Iron chelation therapy effective, safe in lower-risk myelodysplastic syndrome
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Iron chelation therapy with deferasirox conferred a clinically meaningful EFS benefit among transfusion-dependent patients with lower-risk myelodysplastic syndrome, according to results of a randomized phase 2 study published in Annals of Internal Medicine.
The treatment also exhibited a manageable safety profile.
“Myelodysplastic syndromes comprise a group of disorders characterized by bone marrow failure, cytogenetic and molecular alterations, and potential for progression to acute myeloid leukemia,” Emanuele Angelucci, MD, hematologist and clinical researcher at the National Institute for Cancer Research in Italy, and colleagues wrote. “Although specfic therapies, such as erythropoiesis-stimulating agents and growth factors, may alleviate anemia in some lower-risk patients, about 40% of patients with myelodysplastic syndromes require chronic red blood cell transfusions as supportive care.”
Clinical guidelines recommend iron chelation therapy for some patients with myelodysplastic syndrome (MDS), however, the clinical utility of this therapy remains subject to debate.
Angelucci and colleagues assessed EFS and safety of iron chelation therapy among 225 patients with low- or intermediate-1-risk MDS and serum ferritin levels greater than 2,247 pmol/L. The researchers randomly assigned patients to deferasirox dispersible tablets at doses of 10 mg/kg to 40 mg/kg daily (n = 149) or matching placebo (n = 76).
All patients previously received 15 to 75 packed blood cell units and had no severe cardiac, liver or renal abnormalities.
EFS — from randomization date to first nonfatal event related to liver or cardiac dysfunction or AML transformation or death — served as the primary endpoint.
Patients in the deferasirox group remained on treatment for a median 1.6 years (interquartile range [IQR], 0.5-3.5) vs. a median 1 year (IQR, 0.6-2) for the placebo group.
Results showed median EFS of 3.9 years (95% CI, 3.2-4.3) for the deferasirox group compared with 3 years (95% CI, 2.2-3.7) for the placebo group (HR = 0.64; 95% CI, 0.42-0.96). Median OS was 5.2 years (95% CI, 3.9-not evaluable) with deferasirox and 4.1 years (95% CI, 3-4.9) with placebo.
Adverse events occurred among 97.3% of patients in the deferasirox group and 90.8% of patients in the placebo group.
Researchers calculated exposure-adjusted incidence rates of adverse events, defined as 15 or more events per 100 patient treatment-years, among deferasirox vs. placebo recipients of 24.7 vs. 23.9 for diarrhea, 21.8 vs. 18.7 for pyrexia, 16.7 vs. 22.7 for upper respiratory tract infection and 15.9 vs. 0.9 for increased serum creatinine concentration.
Researchers acknowledged that the study’s conversion from a phase 3 to a phase 2 trial with a smaller target sample size served as a limitation.
“[This trial] was the rst prospective, placebo-controlled, randomized study to evaluate the clinical benefit of [iron chelation therapy] in iron-overloaded patients with low- or intermediate-risk myelodysplastic syndromes,” Angelucci and colleagues wrote. “The study was designed as a phase 3 trial, but slow enrollment prompted a reduction in patient recruitment; consequently, confirmatory, superiority hypothesis testing was no longer considered, and the objective of the study was amended to focus on assessing clinical benefit by evaluation of treatment effect. Nonetheless, patients who were randomly assigned to receive deferasirox experienced a clinically meaningful 36% reduction (95% CI, 4-58) in the [hazard ratio] of an event comprising the primary composite endpoint of EFS compared with placebo, with longer median EFS (approximately 1 year) vs. placebo.”
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