Managing Non-Transfusion-Dependent Thalassemia Presents Challenges

An essential factor in distinguishing thalassemia phenotypes is transfusion dependence.

While beta-thalassemia major requires life-long blood transfusions for survival, non-transfusion-dependent thalassemia usually only requires occasional transfusions, though some patients may require more frequent transfusions.

Non-transfusion-dependent thalassemia encompasses three clinically distinct forms — beta-thalassaemia intermedia, hemoglobin E/beta-thalassaemia (mild and moderate forms), and alpha-thalassaemia intermedia (hemoglobin H disease).

“In the beginning, it was considered a milder form of thalassemia because patients did not receive a lot of transfusions,” explained Ali Taher, MD, PhD, director of the Naef K. Basile Cancer Institute of the American University of Beirut Medical Center in Lebanon. “And we could splenectomize them and increase their hemoglobin.”

However, while patients who are transfusion dependent are very well controlled, non-transfusion-dependent thalassemia has become a more “malignant” disease, he told MedPage Today. “Our understanding of the disease has changed completely.”

For example, although splenectomy can effectively increase hemoglobin levels, and thus avoid transfusion, it can also make patients more susceptible to thrombotic and vascular events, as well as iron-related organ morbidity.

Taher and colleagues previously published results from the OPTIMAL CARE study — a retrospective review of 584 patients with beta-thalassemia intermedia — that identified specific complications believed to be more frequent with non-transfusion-dependent thalassemia, including thrombosis, pulmonary hypertension, extramedullary hematopoiesis, leg ulcers, and cholelithiasis.

In addition to concerns about these complications, Taher pointed out that patients with non-transfusion-dependent thalassemia are also susceptible to increased mental health issues, such as anxiety and depression.

Changing attitudes concerning how non-transfusion-dependent thalassemia should be managed resulted in updated guidelines (also co-authored by Taher) on the treatment of non-transfusion-dependent beta-thalassemia from the Thalassemia International Federation.

Take-home messages from the guidelines include:

• Patients with non-transfusion-dependent beta-thalassemia should be considered for interventions targeting ineffective erythropoiesis and anemia when hemoglobin levels are <10 g/dL
• Blood transfusions can be considered to manage anticipated drops in hemoglobin in acute clinical settings such as during acute infection, pregnancy, blood loss, or surgery
• Iron overload should be monitored and promptly treated to decrease morbidity risk and improve patient quality of life
• Long-term complications require close monitoring by a multidisciplinary team of specialists

Non-transfusion-dependent thalassemia can eventually evolve into transfusion-dependent thalassemia. “One should think of it as a spectrum — some patients require transfusions, some no transfusions, some moderate, and some many,” Taher said. “With age, and if not treated well, patients can start requiring transfusions. You might say they acquire ‘neo-transfusion-dependent thalassemia.'”

In a study presented at the 2023 American Society of Hematology annual meeting, researchers reported that of 94 patients with non-transfusion-dependent thalassemia who were referred to a comprehensive adult thalassemia program, 41 met the criteria to initiate a chronic transfusion program — a number that was significantly higher than previously published rates outside of the U.S.

“These findings indicate a critical need for thalassemia education of adult providers that emphasizes the importance of monitoring for early complications of non-transfusion-dependent thalassemia, as well as criteria for initiating a chronic transfusion program to mitigate complications and provide meaningful impacts in clinical outcomes,” the authors concluded in their abstract.

Preventing or delaying this process can be achieved, Taher said, with blood transfusions, iron chelation when needed, treatment of morbidities, bone marrow transplantation (if feasible), and treatment with novel therapies such as luspatercept (Reblozyl) or mitapivat (Pyrukynd).

In late 2019, the FDA approved luspatercept — an erythroid maturation agent administered subcutaneously every 3 weeks — for the treatment of anemia in adults with thalassemia who require regular red blood cell transfusions. In June 2020, a marketing authorization valid through the European Union was issued for luspatercept for the treatment of adults with transfusion-dependent beta-thalassemia.

Luspatercept has also been granted full marketing authorization by the European Union for non-transfusion-dependent thalassemia, based on data from the phase II BEYOND study, which showed that patients with non-transfusion-dependent beta-thalassemia treated with luspatercept maintained clinically meaningful and durable erythroid responses.

Specifically, 77.1% of patients in the luspatercept treatment arm achieved the study’s primary endpoint — a ≥1.0 g/dL increase in mean hemoglobin from baseline — versus no patients in the placebo arm (P<0.0001).

However, Bristol Myers Squibb, the drug’s developer, withdrew a supplemental biologics license application to the FDA for the indication of non-transfusion-dependent beta-thalassemia, noting that it “could not appropriately address” the FDA’s questions about the benefit-risk profile of luspatercept in this patient population based on the current data from the BEYOND trial.

In the meantime, the FDA has accepted a supplemental new drug application for mitapivat, a pyruvate kinase activator, for the treatment of patients with both transfusion-dependent and non-transfusion-dependent thalassemia, based on results from the ENERGIZE-T (transfusion-dependent thalassemia) and ENERGIZE (non-transfusion-dependent) trials.

Results from the ENERGIZE trial showed that mitapivat met the primary endpoint of hemoglobin response, defined as an increase of ≥1 g/dL in average hemoglobin concentrations from week 12 through week 24 compared with baseline, with 42.3% of patients in the mitapivat arm achieving a hemoglobin response compared with 1.6% of patients in the placebo arm (P<0.0001).

“Mitapivat is an oral drug, which is a major difference between the two [mitapivat and luspatercept],” said Taher, who was involved in the trials involving both drugs. “I think in the end we will have a menu where we will be using both agents, whether alone or in combination.”

However, up to 90% of patients live in less-developed countries where those drugs may not be readily available, he noted. “So, good transfusions and good chelation will remain the main treatments for these patients until these novel therapies are available to each and every patient.”

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