A Phase 2 Prospective Study Evaluating Low-Dose Deferasirox in Patients with Low-Risk Myelodysplastic Syndrome Resistant or Relapsing after Erythropoietin Stimulating Agents (LODEFI)

Introduction: There is still an unmet medical need for patients with low riskmyelodysplastic syndrome (MDS) who are refractory or relapsing to erythropoietin stimulating agents and transfusion dependent. Transfusion burden leads to iron overload needing iron chelation therapy. In vitro data from our team demonstrate that low dose of deferasirox (DFX) (3µM) induced MDS erythroid progenitors proliferation by decreasing oxidative stress (Meunier al, Oncotarget 2017). Several case reports from patients under iron chelation therapy have already shown an improvement of hemoglobin level. Thus, we initiated a multicenter study named LODEFI, prospectively assessing the potential benefit of low dose deferasirox on transfusion burden for low risk MDS patients.

Methods: This is a single arm, multi-center, open-label, Phase II trial for patients with very low, low and intermediate myelodysplastic syndrome according to IPSS-R and WHO 2016 classification, refractory or relapsing to erythropoietin stimulating agents, with low transfusion burden and ferritin level under 1000 µg/l.Deferasirox 3.5mg/kg was given orally every day for 12 months. Baseline patient characteristics and biology including iron metabolism data were collected. Primary endpoint was the efficiency of low dose DFX on transfusion dependence at one year from the beginning of DFX, defined by the need of 2 and more red blood cells units per 8 weeks on 3 time periods of 8 weeks (24 weeks), from the 6th to the 12th month of the beginning of DFX. Some of the secondary endpoints were to assess the impact of low dose DFX on transfusion dependance (TD) defined as a transfusion burden of more than 4 red blood cells units every 8 weeks on an evaluation period of 24 weeks and to evaluate the clinical and biological tolerability of low dose of DFX in this population of patients.

Results: Between February 2018 and April 2023,thirty-eight patients were enrolled with a median age of 73.5 years (interquartile range (IR): 69.0-78.0 years). Of these, 57.9% were male and the median Charlson index was 4 (IR: 3-5). MDS subtype were: MDS-SLD (8), MDS-RS (14), MDS-MLD (8), CMML-1 (1), MDS EB-1 (3) and MDS-U (4). The IPSS-R categories for the patients were very low (16), low (19) and intermediate (1), NA (2). The median hemoglobin level at inclusion was 86 g/L (IR: 81- 97) and the median ferritin level was 547µg/L (IR: 399; 849). The baseline biological parameters in MDS-RS versus the other MDS subtypes were: a lower median hemoglobin level (84g/L vs 88g/L), a higher median transferrin saturation (80% vs 50%, p=0.005) with a tendency for higher median non-transferrin-bound iron (NTBI) level (1.49 vs 1.00µmol/L), and a lower median hepcidin level (3.5ng/ml vs 16.4ng/ml, p=0.007). The majority of patients (86.8%) were considered non-TD according to IWG 2018 and 13.2% were low transfusion burden. All patients had received ESA prior to deferasirox. All patients received DFX at inclusion at 3.5mg/kg. Residual dosages of DFX were done at month 1 (M1) to adapt the dosage at M3 to reach around 3µM. The dosage of DFX was decreased in 26.3% of patients (mainly in MDS-RS patients) and increased in 15.8% of them. The primary objective was met: we observed a transfusion independence (TI) at 12 months in 47.4% (CI-95%: 31.0%; 64.2%) of the patients treated by DFX. If we used a more stringent definition of transfusion dependence described in secondary endpoints, we observed a TI at 12 months in 68.4% (CI 95%: 51.3%; 82.5%) of the patients treated by DFX. TI rate according to primary endpoint was numerically lower in MDS-RS than in the other types of MDS (28.6% vs 58.3%). Low dose DFX was also well tolerated (mainly grade 1 to 3 digestive, auditive renal adverse reactions), with only one diabetic patient having overdose of DFX and renal and hepatic impairment leading to DFX discontinuation.

Conclusion: Low dose DFX induces 47.4% of transfusion independency at M12 in low risk MDS anemic patients refractory or relapsing to ESA, with a favorable tolerance profile. It could be a potential treatment option for anemia in selected MDS patients who are refractory or relapsing to ESA and with low transfusion burden.

Meunier:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Alexion: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Speakers Bureau. Ame:Novartis: Consultancy, Speakers Bureau. Park:Janssen: Research Funding; BMS/Celgene: Honoraria, Other: Travel Support & Meetings, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Other: Travel Support & Meetings, Research Funding.