Introduction

A combination of two or more iron chelators may be considered for patients (pts) with transfusion-dependent thalassemia (TDT) who do not adequately respond to monotherapy (MT), have dose-dependent toxicity, or require a rapid decrease in their liver and/or heart iron overload. Combination chelation therapy has the advantage of targeting various iron pools and increasing overall iron excretion. It may also improve tolerability and adherence. Currently, 3 iron chelators are approved for clinical use: deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), all of them with comparable efficacy. Numerous studies have assessed the combination of DFP and DFO, however, evidence on combination of DFP and DFX is limited. Combination of DFP and DFX has shown effectiveness in pts who show limited response to MT. Additionally, this regimen may be more acceptable to pts considering both are oral chelators. In this systematic review, we aimed to assess the evidence regarding the efficacy and safety of combined DFP and DFX in pts with TDT.

Methods

A systematic search of the Embase and MEDLINE databases was conducted to identify studies (through May 28, 2024) related to the use of combination of DFP and DFX in pts with TDT. The publications were screened based on a priori criteria (Inclusion: prospective or retrospective interventional studies, including randomized or non-randomized controlled trials, crossover, open-label, and single-arm studies; all retrospective database, chart review, or real-world evidence studies. Exclusion: combination of iron chelator with non-chelator, congress abstracts, narrative reviews, economic analyses, pre-clinical studies, case reports, and cross-sectional studies). All studies meeting inclusion criteria from the title and abstract screening were reviewed in full.

Results

Of the 2069 articles retrieved, 13 studies (n=455) were included in this review. A total of 292 pts received the combination regimen of DFP and DFX.

Among the 13 studies, duration of treatment was ≤1 year in 9 studies , ≤2 years in 2 studies, variable (<1 year to >4 years) in 1 study, and >4 years in 1 study. In 11 studies, DFP was administered daily at 75-100 mg/kg/day (3 divided doses, 8 studies; 2 divided doses, 2 studies); 2 studies administered reduced dosage of DFP (mean: 54 mg/kg/day and 68.7 mg/kg/day, respectively). All studies used once daily DFX dosage of 20-40 mg/kg/day. In 1 study, DFP and DFX were alternated. Twelve studies reported reduction in serum ferritin from baseline, and 9 reported outcomes on liver and cardiac overload (significant reduction in liver iron [7 studies]; improvement in cardiac iron overload [7 studies]). One pilot pharmacokinetic study (n=13) reported an additive effect of DFP and DFX on the total iron excretion compared with MT.

Type and frequency of AEs reported with DFP and DFX combination were consistent with previously reported AEs for either MT; no new AEs were observed. Across studies, most common AEs reported were: gastrointestinal symptoms (8 studies; range, 6.2%-44%), elevation in creatinine (6 studies; range, 6.2%-84.8%), arthralgia (6 studies; range, 6.7%-44%), and elevation in alanine aminotransferase and/or aspartate aminotransferase (5 studies; range, 8.3%-48%). Three studies reported neutropenia (range, 10.4%-16.6%), and 2 reported transient thrombocytopenia (range, 6%-29%). Agranulocytosis was not observed. Two studies (n=105) reported 5 serious AEs (4 unrelated and 1 acute cholecystitis related to treatment) in 4 pts.

Overall, 6 studies (n=158) reported discontinuation of combination therapy in 21 pts (13.3%). Of these, 7 discontinued due to arthropathy associated with DFP and 1 discontinued due to neutropenia. Only 4 studies reported adherence, including 2 studies that compared adherence between DFP+DFX and other combinations. Adherence, defined as percentage of dose taken in relation to the prescribed dosage, was higher with DFP+DFX compared with other combinations, ranging from 60% to 95% across the 4 studies.

Conclusion

This systematic literature review suggests that combination of oral iron chelators DFP and DFX can effectively reduce overall iron overload from liver and/or heart without new safety concerns. Limitations include small sample size, variability in dosages, and nonrandomized patient population.

Disclosures

Kwiatkowski:Silence Therapeutics: Consultancy; Imara: Consultancy, Research Funding; CRISPR/Vertex: Consultancy, Research Funding; BioMarin: Consultancy; Agios: Consultancy, Research Funding; Vertex Pharmaceuticals: Consultancy; Forma Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Chiesi: Consultancy; Editas Medicine: Research Funding; Bristol Myers Squibb: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novo-Nordisk: Consultancy. Sheth:Bristol Myers Squibb (Celgene): Consultancy, Research Funding; Forma (now Novo Nordisk): Consultancy, Research Funding; bluebird bio: Consultancy; Chiesi: Consultancy; Fulcrum: Consultancy; Vertex Pharmaceuticals: Consultancy, Other: participation on a data safety monitoring board/steering committee; CRISPR Therapeutics: Other: participation on a data safety monitoring board/steering committee; CCO: Honoraria; PER: Honoraria; Plexus: Honoraria; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. Kattamis:Novo Nordisk: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Vifor: Consultancy; Pfizer: Consultancy; Vertex Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee Membership; Agios Pharmaceuticals: Consultancy, Honoraria. Bianchi:Chiesi Canada Corporation: Current Employment. Tricta:Chiesi Canada Corporation: Current Employment. Fradette:are full-time employees of Chiesi Canada Corporation: Current Employment. Luzzi:Chiesi Farmaceutici S.p.A.: Current Employment. Piga:Celgene (Bristol Myers Squibb): Other: Consultancy Fees, Research Funding; Acceleron: Research Funding; Apopharma: Research Funding; Chiesi: Research Funding; Novartis: Research Funding.

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2024
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