Non-Transfusion-Dependent Thalassemia: An Image Gallery Worth a Thousand Words

Abstract

Our understanding of the molecular pathways and associated clinical presentations characterizing various thalassemia phenotypes has substantially improved over the years. Non-transfusion-dependent thalassemia (NTDT) refers to patients who present with mild–moderate anemia, which does not necessitate lifelong, regular transfusion therapy. This typically includes patients with β-thalassemia intermedia, mild–moderate hemoglobin E/β-thalassemia, and α-thalassemia intermedia (hemoglobin H disease) (Figure 1) [1-7]. The underlying α/non-α globin chain imbalance and subsequent ineffective erythropoiesis and peripheral hemolysis lead to chronic anemia, primary iron overload, and a hypercoagulable state. These, in turn, are associated with a range of clinical morbidities that can impact quality of life and lead to premature death (Figure 2) [2, 8-22]. In view of the growing evidence on the negative impact of untreated anemia in these patients, long-term management becomes key. However, the only options that have been available so far include transfusions which can worsen iron overload and introduce transfusion-dependence burden, off-label use of hydroxyurea based on data from small trials or observational studies, and splenectomy which is associated with increased risks of infections and thrombosis (Figure 3) [6, 9, 23, 24]. Beyond anemia, cumulative iron overload due to increased intestinal iron absorption needs to be regularly monitored and managed with iron chelation therapy. Multimorbidity in NTDT also requires close monitoring and early intervention through a multidisciplinary team approach (Figure 4) [2, 6, 25-27]. In the last decade, we have witnessed several novel agents being developed to manage anemia in NTDT. Agents targeting hepcidin dysregulation have not been successful in clinical trials, despite encouraging data in animal models. Luspatercept, an erythroid maturation agent, showed efficacy in improving hemoglobin level in adults with β-NTDT and is now approved in Europe (but not the United States). Mitapivat, a pyruvate kinase activator, has also shown efficacy in improving hemoglobin level and functional status in a recent phase 3 trials in adult patients with both α- and β-NTDT (Figure 5) [24, 28-30]. Clinical management guidelines are now available, but awareness of the various morbidities and treatment options in NTDT, especially among patients remains essential (a patient friendly summary is provided in the Appendix S1).

All authors contributed to conceptualization and manuscript drafting or critical review. K.M.M. was also involved in the creation of visualizations. All authors validated the manuscript and gave final approval for submission.

Ethics approval not applicable as no patients were involved in this work.

K.M.M. reports consultancy fees from Novartis, Bristol Myers Squibb (Celgene Corp), Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, Novo Nordisk, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. S.S. reports consultancy fees from Agios Pharmaceuticals, Bristol Myers Squibb, and Novo Nordisk; being a member of a clinical trial steering committee for Vertex Pharmaceuticals; and research funding (for clinical trials) from Agios Pharmaceuticals, Bristol Myers Squibb, Novo Nordisk, and Regeneron. T.D.C. reports advisory support to Agios Pharmaceuticals, Bristol Myers Squibb, and Chiesi. H.A.-S. reports consultancy fees from Agios Pharmaceuticals, Alnylam, Alpine, Amgen, argenx, Novartis, Pharmacosmos, and Sobi; and research funding to institution from Agios Pharmaceuticals, Amgen, Novartis, Sobi, and Vaderis. M.D.C. reports consultancy fees from Novartis, Bristol Myers Squibb (Celgene Corp), Vifor Pharma, and Vertex Pharmaceuticals; and research funding from Novartis, Bristol Myers Squibb (Celgene Corp), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. K.H.M.K. reports grants from Agios Pharmaceuticals and Pfizer; consulting fees from Agios Pharmaceuticals, Alexion Pharmaceuticals, Biossil, Bristol Myers Squibb, Forma, Novo Nordisk, Pfizer, and Vertex Therapeutics; honoraria from Agios Pharmaceuticals and Bristol Myers Squibb; and being on a data safety monitoring board/advisory board for Sangamo. V.V. reports grants from Agios Pharmaceuticals, Bristol Myers Squibb (Celgene Corp), DisperSol Technologies, IONIS Pharmaceuticals, Novartis, Pharmacosmos, The Government Pharmaceutical Organisation, and Vifor; and consulting fees from Agios Pharmaceuticals, Bristol Myers Squibb (Celgene Corp), DisperSol Technologies, IONIS Pharmaceuticals, Novartis, Pharmacosmos, and Vifor. A.T.T. reports consultancy fees from Novo Nordisk, Bristol Myers Squibb (Celgene Corp), Agios Pharmaceuticals, Pharmacosmos, and Roche; and research funding from Novo Nordisk, Bristol Myers Squibb (Celgene Corp), Agios Pharmaceuticals, Pharmacosmos, and Roche.