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This new study suggests that mitapivat may have a role in managing various hematological conditions like KLF1 mutation-related anemia, thalassemia, and other hemolytic conditions.

Human erythroid Krüppel-like factor 1 (EKLF or KLF1) plays an important role in erythroid development. Most patients with KLF1 mutation suffer from severe hemolytic anemia and require regular blood transfusions. These patients also have low pyruvate kinase-red blood cell (PKR) activity.

The study, shared at the proceedings of the 65th ASH Annual Meeting & Exposition, explores the impact of ex vivo mitapivat treatment on the terminal erythropoiesis characteristics of a severe hemolytic anemia patient with KLF1 mutations, aiming to assess parameters such as cell viability, oxidative stress, necrosis, and erythroid differentiation. 

Mitapivat Alleviates Oxidative Stress, Promoting Cell Viability

The patient under investigation, identified with compound heterozygous KLF1 mutations (Q58X, an unusual amino acid; and A298P, a missense mutation), exhibited typical markers of severe hemolytic anemia, including low hemoglobin levels, elevated reticulocyte count, and increased Hb F levels.

The study employed a three-phase primary erythroid culture system, tracking erythroblast transformation, expansion, and differentiation. Throughout the phases, a gradual decrease in erythroblast viability and an increase in intracellular reactive oxygen species (ROS) were observed during erythroid differentiation, indicative of the challenges in terminal erythropoiesis for this patient. Moreover, necrotic cell numbers increased during this process.

Intriguingly, ex vivo treatment with mitapivat mitigated these adverse effects, resulting in decreased intracellular ROS and necrotic cell numbers, ultimately promoting higher cell viability during terminal erythropoiesis.

The study further highlighted the positive influence of mitapivat on stage differentiation in terminal erythropoiesis. The treatment demonstrated a capacity to support effective stage differentiation, as evidenced by favorable changes in stage-specific erythroid markers (glycophoryn A (CD235a) and transferrin receptor (CD71)) compared to untreated differentiated erythroblasts. 

Hence, the findings suggest that ex vivo treatment with mitapivat holds promise for alleviating the challenges associated with terminal erythropoiesis in patients with severe hemolytic anemia due to KLF1 mutations. The observed reduction in oxidative stress, improved cell viability, and enhanced stage differentiation underscore the potential therapeutic value of mitapivat in this context.

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The Bottom Line

The study’s outcomes advocate for further exploration and evaluation of mitapivat as a potential treatment option for patients with severe hemolytic anemia due to KLF1 mutations. With ongoing clinical trials exploring mitapivat in various hematological conditions, including PK deficiency, thalassemia, and sickle cell disease, the study adds to the growing body of evidence supporting the drug’s potential efficacy in diverse erythropoietic disorders.


Suksangpleng, T. (2023, December 9). Ex Vivo Treatment By Mitapivat, an Allosteric Pyruvate Kinase Activator, Reduced Oxidative Stress and Promoted Terminal Erythropoiesis in a Severe Hemolytic Anemia Patient Due to Krϋppel-like Factor 1 Mutations. https://ash.confex.com/ash/2023/webprogram/Paper179130.html