Impact on overall and progression-free survivals of iron chelation given 6 months after allogeneic hematopoietic stem cell transplantation for Acute Myeloid Leukemia and myelodysplastic syndrom

Abstract

Abstract Background The ferritin level appears to be a good biomarker of iron overload in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In allo-HSCT setting, some studies have shown that iron overload was associated with lower overall survival (OS), and that deferasirox, an oral iron-chelating agent, may have possible antileukemia effect. On behalf of the SFGM-TC, we conducted a prospective, interventional study on iron chelation, matched with retrospective data of non-chelated patients from the SFGM-TC registry. Objectives The study aimed to evaluate the impact of iron chelation therapy (deferasirox) on OS and progression free survival (PFS) from 6 months after allo-HSCT for AML and MDS. Methods The characteristics of the patients at inclusion were as follows: (1) in complete remission at 6 months after allo-HSCT for AML or with a blast cell count < 10% for MDS (2) with a ferritin level above 1,000 µg/L. All patients received deferasirox (7–10 mg/kg/day) starting 6 months after allo-HSCT until ferritin levels reached the target of 500 µg/L, unless intolerant to treatment. In parallel, we created a control group of allo-HSCT patients from the SFGM-TC registry and who did not receive iron chelation therapy. the control group was built using a propensity score matching (PSM) method, which balances between the two groups of patients potential confounding factors such as age, gender, type of hematological malignancy (AML/MDS), ELN or IPSS prognostic score, first/second allo-HSCT, allo-HSCT centre, kind of donor, HSCT source, type of conditioning and acute graft versus host disease (GVHD) grade. A 1:2 ratio (chelated vs non-chelated) with a calliper <= 0.18 was set. The analysis period began 6 months after allo-HSCT and continued until the end of the data availability period or until death. Time-to-event outcomes within the PSM population were analysed using the stratified log-rank method and Cox proportional hazard modelling. Sensitivity analysis were realized with an estimation of the e-value, and without PSM. Results A total of 41 AML/MDS patients treated by iron chelation were included between April 2015 and February 2022 from 7 allo-HSCT centres. The median age was 58 years (20-70), 66% were male, 85% had an AML, a majority of ELN 2010 intermediate-II score (76%), and a median ferritin level before and after allo-HSCT of 1529 (14-4157) and 1781 (1000-10 041) µg/L respectively. A control group of 82 patients from 950 AML/MDS allo-HSCT patients from SFGM-TC registry who did not receive iron chelation was built from PSM with a standard mean difference < 0.1 for each potential confounding factors. The median OS and PFS were not reached in either group. Cox multivariate model integrating chronic GVHD effect showed a trend of OS improvement (HR = 2.32, 95% CI [0.95-5.69], p = 0.065) but a significant improvement for PFS (HR = 2.27, 95% CI [1.04-4.93], p = 0.039). Sensitivity analyses without PSM showed a significant improvement of OS: HR = 2.88 (95% CI, [1.26-6.59]) and p=0.003, e-value=3.5 [lower limit of the CI, 1.6]) and of PFS: HR = 2.45 (95% CI [1.2-5]) and p=0.005, e-value=3.1 [lower limit of the CI, 1.6]) for patients who received iron chelation. The adverse events (AE) associated with iron chelation therapy were acceptable: acute renal failure (16.7%), diarrhea (7.1%), hepatic cytolysis (4.8%), nausea (4.8%), hepatic cholestasis (2.4%), hematuria (2.4%), headache (2.4%), and asthenia (2.4%). They were reported predominantly 3 months after the start of treatment and decreased gradually until the end of the treatment. The median duration of iron chelation was 12.5 (0.8-24.3) months. A reduction in dosage occurred in 9.5% of cases. Discontinuation due to an AE, followed by reintroduction, was observed in 12% of cases, and permanent discontinuation was observed in 33% of patients. The main reasons for permanent discontinuation were related to acute renal failure (n=4) and altered of renal biomarkers (n=4). Conclusion In our study we evaluated the use of deferasirox after allo-HSCT for AML/MDS and we demonstrated a significant benefice of iron chelation on PFS. The tolerance profile was acceptable, but special attention to renal function should be considered to modulate potentially the dose of deferasirox. This study reinforces the place of iron chelation in the therapeutic arsenal after-HSCT in AML/SMD patients.