Alan List, MD, speaks at 1:11 pm on Wednesday, September 9.
As the recipient of this year’s Emil J. Freireich Distinguished Pioneer Award, Alan List, MD, will present the Wednesday plenary session, “The emerging promise of biologically rational therapies for lower-risk MDS.”
Alan List, MD, of Stelexis BioSciences, will deliver this afternoon’s plenary session, the first of the annual meeting. Widely regarded as one of the clinicians who helped reshape the understanding and treatment of lower-risk myelodysplastic syndromes (MDS), Dr. List has played a central role in many of the discoveries that have transformed the field.
The past decade has brought significant advances in our understanding of MDS pathogenesis through the study of clonal evolution, precursor states, inflammatory signaling, and immune dysregulation. These discoveries have translated into meaningful therapeutic progress, including the US Food and Drug Administration approvals of luspatercept and imetelstat, both of which have significantly altered the treatment landscape for patients with lower-risk MDS.
Practice-changing advances
Few investigators have contributed more to that evolution than Dr. List. An internationally recognized expert in MDS, he was a pioneer in elucidating the underlying biology of the disease, particularly the role of inflammation in disease pathogenesis. His laboratory has been instrumental in advancing our understanding of inflammasome activation and its contribution to ineffective erythropoiesis.
Dr. List and colleagues demonstrated that chronic inflammation and pyroptotic cell death are key drivers of ineffective hematopoiesis in lower-risk MDS. This work provided the strong biological rationale for targeting innate immune pathways and suppressing the inflammatory cascade that underlies bone marrow failure.
His clinical research established lenalidomide as the standard of care for patients with del(5q) MDS and contributed to the development and approval of luspatercept for the treatment of anemia in lower-risk MDS. His team has led numerous clinical trials inspired by insights from his translational research program.
Dr. List has authored more than 425 peer-reviewed publications and book chapters. He previously served as president of the Society of Hematologic Oncology and as a member of the MDS Foundation Board of Directors. He is a Charter Fellow of the National Academy of Inventors, an inductee into the Florida Inventors Hall of Fame, and holds 18 US patents with more than 45 additional patent applications filed. His previous honors include the 2016 Celgene Career Achievement Award for Clinical Research in Hematology, the General Motors Cancer Research Foundation Merit Award, the J.P. McCarthy Foundation International Prize, recognition from the Joshua Lederberg Society, and the Aplastic Anemia & MDS International Foundation Leadership in Science Award.
Biologic insights drive therapeutic development
Increasingly, biologic insights are driving therapeutic development. Early-intervention studies in clonal cytopenia of undetermined significance are exploring whether anti-inflammatory and molecularly targeted therapies can prevent or delay progression to overt MDS. Future drug development is expected to focus on biologically rational approaches that target the specific mechanisms driving disease.
Targeted therapies are also being investigated earlier in the disease course. For example, the Spanish Sintra-REV study demonstrated that earlier use of lower-dose, fixed-duration lenalidomide prolonged the time to red blood cell transfusion dependence in patients with del(5q) MDS. Similarly, early studies evaluating IDH inhibitors in clonal cytopenia of undetermined significance have shown encouraging activity, and the use of these agents as frontline therapy in select patients with higher-risk MDS could potentially challenge the longstanding hypomethylating agent standard of care for molecularly defined patient subsets.
Several strategies aimed at suppressing inflammatory signaling in MDS have been evaluated, including Toll-like receptor blockade, anti-interleukin therapies, anti-CD33 approaches to reduce myeloid-derived suppressor cells, IRAK inhibitors, and NLRP3 inflammasome inhibitors. Recently, an oral NEK7 inhibitor that prevents assembly of the NLRP3 inflammasome reported promising early clinical results, highlighting the continued potential of targeting innate immune pathways.
The development of immunotherapy in MDS has proven challenging, largely due to a lack of ideal target antigens and the well-described T-cell dysfunction and exhaustion observed in these patients. Future efforts may increasingly focus on allogeneic immune-based approaches and novel strategies to restore T-cell function. Indeed, allogeneic hematopoietic cell transplantation remains the only curative therapy for MDS and provides proof of principle for the potential effectiveness of immune-mediated disease eradication.
Targeting apoptosis pathways remains another area of active investigation. While BCL-2 inhibitors have become a cornerstone of treatment in acute myeloid leukemia (AML), their role in higher-risk MDS remains uncertain. The phase 3 VERONA trial did not meet its primary endpoint of overall survival; however, many investigators continue to believe that BCL-2 inhibition has therapeutic potential in higher-risk disease, and several studies evaluating next-generation BCL-2 inhibitors are ongoing. Additional approaches targeting MDS and leukemia stem cells, including selective PI3Kγ inhibitors, are also advancing in clinical development. Restoring normal TP53 function or overcoming TP53-associated therapeutic resistance remains one of the greatest unmet needs in the field.
MDS represents a highly heterogeneous group of hematologic malignancies that share the clinical manifestations of bone marrow failure and a propensity to progress to AML. As our understanding of the molecular, inflammatory, and immunologic drivers of disease continues to deepen, the future of MDS therapy will increasingly depend on accurately defining the biology of each disease subtype and matching patients with biologically rational, mechanism-based treatments. Such an approach offers the greatest promise for improving outcomes and changing the natural history of MDS.
Rami Komrokji, MD, is an editor at SOHO Insider, and the Vice Chair of the Malignant Hematology Department at the Moffitt Cancer Center in Tampa, Florida.
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