PB2231: RATIONALE FOR THE USE OF COMBINATION CHELATION THERAPY IN PATIENTS WITH THALASSEMIA SYNDROMES OR SICKLE CELL ANEMIA: A SYSTEMATIC LITERATURE REVIEW

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Background: Patients with thalassemia syndromes or sickle cell disease receiving regular blood transfusions may experience iron overload. Currently, 3 iron chelators are approved for clinical use: deferoxamine administered parenterally (DFO), oral deferiprone (DFP), and oral deferasirox (DFX). Combination therapy of DFP was approved by the European Medicines Agency in 2016, and recent British Society for Haematology guidelines state that DFP+DFX is highly effective. Combination therapy is commonly used in patients who do not adequately respond to monotherapy, have increased iron overload in the heart or liver, or have dose-dependent toxicity, but there is a need to understand which combination therapy to initiate, and when to do so. Aims: A systematic literature review was conducted to explore the use-rationale of 3 combination therapies (DFP+DFO, DFX+DFO, and DFP+DFX) in patients with thalassemia syndromes or sickle cell disease. Methods: A systematic search was performed of the Embase and MEDLINE databases to identify trials related to use of 3 combination iron chelation therapies (DFP+DFO, DFX+DFO, or DFP+DFX) in patients with thalassemia syndromes or sickle cell disease. The literature search was conducted in May 2021 and was not restricted to a specific start date. The search strings were established by logical association of appropriate words and MESH terms. Publications were screened based on a priori exclusion and inclusion criteria (eg, case-report exclusion). Use rationales were extracted from trial-inclusion criteria and patient-history data. Results: Of 1725 publications found in the search, 71 (prospective, 48 studies; retrospective, 23 studies) assessed combination chelation therapies in patients with transfusional iron overload. Half (35 studies) explicitly described the rationale for combination chelation therapy: DFP+DFO, 24 studies, 33.8%; DFX+DFO, 6 studies, 8.5%; and DFP+DFX, 5 studies, 7.0%. Reasons for initiating DFP+DFO included patients having elevated serum ferritin despite previous DFO therapy (9 studies, 12.7%); poor compliance to DFO (7 studies, 9.9%); elevated cardiac or liver iron content (5 studies, 7.0%); cardiac disease/complications (4 studies, 5.6%); and decreased left ventricular ejection fraction, assessment of sequential dosing, adverse events with DFP, and inadequate chelation with DFP (1 study each, 1.4%). Reasons for initiating DFX+DFO included elevated serum ferritin or severe liver or cardiac iron load despite previous use of monotherapy (DFP, DFO, or DFX) or combination therapy (DFP+DFO, DFX +DFO) (5 studies, 7.0%); adverse events due to elevated doses of unspecified monotherapy, agranulocytosis due to DFP in DFP+DFO combination, end-organ injury, and compliance issues with DFO (1 study each, 1.4%). Reasons for initiating DFP+DFX included severe serum iron load despite previous monotherapy (5 studies, 7.0%), of which 3 studies reported patients having elevated liver or cardiac iron and 2 studies noted DFP, DFO, or DFX monotherapy at the maximum tolerated dose. Summary/Conclusion: As expected, this systematic literature review of iron chelation combination therapy captured studies on DFP+DFO, with recent publications focusing on DFP+DFX. Most studies did not explicitly report the rationale for use. The most common reasons for combination therapy were severe iron overload despite previous chelation therapy, followed by compliance or toxicity concerns. A meta-analysis of available clinical evidence may provide insights to help standardize clinical practice for combination chelation therapy.

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