Going, going, gone! As we brought down the curtain on #ASH24, the late-breaking abstracts provided a final burst of data. This year, they feature abstracts on novel mechanisms of erythrocytosis, two practice-changing trials in the management of lymphoma, and clinically informative trials in sickle cell anemia and venous thromboembolism (VTE).
First-up, Laurie H. Sehn, MD, MPH, presented the phase III inMIND trial (LBA-1), which evaluated adding tafasitamab, a humanized CD19-targeting antibody already approved in relapsed refractory (R/R) diffuse large B cell lymphoma, to lenalidomide plus rituximab (LR) in 548 R/R follicular lymphoma (FL) patients. FL is typically a relapsing-remitting disease involving multiple rounds of therapy, where a key goal is to prolong the treatment-free interval. The trial showed that the combination of tafasitamab and LR improved progression-free survival compared to placebo and LR (22.4 months vs. 13.9 months, respectively). Additionally, the overall response rate was higher in the tafasitamab group (83.5% vs. 72.4%), with comparable safety profiles, suggesting that this combination could become a new standard of care (SOC) for FL patients.
Continuing the theme was the EA4151 trial (LBA-6), which queried the current SOC approach of autologous hematopoietic cell transplantation (auto-HCT) in 650 patients with mantle cell lymphoma (MCL) in first remission. Those who had achieved undetectable measurable residual disease (MRD), assessed with a highly sensitive assay, were randomized to auto-HCT plus three years of maintenance rituximab (arm A) or rituximab alone (arm B). MRD-positive or indeterminate patients (arms C and D) received auto-HCT plus rituximab. “Our data indicate that, for patients who achieve [complete remission] with undetectable MRD (regardless of which induction regimen gets them to that point), auto-HCT offers no clear survival or PFS benefit,” said presenting author Timothy S. Fenske, MD. Is this a shift in treatment paradigms? “I think that this ushers in a new era in which auto-HCT will have a very limited role for MCL in first remission,” Dr. Fenske said.
It’s standard practice to advise indefinite anticoagulation in patients at high risk of VTE recurrence, which brings an increased risk of bleeding. Francis Couturaud, MD, PhD, presented the RENOVE study, which compared reduced-dose versus full-dose direct oral anticoagulants in high-risk patients with VTE (LBA-3). The findings provide objective data for this common clinical scenario. Among 2,768 patients followed for a median of 36 months, recurrent VTE occurred in 19 reduced-dose patients and 15 full-dose, resulting in failure to prove noninferiority for reduced-dose anticoagulation. Of note, clinically relevant bleeding and the composite outcome of VTE recurrence or bleeding were both lower in the reduced-dose group.
The DREPAGREFFE-2 trial provided 10-year follow-up from the original study (DREPAGREFFE-1) that compared allogeneic stem cell transplantation (alloSCT) to SOC in children with sickle cell anemia receiving chronic transfusions (LBA-5). “There is no doubt that early transplantation in children with sickle cell anemia offers them a better quality of life and social and professional integration into adulthood,” said presenting author Françoise Bernaudin, MD. The 10-year data confirmed that alloSCT continued to outperform SOC in improving patient outcomes, including reducing silent cerebral infarcts, enhancing cognitive function, and improving quality of life. “This study really underlines the importance of eradicating sickle red blood cells, as is the case in alloSCT,” Dr. Bernaudin said.
Finally, two abstracts outlined novel mechanisms of erythrocytosis. Betty Gardie, PhD, coined the term for a new condition: hepatic-like erythropoietin polycythemia. Through detailed analysis of six families exhibiting hereditary erythrocytosis with normal erythropoietin (EPO) levels, her laboratory discovered three non-coding mutations in regulatory regions of the EPO gene, which affect its response to hypoxia-inducible factor (HIF) 2 alpha (LBA-2). EPO from affected individuals displayed a distinct isoelectric focusing profile, resembling fetal liver-produced EPO rather than the kidney-derived EPO seen in adults. Functional studies revealed that this liver-type EPO has enhanced receptor signaling activity compared to kidney-type EPO, providing insight into the observation that hemoglobin levels drop rapidly after birth, concomitant with a shift in EPO production from the liver to the kidney.
Polycythemia vera (PV) and essential thrombocythemia (ET) are marked by chronic inflammation, driven in part by activation of nuclear factor-kappa beta (NF-κB), which augments HIFs and prothrombotic gene expression. The research of Jihyun Song, PhD, focused on understanding the high hematocrit found in Andean Aymara populations. She identified novel NFKB1 splice variants, which reduce NF-κB’s suppressive function and increase HIF activity (LBA-4). The NFKB1 rs230511 T allele, present in 90% of Aymara and approximately 30% of other populations, lowers inflammatory and HIF-targeted gene expression. In PV and ET patients, the T allele also correlated with reduced inflammation and thrombosis markers (e.g., IL1B, VEGFA, F3), while those with the CT genotype responded better to ropeginterferon alfa-2b (Ropeg) therapy. This study suggests that NFKB1 rs230511 may serve as a biomarker for predicting Ropeg efficacy and represent a novel therapeutic target.
“This study is the first to demonstrate a link between genetic variants associated with high-altitude adaptation and their role in pathological changes and therapeutic outcomes in PV and ET,” said Dr. Song, a research assistant professor at the Huntsman Cancer Institute at the University of Utah. “These findings suggest that the NFKB1 variant could serve as a valuable biomarker for inflammation and treatment responsiveness.”
As the ASH annual meeting concluded, these abstracts underscore the power of clinical and translational research in hematology to challenge longstanding practices and transform treatment approaches. See you next year!
