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Revisiting iron overload status and change thresholds as predictors of mortality in transfusion-dependent β-thalassemia: a 10-year cohort study

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Abstract

Data on iron overload status and change thresholds that can predict mortality in patients with transfusion-dependent β-thalassemia (TDT) are limited. This was a retrospective cohort study of 912 TDT patients followed for up to 10 years at treatment centers in Italy (median age 32 years, 51.6% female). The crude mortality rate was 2.9%. Following best-predictive threshold identification through receiver operating characteristic curve analyses, data from multivariate Cox-regression models showed that patients with Period Average Serum Ferritin (SF) > 2145 vs ≤ 2145 ng/mL were 7.1-fold (P < 0.001) or with Absolute Change SF > 1330 vs ≤ 1330 ng/mL increase were 21.5-fold (P < 0.001) more likely to die from any cause. Patients with Period Average Liver Iron Concentration (LIC) > 8 vs ≤ 8 mg/g were 20.2-fold (P < 0.001) or with Absolute Change LIC > 1.4 vs ≤ 1.4 mg/g increase were 27.6-fold (P < 0.001) more likely to die from any cause. Patients with Index (first) cardiac T2* (cT2*) < 27 vs ≥ 27 ms were 8.6-fold (P < 0.001) more likely to die from any cause. Similarly, results at varying thresholds were identified for death from cardiovascular disease. These findings should support decisions on iron chelation therapy by establishing treatment targets, including safe iron levels and clinically meaningful changes over time.

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Data can be made available upon reasonable request to the corresponding author.

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Acknowledgements

Members of the Webthal® project also include Valeria Pinto (Galliera Hospital, Genoa, Italy), Roberta Sciortino (ARNAS Garibaldi, Catania, Italy), Domenico Roberti (Università Vanvitelli, Napoli, Italy), Lucia De Franceschi (Università di Verona AOIU, Verona, Italy), Martina Culcasi (Azienda Ospedaliero Universitaria S. Anna, Ferrara, Italy), Valeria Orecchia (S.C. Centro delle Microcitemie e Anemie Rare, ASL Cagliari, Cagliari, Italy), and Carmen Maria Gaglioti (Hemoglobinopathies and Rare Anemia Reference Center, San Luigi Gonzaga University Hospital, Department of Biological and Clinical Sciences, University of Turin, Turin, Italy).

Funding

The study was funded by Pharmacosmos A/S, Denmark.

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Authors and Affiliations

  1. Center for Research On Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, United Arab Emirates

    Khaled M. Musallam

  2. S.C. Centro Delle Microcitemie E Anemie Rare, ASL Cagliari, Cagliari, Italy

    Susanna Barella

  3. Università Di Cagliari, S.C. Centro Delle Microcitemie E Anemie Rare, ASL Cagliari, Cagliari, Italy

    Raffaella Origa

  4. Hemoglobinopathies and Rare Anemia Reference Center, Department of Biological and Clinical Sciences, San Luigi Gonzaga University Hospital, University of Turin, Turin, Italy

    Giovanni Battista Ferrero

  5. Thalassemia Unit, ARNAS Garibaldi, Catania, Italy

    Roberto Lisi

  6. Centro Della Microcitemia A.Quarta, Hematology Unit, A. Perrino Hospital, Brindisi, Italy

    Annamaria Pasanisi

  7. Day Hospital Della Talassemia E Delle Emoglobinopatie, Azienda Ospedaliero Universitaria S. Anna, Ferrara, Italy

    Filomena Longo

  8. ForAnemia Foundation, Genoa, Italy

    Barbara Gianesin & Gian Luca Forni

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the Webthal® project

Contributions

Study conception and design: KMM, GLF. Data collection: SB, RO, GBF, RL, AP, FL, BG, GLF. Statistical analysis: KMM, BG. Review and interpretation of results: KMM, SB, RO, GBF, RL, AP, FL, BG, GLF. Manuscript drafting: KMM, GLF. Manuscript review for important intellectual content: SB, RO, GBF, RL, AP, FL, BG. All authors approved the manuscript before submission.

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Correspondence to Gian Luca Forni.

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An Ethics Committee approval was obtained at each participating center.

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Written informed consents for data collection and use were retrieved from all patients.

Competing interests

KMM reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. SB reports being on the advisory board of Vertex Pharmaceuticals and Bristol Myers Squibb and receiving speaker honoraria from Bristol Myers Squibb and Chiesi. RO reports being on the advisory board of Chiesi and Bristol Myers Squibb and consultancy fees from Vertex Pharmaceuticals and Bristol Myers Squibb. GBF reports consultancy fees from Bristol Myers Squibb, Agios Pharmaceuticals, FORMA Therapeutics, Vertex Pharmaceuticals. RL reports receiving speaker honoraria from Bristol Myers Squibb. AP reports receiving speaker honoraria from Bristol Myers Squibb. FL reports being on the advisory board of Vertex Pharmaceuticals and Bristol Myers Squibb. GLF reports receiving speaker honoraria and being on the advisory board Vertex Pharmaceuticals, Bristol Myers Squibb, Hemanext and Garuda Pharmaceuticals. The remaining authors have no relevant financial or non-financial interests to disclose.

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Musallam, K.M., Barella, S., Origa, R. et al. Revisiting iron overload status and change thresholds as predictors of mortality in transfusion-dependent β-thalassemia: a 10-year cohort study. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05715-x

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