Malignancy-associated hemophagocytic lymphohistiocytosis (mHLH) is a highly aggressive and fatal disease, with innovative treatment strategies being a major focus and challenge in hematology research. Recently, ELA026—a novel monoclonal antibody targeting signal regulatory proteins (SIRP)-a/b1/g—has shown promising preliminary efficacy in clinical trials for treating mHLH. At the 29th European Hematology Association Annual Meeting (EHA 2024) held from June 13-16, Dr. Swaminathan Iyer from the University of Texas MD Anderson Cancer Center, USA and his team reported that ELA026 not only improved the response rate in treatment-naïve mHLH patients but also significantly enhanced their 2-month survival rate. This finding offers new hope for mHLH treatment. Oncology Frontier-Hematology Frontier invited Dr. Swaminathan Iyer to discuss the mechanism and clinical significance of ELA026 in mHLH treatment.Oncology Frontier-Hematology Frontier: As a novel monoclonal antibody targeting signal regulatory proteins (SIRP)-a/b1/g, ELA026 has shown high response rates and improved survival in secondary hemophagocytic lymphohistiocytosis (sHLH). Could you explain how this new approach could change our treatment strategies?
Dr. Swaminathan Iyer: Dr. Abhishek Maite presented our team’s findings at the EHA meeting. As the principal investigator of this phase 1 study, I am honored to share these significant discoveries. This ongoing open-label, single-arm phase 1b global study (NCT05416307) primarily investigates the application of ELA026 in treating secondary hemophagocytic lymphohistiocytosis (sHLH). Our research specifically focuses on patients with malignancy-associated HLH (mHLH).
We analyzed data from three cohorts. The first two cohorts were aimed at determining the dosage and treatment protocol, while the third cohort included treatment-naïve or early refractory mHLH patients. HLH is an extremely aggressive and fatal condition, with a two-month mortality rate of approximately 50% . This high mortality rate is mainly due to complications related to the underlying malignancy. These complications often prevent necessary treatments for both the malignancy and the associated cytokine storm.
ELA026 depletes SIRP proteins in macrophages or tumor cells, thereby inhibiting the cytokine storm and disease progression. In cohort 3, which included treatment-naïve mHLH patients, the 2-month survival rate was approximately 100%. Many patients, including those with T-cell lymphoma, were able to be discharged and return to normal life after treatment. This represents a significant medical advancement, and we look forward to exploring ELA026 in combination with chemotherapy to enhance therapeutic outcomes.
Oncology Frontier-Hematology Frontier: When evaluating the efficacy of ELA026, biomarker responses such as ferritin, sCD25, and C-reactive protein are closely related to the clinical response. How does monitoring these biomarkers help us better understand the pathology of sHLH and guide the development of personalized treatment strategies?
Dr. Swaminathan Iyer: Biomarkers play a crucial role in assessing disease response and cytokine storms. In sHLH, we use ferritin and soluble IL-2 receptor (sIL-2R, also known as sCD25) as part of the diagnostic and response assessment criteria. The Optimized Hematological Inflammatory Index (OHI) is a specific measure incorporating both ferritin and sCD25. Additionally, C-reactive protein serves as a biomarker indicating the response to therapy. The initial response is typically seen in sIL-2R, while ferritin is recognized as a later response.
A reduction in ferritin and sIL-2R levels is one of the response criteria, consistent with data from a study published in the New England Journal of Medicine on the efficacy and safety of emapalumab (a human anti-interferon-gamma antibody) combined with dexamethasone in children with primary HLH . We applied the modified complete remission (CR) criteria from that study, requiring a 90% reduction in ferritin levels.
Oncology Frontier-Hematology Frontier: Given the high risk of infection, what measures were taken in the study to mitigate these risks, and how feasible and effective are these measures in clinical practice?
Dr. Swaminathan Iyer: Low blood cell counts, including white blood cells, anemia, or thrombocytopenia, pose significant challenges as they can lead to severe complications like bleeding or infections. This is particularly problematic in patients with relapsed or refractory HLH, who have often undergone extensive chemotherapy and steroid treatments, increasing their risk of fungal infections.
In the treatment-naïve cohort, we observed fewer infection risks. This can be attributed to two factors: the extent of chemotherapy received by the patients and the prophylactic use of antifungal, antibacterial, and antiviral medications. Although blood cell counts may remain low for an extended period, and recovery might be delayed even after achieving a biomarker response, it is crucial to continue anti-infective therapies. This approach is essential to prevent patients from succumbing to infections, thereby improving their overall prognosis and quality of life.
References
- J Clin Oncol. 2023 Apr 1;41(10):1888-1897. doi: 10.1200/JCO.22.00437.
- Locatelli F, et al. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med 2020;382:1811-1822.
- 2024 EHA abstract LB3442: ELA026 TARGETING OF SIRP(+) IMMUNE CELLS RESULTS IN A HIGH RESPONSE RATE AND IMPROVED 2-MONTH SURVIVAL OF TREATMENT-NAIVE MALIGNANCY-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PHASE 1 STUDY
