=5 (5%)]. After HCT, all patients expressed donor HFE genotype. HFE genotype of patients and donors did not correlate with TRM. Acute GvHD &gt; grade II was significantly more in pts who died (p=0.0002). Acute GvHD of the liver strongly correlated with excess body iron (p=0.009). Interestingly, chronic GvHD of the skin and liver tended to be more frequent in patients with mutant HFE genes prior to HCT (p=0.03).

Conclusions: This is, to our knowledge, the first retrospective analysis where excess body iron and the number of BT at HCT strongly correlated with acute GvHD of the liver and TRM after HCT. These data must be confirmed in prospective studies. Whether morbidity and TRM after HCT can be reduced by iron chelation needs to be evaluated.