Since its inaugural meeting in 1958 in Atlantic City, where more than 300 hematologists first gathered, ASH has been at the forefront of advancing hematology and fostering the development of countless generations of hematologists. This legacy continues to thrive, with the 2024 meeting bringing together more than 30,000 attendees who filled the streets, venues, and waterfronts of San Diego with vibrant energy (or participated virtually), echoing the spirit of that first gathering. As the meeting wraps up, it leaves behind a treasure trove of new data — sparking fresh possibilities and setting the stage for the next wave of innovation in research and clinical practice. While major breakthroughs often capture the spotlight, the true value of this year’s research lies in the steady, incremental progress that it embodies — embracing change while remaining firmly anchored in the enduring momentum of scientific continuity. Let’s take a closer look at some of the most compelling abstracts in malignant hematology, as presented by 2024 Scientific Program co-chairs Jennifer Trowbridge, PhD, and Sant-Rayn Pasricha, MD, PhD, at the Best of ASH session.
Unveiling the Secrets of Clonal Hematopoiesis
Clonal hematopoiesis (CH) arises from somatic mutations in hematopoietic stem cells (HSCs), with mutations in genes like TET2 and DNMT3A conferring a competitive advantage to certain clones, potentially contributing to myeloid malignancies and age-related conditions. However, the mechanisms driving this clonal expansion remain unclear. A novel approach explored in Abstract 188 uses CRISPR-Cas9 with unique molecular identifiers to track the size and number of HSC clones more precisely. This enhanced screening identified Ncoa4, a gene crucial for the growth of TET2-deficient HSCs. Investigators showed that Ncoa4 mediates ferritinophagy, a process that breaks down ferritin to release iron, thereby fueling mitochondrial energy production and supporting the growth of these mutant cells.
In Abstract 25, investigators uncovered a noncanonical role for DNMT3A in regulating telomere length and telomerase activity in HSCs. This discovery challenges the prevailing view that the role of DNMT3A in CH is primarily through DNA methylation, suggesting instead that it also maintains HSC fitness by regulating telomere stability. These findings offer new insights into the mechanisms underlying CH.
Reviving Telomeres in Dyskeratosis Congenita
Leveraging telomere biology, Abstract 443 offers a potential therapeutic approach for dyskeratosis congenita (DKC), a disorder characterized by bone marrow failure and an increased risk of myeloid malignancies. DKC is caused by insufficient TERC, a key component of the telomerase complex that maintains telomere length. The investigators developed an engineered TERC that functionally integrates into human telomerase, with the potential to robustly extend both the replicative lifespan and telomere length in patient-derived stem cells. This innovative approach could open the door to novel ex vivo cell therapies for treating telomere-related disorders.
Novel Approach to Treating Acute Myeloid Leukemia
The study detailed in Abstract 953 used a targeted protein degradation approach to uncover a mechanism that maintains stemness in high-risk acute myeloid leukemia (AML). In AML, a higher proportion of stem-like cells is linked to poor prognosis. The study focused on a subset with chromosome 3 inversion that overexpresses MECOM, a key transcription factor for HSCs. By degrading MECOM, the team revealed that it represses a critical cis-regulatory element in the CEBPA gene, maintaining the stem-like state in AML cells. Activating this element promoted differentiation and reduced leukemia burden, highlighting a promising therapeutic target for patients with high-risk AML.
CAR-T: A New Hope for Myeloproliferative Neoplasms
Myeloproliferative neoplasms (MPNs), driven by mutant calreticulin (mutCALR) and a fibrotic tumor microenvironment, present significant treatment challenges. Abstract 871 introduces a chimeric antigen receptor T-cell (CAR-T) therapy that selectively targets mutCALR HSCs at both high and low allele frequencies. This CAR-T therapy depleted 40 to 90% of CD34+ hematopoietic stem and progenitor cells from 12 patients with MPN with minimal impact on JAK2 V617F+ cells. Additionally, CAR-T showed strong efficacy in 3D human bone marrow organoid models, marking the first use of organoids to test immunotherapies in a relevant tumor microenvironment.
Intercepting Smoldering Multiple Myeloma
High-risk smoldering multiple myeloma (SMM) carries a significant risk of progression to active multiple myeloma, and, until now, no approved treatment has been available. Results from the AQUILA study (Abstract 773), presented at ASH and published in The New England Journal of Medicine, demonstrated that daratumumab significantly reduces the risk of progression and improves survival compared to active monitoring. In this phase III randomized trial, 390 patients were randomized to receive either daratumumab or active monitoring. After a median follow-up of 65.2 months, daratumumab reduced the risk of disease progression or death by 51%. At five years, 63.1% of patients on daratumumab remained progression-free, compared to 40.8% in the active monitoring group, with survival rates significantly higher (93% vs. 86.9%). These results have the potential to change the way we manage high-risk SMM in clinical practice.
Targeted Therapy Breakthroughs
Seeking to combine aspects of different treatment paradigms for chronic lymphocytic leukemia, investigators involved in the multicenter, open-label, randomized phase III AMPLIFY trial (Abstract 1009) found that combinations of acalbrutinib and venetoclax with or without obinutuzumab, in a fixed duration of 14 cycles, led to superior progression-free survival (PFS) compared to the investigator’s choice of fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab, while maintaining a manageable side-effect profile. Additionally, investigators involved in an international randomized controlled trial (Abstract 235) demonstrated that ibrutinib and rituximab outperformed chemoimmunotherapy (such as the regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated older adults with mantle cell lymphoma in terms of PFS, reduced hematological toxicity, and improved quality-of-life scores. This combination is now considered a standard-of-care treatment for this patient population.
Transforming the Standard
The investigators behind Abstract 524 sought to blaze a new trail in the treatment of transformed indolent non-Hodgkin lymphoma (tiNHL), a condition for which no consistent standard of care has been established. The study explored the safety and efficacy of CD19 CAR-T therapy in this population and compared results retrospectively to those of patients receiving CD19 CAR-T for relapsed/refractory aggressive large B-cell lymphoma (aLBCL). The investigators found that patients with tiNHL receiving CD19 CAR-T had higher complete response rates compared to de novo aLBCL, with comparable PFS and overall survival. Additionally, patients with tiNHL had a slower onset of cytokine release syndrome, a lower incidence of immune effector cell-associated neurotoxicity syndrome (iCANS), and reduced use of glucocorticoids for managing iCANS. These findings suggest that CD19 CAR-T is both effective and safe in patients with tiNHL, particularly when compared to de novo aLBCL.
ASH 2024 ignited the spark for bigger and bolder questions and possibilities, building on the pioneering discoveries presented throughout the meeting. After all, every innovation begins as an idea — a spark of imagination. Let’s continue to dream electric thoughts and push the boundaries of what's possible, because the future of hematology is already unfolding before us. Until next time!
