Researchers at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition shared significant progress in treating non-malignant blood disorders, specifically sickle cell disease (SCD) and immune thrombocytopenia (ITP). Several studies highlighted new therapeutic options and improvements in patient quality of life.
Rilzabrutinib for Refractory Immune Thrombocytopenia
A Phase III trial (LUNA 3) evaluated rilzabrutinib, a first-in-class oral Bruton tyrosine kinase inhibitor, in adults with persistent or chronic ITP who had not responded to previous treatments. The study, involving 202 participants, showed that 23% of patients on rilzabrutinib achieved a durable platelet response, defined as a platelet count of 50x109/L or higher for at least 8 of the final 12 weeks of the 24-week blinded period, without needing rescue therapies, compared to 0% in the placebo group.
David J. Kuter, MD, DPhil, from Massachusetts General Hospital, noted, "The drug is highly active in a highly refractory group of patients... In addition to raising platelet counts, bleeding events decreased significantly and quality of life improved." The drug also demonstrated a rapid response, with improvements observed within 15 days.
Rilzabrutinib's mechanism of action involves reducing platelet-targeting autoantibodies, decreasing platelet destruction by macrophages, and inhibiting B cell activation and inflammatory pathways. Common adverse events were mild and included diarrhea, nausea, headache, and abdominal pain. The study was funded by Sanofi, the maker of rilzabrutinib.
Etavopivat Reduces Pain Episodes in Sickle Cell Disease
New findings from a Phase II clinical trial of etavopivat, an experimental drug for SCD, revealed a significant reduction in vaso-occlusive crises (VOCs). The trial enrolled 60 adolescents and adults with SCD, who were randomized to receive either 200 mg/day of etavopivat, 400 mg/day of etavopivat, or a placebo for 52 weeks. Results showed that participants taking etavopivat experienced nearly half the number of VOCs compared to those on placebo.
Julie Kanter, MD, from the University of Alabama at Birmingham, stated, "The results are very encouraging. We see a reduction in VOCs, an improvement in overall hemoglobin, and a decrease in hemolysis, as well as some early improvements in important patient-reported outcomes like fatigue." Participants on etavopivat also showed improvements in hemoglobin levels, with 38% of those taking the 200 mg dose and 25% of those taking the 400 mg dose experiencing an increase of over 1 g/dL from baseline to week 24, compared to 11% in the placebo group.
Etavopivat is designed to improve red blood cell health by enhancing energy dynamics and oxygen retention. The study was funded by Novo Nordisk. A Phase III trial is currently underway in the United States, with plans for a second global Phase III trial.
Hydroxyurea Benefits in Hemoglobin SC Sickle Cell Disease
A Phase II clinical trial (PIVOT) in Ghana assessed the use of hydroxyurea in patients with the hemoglobin SC (HbSC) variant of SCD. While the study did not meet its primary endpoint related to hematologic toxicities, it provided valuable insights into the morbidity of HbSC and the potential of hydroxyurea as a disease-modifying therapy.
Yvonne Dei-Adomakoh, MBBS, from the University of Ghana Medical School, noted, "Hydroxyurea was well tolerated by most patients with HbSC, with hematologic dose-limiting toxicities that were typically mild and transient. We also observed laboratory and clinical benefits, including fewer VOCs and hospitalizations." Participants taking hydroxyurea showed improvements in red blood cell volume and fetal hemoglobin levels, as well as reduced VOC rates and hospitalizations.
Fertility Preservation in Sickle Cell Disease
A retrospective study of 46 individuals with SCD undergoing fertility preservation found the procedures to be safe when performed by a multidisciplinary team of SCD and reproductive endocrinology experts. While complications were more common than in the general population, they were manageable. The study highlights the importance of ensuring access to fertility preservation for individuals with SCD, especially those considering curative therapies that may impact fertility.
Marti Goldenberg, DO, from Johns Hopkins University School of Medicine, emphasized the need for patients to understand the risks and benefits of fertility preservation. The study found that VOCs and unplanned transfusions were the most common complications, particularly in patients with a history of frequent VOCs.
Base-Edited Gene Therapy for Sickle Cell Disease
Initial results from a Phase 1/2 clinical trial of BEAM-101, a novel base-edited gene therapy for SCD, showed promising outcomes. The first seven patients treated experienced a robust response, with high production of fetal hemoglobin and no VOCs post-engraftment. This trial marks the first use of base editing, a high-precision gene-editing approach, in SCD patients.
Matthew M. Heeney, MD, from Dana-Farber/Boston Children's Cancer and Blood Disorders Center, described the therapy as a potentially transformative treatment for SCD. BEAM-101 targets the promoter sequence of fetal hemoglobin genes, reactivating fetal hemoglobin production and silencing the disease-causing sickle hemoglobin. All patients showed successful engraftment, increased total hemoglobin production, and stabilized or reduced red blood cell breakdown. One patient, however, died of respiratory failure likely related to busulfan conditioning.
These studies, presented at the ASH Annual Meeting, represent significant advancements in the treatment of SCD and ITP, offering new hope for improved outcomes and quality of life for patients with these conditions.
