Sant-Rayn Pasricha, MD, PhD, opened the Best of ASH session with a question: “How will you respond when your division chief asks, ‘What did you learn at ASH?’ Or when your patients ask, ‘What did you learn at your conference that could help my care?’” As he reflected on his Friday morning clinic filled with patients battling hereditary hemorrhagic telangiectasia (HHT), thrombophilia, hemophilia, and inherited red cell disorders, he emphasized the profound relevance of the insights presented during the meeting. This year’s Best of ASH highlighted breakthroughs in classical hematology that offer hope for improved patient outcomes across various conditions.
Breakthroughs in Hereditary Hemorrhagic Telangiectasia
Hanny Al-Samkari, MD, presented the results of a randomized, placebo-controlled, multicenter proof-of-concept study assessing the safety and efficacy of VAD044, an oral allosteric AKT1/2 inhibitor, as the first disease-modifying therapy for HHT (Abstract 553). HHT is the second most common inherited bleeding disorder, marked by severe epistaxis and vascular abnormalities. Results from the trial demonstrated that VAD044 significantly reduced epistaxis frequency and severity while increasing hemoglobin levels. Patients also reported visible regression of telangiectasia, suggesting a potential for long-term vascular remodeling. These findings represent a leap forward in managing a condition affecting many lives and mark a significant breakthrough in the management of HHT, offering hope and improved outcomes and quality of life for countless individuals affected by this condition.
Population-Scale Insights Into Thrombosis Risk
Sharjeel A. Chaudhry, MD, presented the results of a study using population-scale multiomic datasets to help further clarify the genetic underpinnings of thrombosis risk linked to protein S deficiency (Abstract 17). With data from more than 600,000 individuals, including participants from the UK Biobank and the National Institutes of Health’s All of Us Research Program, the study demonstrated a nearly 14-fold increased risk of venous thromboembolism (VTE) for carriers of severe PROS1 mutations. Relying on the same dataset, Justine Ryu, MD, presented the results of a study identifying both common and rare genetic factors, including novel variants and rare loss-of-function mutations in anticoagulant genes, that significantly influence VTE risk in individuals with factor V Leiden and prothrombin G20210A mutations (Abstract 18). This study highlights the potential role of the fibrinolytic system in improving patient risk stratification, paving the way for tailored interventions.
Continuing the trend of thrombosis risk as part of this year’s Best of ASH, Amelia K. Haj, MD, PhD, presented her team’s analysis of factor XII haploinsufficiency, which revealed a protective effect against VTE without increasing bleeding risk (Abstract 133). This discovery supports factor XII as a promising target for developing safer antithrombotic therapies.
Gene Therapy for Hemophilia
Gene therapy continues to revolutionize hemophilia treatment. Andrew D. Leavitt, MD, presented results from the phase III AFFINE trial, which found that giroctocogene fitelparvovec, a single-dose gene therapy, achieved sustained factor VIII expression, drastically reducing bleeding episodes in adults with moderately severe to severe hemophilia A (Abstract 1053). This transformative therapy offers patients a new level of independence and quality of life.
Advances in Inherited Red Cell Disorders
Fetal hemoglobin (HbF) reactivation emerged as a key therapeutic strategy for sickle cell disease (SCD) and beta-thalassemia. Franco Locatelli, MD, shared long-term data from a study on exagamglogene autotemcel, a CRISPR-Cas9-based therapy targeting the BCL11A enhancer (Abstract 512). More than 94% of study participants achieved transfusion independence with durable HbF levels, marking a functional cure for many patients. Matthew M. Heeney, MD, presented initial results from the phase I/II BEACON clinical trial, which evaluated the safety and efficacy of a single dose of autologous CD34+ base-edited hematopoietic stem cells in patients with SCD with severe vaso-occlusive crises (Abstract 513). BEAM-101, a base-editing therapy that achieves HbF induction comparable to hereditary persistence of fetal hemoglobin, led to reduced sickling and improved hemolysis markers. Early results suggest a powerful new approach to treating SCD.
Expanding Options for Thalassemia
Maria Domenica Cappellini, MD, presented results from the global, phase III, double-blind, randomized, placebo-controlled ENERGIZE-T trial, which evaluated the use of mitapivat, a pyruvate kinase activator, as a disease-modifying therapy for transfusion-dependent thalassemia (Abstract 409). Results showed a significant reduction in transfusion burden and improved quality of life, heralding a shift from transfusion dependence for many patients.
Final Thoughts: Bringing the Science to the Clinic
Reflecting on the session, Dr. Pasricha remarked, “When I go back to Melbourne and see my patients … I’ll be able to tell them about these incredible advances and give them hope for even better therapies in the future.” He highlighted how these breakthroughs — from VAD044 for HHT to gene-editing therapies for hemoglobinopathies — are not just academic triumphs but practical solutions poised to transform patient care.
When asked, “What did you learn at ASH?” you can confidently reply: “We are witnessing a revolution in therapies for HHT, hemophilia, and red cell disorders. The science presented this year will improve care and redefine what’s possible for patients worldwide.” These innovations, rooted in rigorous research and clinical trials, reflect the promise of classical hematology to deliver hope and tangible benefits to those who need it most.
