Both Pre- and Post-Allogeneic Stem Cell Transplant Ferritin Are Associated with Relapse: A Large Single Centre Retrospective Study

Introduction: Allogeneic hematopoietic cell transplantation (AlloHSCT) is a curative treatment for numerous hematological disorders. Transfusional iron overload continues to be a challenging complication in spite of advances in supportive care. Studies have shown that elevated ferritin is associated with reduced survival post AlloHSCT. In addition, ferritin is an acute phase protein which is heavily affected by inflammation such as that caused by infection and GvHD, making correlations with outcomes challenging. However, it remains unclear whether both pre- and post-AlloHSCT ferritin correlate with outcomes. Methodology: We conducted a retrospective analysis of 683 patients who underwent transplantation at Princess Margaret Cancer Centre in Toronto between January 2019 and December 2022. This analysis examined the impact of pre-and post-transplant ferritin on transplant outcomes. Four groups were formed according to approximately quartiles (Q1-Q4) using the first post-transplant ferritin (in µg/L). Group A: ferritin < 600, n=72. Group B: ferritin 601-1800, n=157 Group C: ferritin 1801-3600, n=103 Group D: ferritin >3600, n=228 The primary end point was the 3 year-overall survival (OS). Secondary end points were the non-relapse mortality (NRM) and cumulative incidence of relapse (CIR). Results: Among the 683 patients, the average age was 58 years (18-76). Of these patients, 154 (22.5%) received grafts from matched related donors, 328 (48.0%) from matched unrelated donors, 138 (20.2%) from haploidentical donors, and 63 (9.2%) from mismatched unrelated donors. Antithymocyte globulin (ATG) and post-transplant cyclophosphamide (ATG-PTCY) GvHD prophylaxis was given to 456 (66.8%) patients. Additionally, 107 patients (15.7%) received only ATG, while 103 patients (15.1%) received only PTCY. Median follow-up was 36 months. The median pre-transplant ferritin (PreTF) was 1155 (interquartile range [IQR] 366-2408). PreTF was not associated with survival (p=0.17) or NRM (p=0.84), but those patients who relapsed had a PreTF of 1433 (IQR 453-2888) vs 1062 (IQR 336-2245) for those who did not, p=0.02. Median PreTF was 1779 (IQR 655-3022) in those with Karnofsky Performance Scale (KPS) =< 90 vs 1032 (IQR 323-2245, p<0.001) in those with KPS>90; similarly, in those patients with HSCT-specific Comorbidity Index (HCT-CI) => 3, Pre-TF was 1436 (IQR 339-3169) vs 1032 (IQR 370-2200, p=0.003) for other patients. The first Post-TF was measured at a median of 125 days (n=561, IQR 77-272), and was 1832 (n=560, IQR 626-3654). Correlation with Pre-TF was r=0.08. In those patients that survived, median first Post-TF was 1391 (IQR 551-3279) vs those that did not, 2987 (IQR 1158-4475, p<0.001). The 3-year OS for the entire cohort was 64.5% (95% CI: 60.5-68.2), with a NRM rate of 17.0% (95% CI: 14.2-20.0). The incidence of chronic GVHD was 33.3% (95% CI: 29.5-37.2). The 3-year OS was highest in Group A at 82.4% (95% CI: 68.8-90.4), compared to 79.7% (95% CI: 71.1-85.9) in Group B, 73.3% (95% CI: 62.6-81.3) in Group C, and 60.1% (95% CI: 52.8-66.7) in Group D (p<0.0001). Higher ferritin adversely affected 1-year NRM, which was 16.0% (95% CI: 11.6-21.1) in group D, while it was 5.8% (95% CI: 2.4-11.6), 3.8% (95% CI: 1.6-7.7), 1.4% (95% CI: 0.1-6.7) in groups C, B, and A, respectively (p<0.0001). CIR at 3 years was also adversely correlated with higher ferritin; 3-year CIR was 30.5% (95% CI: 24.2-37.0), 30.4% (95% CI: 21.2-40.1), 19.4% (95% CI: 13.3-26.3) and 19.3% (95% CI: 10.4-30.1), for groups D, C, B, and A, respectively (p=0.015). There were no significant differences among the four groups in the incidence of grade II-IV acute GVHD (p=0.08); however, Group D exhibited a higher incidence Grade III-IV acute GvHD compared to the other groups, 11% (p<0.001). There was no association between first ferritin level and chronic GvHD. The incidence of graft failure was about 1% or for groups A, B and C, whereas it was 4.4% (95% CI: 2.2-7.6, p<0.001) for group D. Conclusion: The results confirm that higher first post-transplant ferritin is associated with higher NRM and lower OS. Moreover, relapse incidence and graft failure were adversely affected by higher first post-transplant ferritin. Further work is required to determine the significance and mechanisms of these findings.

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