GLP-1a Therapy Improves Survival in Patients with Polycythemia Vera and Myelodysplastic Syndromes

A three-year retrospective study found patients with polycythemia vera (PV) or myelodysplastic syndromes (MDS) who received GLP-1 RA medications fared better than their peers. Researchers believe that the antineoplastic properties of the therapy led to these results.

The data was presented at the Society for Hematological Oncology (SOHO) conference, winning second place recognition for excellence in research, in addition to a post-abstract honorarium. Lead author Dr. Asfand Yar Cheema also received the Young Investigator award for this work.

Background

PV and MDS are driven by inflammation, thrombosis and clonal evolution. Preclinical data suggests that GLP-1 signaling (GLP-1 receptors on myeloid lineage) may tamp down inflammasone activation and oxidative stress, which lead to DNA damage and somatic mutations. Researchers were looking to understand at the population level whether GLP-1 RAs could improve progressive-relevant outcomes in patients with these conditions.

The addition of GLP-1R activation modulates P13K/AKT/mTOR and ERK/MAPK pathways and indirectly alters JAK-STAT tone by reducing upstream cytokine signaling and modulation of STAT dimerization. Additional effects of GLP-1R include AMPK activation and metabolic rewiring, improved endothelial function and platelet reactivity as well as attenuation of pro-fibrotic cytokines. These effects are consistent with lower thrombo-inflammation, slower progression toward myelofibrosis and decreased leukemic transformation risk.

Using the TriNetX database, Dr. Cheema and his research colleagues identified patients diagnosed with PV and MDS between 2010 and 2022 and compared those treated with GLP-1a therapy against a matched control group. After propensity-score matching, they identified 4,119 matched pairs of patients with PV and 2,765 matched pairs of patients with MDS.

They followed patients for three years from diagnosis to evaluate survival rates as well as disease complications.

Study findings

The researchers found patients with PV who received GLP-1 RA had markedly lower risk of mortality (from all causes) as well as lower rates of venous thromboembolism (VTE) and progression to myelofibrosis. Patients also had reduced chances of hospitalization, acute kidney injury and ischemic stroke or transient ischemic attack.

In patients with MDS, GLP-1 RA use was associated with less transformation to acute myeloid leukemia (AML), lower morality rates as well as reduced cytopenic complications, acute kidney injury and VTE.

“Although the data does not prove causation, it may support the theory that GLP-1 signaling could reduce inflammasone activity as well as associated ROS burden and mutation accrual,” says Asfand Yar Cheema, MD, a resident a Cleveland Clinic Fairview Hospital

Standard PV/MDS care management does not include GLP-1 RAs. This therapy could prove particularly beneficial in patients with metabolic comorbidity who are experiencing systemic inflammation and oxidative stress. Improving cardiometabolic health is not just supportive but may, in fact, be disease modifying if, in fact, it can slow clonal evolution toward myelofibrosis or AML.

Dr. Cheema was quick to point out that GLP-1 RAs are not currently recommended for all patients with MDS or PV. "Until prospective and randomized data shows clear safety and efficacy benefits, routine off-label use isn't warranted. For patients who already have metabolic indications, shared decision-making is reasonable while monitoring weight, frailty and GI/pancreatobiliary risks.”

Next steps

"GLP1 agonists appear to have pleiotropic effects beyond diabetes and weight loss. This study suggests that in early stages of myelodysplastic syndrome this class of drugs may have beneficial effects,” says Translational Hematology and Oncology Research Department Chair Jaroslaw P. Maciejewski, MD, PhD, FACP. “Ongoing investigations in our laboratory and clinical program aim to further substantiate this surprising observation in MDS and in clonal hematopoiesis of indeterminate significance (CHIP) and in clarifying the mechanism behind these effects.”

Further analysis of prospective cohorts with serial biospecimens would be advantageous to understand the potential connection between GLP-1 exposure and inflammasone markers and how this could influence ROS and DNA damage. Randomized trials with correlative inflammasone/ROS assays are also needed to better assess the therapy's impact on event-free survival. Additionally, it would be instructive to understand the safety profile of GLP-1s in older/frail patients with MDS or PV as well as the optimal dosing in this population.

In the meantime, the researchers are further analyzing the patient database to stratify and perform subgroup analysis.

As researchers gather more insights, it will be beneficial for clinicians to document metabolic and inflammatory metrics to support further investigations into GLP-1 therapy.