Transfusion independence in thalassemia patients after failure of gene therapy or with hemoglobin h constant spring and hb e using luspatercept: A case series

Abstract Background: Individuals with thalassemia who depend on blood transfusions to maintain adequate hemoglobin levels are at high risk of sequelae resulting from frequent blood products. As such, there is increased interest in decreasing transfusion frequency for such patients and limiting side effects. Luspatercept is a recombinant fusion protein that enhances erythropoiesis by binding to select TGF-b ligands and can increase hemoglobin for patients with thalassemia. Luspatercept use was associated with significantly greater reductions in transfusion burden than for the placebo group for transfusion-dependent b-thalassemia (TDT) patients in the BELIEVE trial. Luspatercept was also associated with a significant increase in hemoglobin level among non-transfusion-dependent beta thalassemia (NTDT) in the BEYOND trial. However, currently, there is very limited evidence for the utility luspatercept in thalassemia patients after a failed gene therapy or among those with alpha thalassemia. Here we describe two cases with significant clinical response to luspatercept achieving transfusion independence in distinct thalassemia populations that have not yet been reported in the literature. Case 1: This patient underwent LentiGlobin gene therapy for b-thalassemia (β0/β0) at the age of 34 years in 2015. Prior to gene therapy, she required regular packed red blood cell (pRBCs) transfusions every 4 weeks. After admission for gene therapy per protocol HGB-204, her transfusion needs initially decreased to every 6 to 9 months. However, she was not able to fully wean off transfusions which slowly increased in frequency to every 3 months. She began treatment with luspatercept at the age of 42, and has maintained hemoglobin levels above 10 g/dL without need for a blood transfusion for almost two years since then. Case 2: This patient was diagnosed with hemoglobin H Constant Spring and homozygous HbE by hemoglobin electrophoresis and hemoglobinopathy genetic testing (c.427T>C , Hb Constant Spring; c79G>A, HbE). Up to her third decade of life, she was requiring regular pRBCs transfusions every 3-4 weeks with a pre-transfusion hemoglobin goal of 9-10 g/dL. She also had evidence of significant iron overload due to her transfusion frequency and suboptimal adherence to iron chelation (maximum liver iron content (LIC) of 16.4 mg/g dry weight) with a normal cardiac T2* (42.7 +/- 2.6 msec). She started treatment with luspatercept at the age of 30 years and her transfusion needs soon decreased and she achieved transfusion independence for more than 2 years with occasional transfusion only every 18 months. Concurrently, she was weaned off iron chelation around two years following initiation of luspatercept with an LIC of <3.5 and a ferritin of less than 500 ng/mL. She continues to be on luspatercept with no tolerability issues. These two patient cases demonstrate that luspatercept can also reduce transfusion needs or achieve independence following gene therapy or in alpha thalassemia. Other case reports have previously explored the potential clinical benefits of luspatercept in other settings. Our cases add to the existing experiences by elucidating possible novel applications of luspatercept to additional thalassemia populations. Our findings suggest that luspatercept can successfully increase and stabilize baseline hemoglobin for these patients, and thus could represent a safe and efficacious long-term disease-modifying therapy option for transfusion-dependent alpha thalassemias and patients who failed or had a suboptimal or incomplete response to gene therapy. Further research, including prospective studies and/or randomized trials, will be necessary to evaluate these indications for luspatercept on a larger study population in the future.