The 2024 European Society for Medical Oncology (ESMO) Annual Meeting was held from September 13-17 in Barcelona, Spain. As one of the largest and most prestigious global clinical oncology conferences, it showcased groundbreaking research from experts around the world, advancing the field of oncology. In the hematologic malignancy space, this year's ESMO also featured many key advancements, including research from China. One such study, led by Dr. Hongyan Tong from The First Affiliated Hospital of Zhejiang University Medical College, was selected for an oral presentation. The study explored the efficacy of Timdarpacept (IMM01) combined with azacitidine (AZA) as a first-line treatment for chronic myelomonocytic leukemia (CMML) (801 MO). Hematology Frontier had the opportunity to interview Dr. Maria Ma, one of the team members, who provided an in-depth explanation of the study.

Hematology Frontier: At this ESMO conference, you reported the results of the phase II study of Timdarpacept (IMM01) combined with azacitidine (AZA) as a first-line treatment for CMML. Could you introduce the background and study design of this research?

Dr. Maria Ma: Chronic myelomonocytic leukemia (CMML) patients generally have poor prognosis, with hypomethylating agents (HMAs) like azacitidine (AZA) being the first-line treatment, though their effectiveness is limited, with a complete remission (CR) rate of only about 10%. IMM01 is a recombinant human signal regulatory protein alpha (SIRPα) antibody fusion protein. By blocking the interaction between CD47 on tumor cells and SIRPα on macrophages, IMM01 inhibits the “Don’t eat me” signal, reversing the suppression of macrophages by tumor cells. Additionally, IMM01 activates the Fc receptor on macrophages, inducing the “eat me” signal and leading to strong antibody-dependent cellular phagocytosis (ADCP) of tumor cells. In vitro studies have shown that IMM01 combined with AZA has synergistic effects in inhibiting CMML cells.

This study is an open-label, multicenter, single-arm phase II clinical trial designed primarily to assess the efficacy of IMM01 combined with AZA in newly diagnosed CMML type 1 and 2 patients. The secondary endpoints include evaluating the safety and tolerability of this combination therapy.

Hematology Frontier: Timdarpacept combined with AZA as a first-line treatment for CMML not only showed promising overall response rates (ORR), but also improved complete remission (CR) rates in patients receiving long-term treatment. What do you see as the core advantages of this combination therapy compared to AZA monotherapy or other standard treatments?

Dr. Maria Ma: To date, 24 patients have been enrolled in this study, and among the 22 evaluable patients, the median time to response was 1.8 months. The overall response rate (ORR) reached 72.7%, including 27.3% complete remission (CR), 13.6% marrow CR (mCR) with hematologic improvement (HI), 4.5% HI, and 27.3% mCR. For patients who received treatment for 4 months or longer, the CR rate increased to 37.5%, and for those treated for 6 months or longer, the CR rate rose to 46.2%. The core advantage of the IMM01 plus AZA combination is that it significantly improved the CR rate compared to AZA monotherapy, with the CR rate increasing as treatment duration extended.

Currently, first-line treatment options for CMML types 1 and 2 are still under investigation, and existing treatments, such as the VA regimen, are not very effective. IMM01 combined with AZA provides a new approach for first-line treatment in CMML patients.

Hematology Frontier: The combination therapy demonstrated good overall tolerability, and the incidence of severe hemolysis was low, even without using a low-dose priming regimen. How do you view these safety data?

Dr. Maria Ma: The most common grade ≥3 adverse events associated with IMM01 plus AZA treatment included lymphopenia (66.7%), leukopenia (62.5%), neutropenia (58.3%), thrombocytopenia (50.0%), anemia (29.2%), and pneumonia (16.7%). These adverse events were primarily hematologic toxicities and were similar to the hematologic toxicities observed with AZA monotherapy. Importantly, only one patient experienced grade ≥3 hemolytic reactions, even without a low-dose priming regimen. Among patients with baseline hemoglobin reduction, 21.1% experienced hemoglobin recovery, and 38.5% of patients with baseline thrombocytopenia saw platelet recovery. Long-term use of the combination did not lead to increased hematologic toxicity. Overall, the combination therapy demonstrated controllable safety and could be extended to a broader patient population.

Hematology Frontier: What are your team’s plans for further developing Timdarpacept in combination with AZA for CMML treatment?

Dr. Maria Ma: Next, we will launch a randomized, controlled, double-blind phase III clinical trial across multiple centers in China. The primary objective is to evaluate the ORR and overall survival (OS) of Timdarpacept combined with azacitidine versus placebo combined with AZA in newly diagnosed CMML types 1 and 2 patients. We aim to validate our conclusions in a larger patient population, offering more CMML patients the dual benefits of improved efficacy and survival.

• PhD, Chief Physician, PhD Supervisor
• Executive Director, Hematology Department, First Affiliated Hospital of Zhejiang University Medical College
• Director, Myelodysplastic Syndrome (MDS) Center and Lymphoma Center
• Vice Chair, Zhejiang Provincial Hematology Research Center
• Chair, Diagnostics Department, Zhejiang University Medical College
• Leading Medical Talent in Zhejiang Province, High-Level Innovative Talent in Zhejiang
• Advanced Visiting Scholar at Royal Free Hospital, UK
• Member of various committees in the Chinese Medical Association and Anti-Cancer Association
• Principal Investigator of multiple national and provincial research projects
• Published over 50 papers in leading journals, including Haematologica and European Journal of Cancer
• Recipient of multiple provincial and national awards for scientific and technological achievements

• Associate Chief Physician, MD, Zhejiang University First Affiliated Hospital
• Youth Committee Member, Zhejiang Hematology Society
• Committee Member, MDS/MPN Group, Zhejiang Medical Association
• Principal investigator of multiple national and provincial clinical research projects
• Published extensively in both domestic and international medical journals
• Awarded for contributions to clinical research in hematological diseases