The European Hematology Association (EHA) annual meeting, an international conference in the field of hematology, gathers numerous experts and scholars from around the world to share and deeply discuss innovative ideas and scientific and clinical research advancements in hematology, promoting continuous development in the field. At this year's conference, the research results on spleen tyrosine kinase (SYK) inhibitors received significant attention. Sovleplenib (HMPL-523), the first SYK inhibitor from China (as of publication date) to apply for market approval, showcased its potential in treating hematological diseases at this EHA meeting. Oncology Frontier - Hematology Frontier has invited Dr. Bing Han from Peking Union Medical College Hospital to provide an in-depth interpretation of the research on Sovleplenib in the field of warm autoimmune hemolytic anemia (wAIHA), aiming to provide references for clinical practice.

Current State and Exploration in wAIHA Treatment

Autoimmune hemolytic anemia (AIHA) is an autoimmune disease characterized by the body’s production of antibodies against its own red blood cells, leading to excessive destruction of these cells and resulting in hemolysis. The main pathogenic mechanism of AIHA involves macrophages expressing immunoglobulin Fc receptors accelerating the clearance of antibody-coated red blood cells. According to foreign data, the annual incidence of AIHA is approximately 0.8-3.0 per 100,000 people. AIHA can be divided into three types based on the optimal temperature at which autoantibodies bind to red blood cells: warm antibody type (wAIHA), cold antibody type (cAIHA), and mixed warm and cold antibody type (mAIHA). Among these, wAIHA accounts for 75-80% of all adult AIHA cases. AIHA can be classified as primary or secondary based on whether the cause is clear. Secondary AIHA is usually secondary to autoimmune diseases, lymphoproliferative diseases, or infections, with patients often exhibiting typical hemolytic symptoms and clinical features of the primary disease, along with an increased risk of thrombosis, which reduces the quality of life and can even be life-threatening.

In current medical practice, first-line treatment methods mainly include corticosteroids or their combination with rituximab. Second-line treatment drugs primarily involve rituximab. Splenectomy, once commonly used in wAIHA treatment, has seen a decline in use, currently accounting for less than 10%. Additionally, wAIHA patients often require blood transfusion support, and the tight supply of blood resources may lead to insufficient transfusion supply and potential transfusion reactions and transfusion-transmitted issues. Therefore, new drugs are needed to further alleviate symptoms and improve patients’ quality of life.

Dual Mechanism of B Cells and Macrophages

SYK is a non-receptor tyrosine kinase widely expressed in various hematopoietic cells related to the immune system, including B cells, macrophages, and monocytes. SYK plays a crucial role in regulating a series of downstream signaling pathways of classical immune receptors, including B cell receptors (BCRs), Fcγ receptors, and natural killer (NK) cell receptors. Given its central role in immune responses, SYK inhibitors are expected to become a novel and potentially effective treatment for autoimmune diseases and hematological disorders.

Sovleplenib, a novel selective SYK inhibitor, works by blocking SYK-dependent signaling pathways and BCR signaling, reducing the stimulation and differentiation of B cells, thereby decreasing the production of plasma cells that secrete antibodies, and consequently reducing the production of autoantibodies against red blood cells. Additionally, by inhibiting SYK activation, it reduces macrophage phagocytosis and destruction. Given these mechanisms, Sovleplenib is expected to play a potential role in the future treatment of wAIHA, and studies have shown that it also has potential in treating immune thrombocytopenia (ITP).

Sovleplenib Offers Hope for Rapid and Sustained Remission

At this EHA meeting, the efficacy and safety results of the Phase II part of the ESLIM-02 Phase II/III study (NCT05535933) on Sovleplenib in wAIHA patients were announced (Abstract S297). This study is the first randomized, double-blind study of a SYK inhibitor in the Chinese wAIHA population (as of publication date). The study included 21 wAIHA patients with hemoglobin (Hb) levels <100 g/L and positive direct antiglobulin test (DAT) (IgG+, with or without C3+), who had failed at least one line of corticosteroid treatment, with 90.5% being primary and 9.5% being secondary. Additionally, 38.1% of patients had been treated with rituximab. All enrolled patients were randomly assigned in a 3:1 ratio to the Sovleplenib (n=16) or placebo (n=5) group, receiving continuous 8-week double-blind treatment, followed by at least 16 weeks of open-label treatment. Hb response was defined as achieving Hb ≥100 g/L at least once without emergency treatment intervention and an increase of ≥20 g/L from baseline. The primary endpoint was the overall Hb response within 24 weeks. The key secondary endpoint was sustained Hb response, defined as Hb ≥100 g/L in at least three consecutive assessments spaced at least 7 days apart, with an increase of ≥20 g/L from baseline, unaffected by emergency treatment.

Study data showed that compared to placebo, the overall response rate (OR) in the Sovleplenib group reached 66.7%, and the sustained response rate (DR) reached 47.6% during the 0 to 24-week period. During the 0 to 8-week double-blind treatment period, the overall Hb response rate (OR) in the Sovleplenib group reached 43.8%, and the sustained response rate (DR) was 18.8%, both higher than the placebo group, which had OR and DR rates of 0%. Additionally, in patients treated with rituximab, the OR and DR rates were 62.5% and 37.5%, respectively. These results suggest that Sovleplenib may have potential clinical significance in the future treatment of wAIHA.

Regarding the time to therapeutic effect, the median time for patients initially treated with Sovleplenib to achieve an Hb increase of ≥15 g/L from baseline was 1.3 weeks. In the overall patient population, the median time to achieve Hb ≥100 g/L and an increase of ≥20 g/L from baseline with Sovleplenib treatment was 4.9 weeks. Furthermore, in terms of sustained remission, the median duration of response for Sovleplenib treatment based on 24-week study data was 20.5 weeks.

Tolerability, Emergency Treatment, and Fatigue Improvement

Long-term use of corticosteroids may lead to various systemic toxic side effects, including inducing or exacerbating infections and disrupting the balance of bone formation and resorption in normal bone tissue. When using rituximab, close attention must be paid to the risk of hypogammaglobulinemia and potential reactivation of infections. Additionally, the risk of infection increases after splenectomy.

In the ESLIM-02 Phase II study, no patients discontinued treatment due to treatment-emergent adverse events (TEAEs). Compared to placebo, the incidence of TEAEs in the Sovleplenib group was lower at all levels, and no ≥4 grade adverse events were observed. TEAEs included grade 1/2 elevations in γ-glutamyl transferase and liver enzymes. These data suggest that Sovleplenib may offer a tolerable treatment option for wAIHA patients.

In addition to these results, Sovleplenib also showed certain effects in reducing the need for emergency treatment and improving patient fatigue symptoms. In this study, emergency treatment was defined as interventions including red blood cell transfusions, intravenous immunoglobulin, and corticosteroids. Compared to placebo, the Sovleplenib group showed a reduced need for emergency treatment during the 0 to 8-week and 0 to 24-week periods. From week 5 to week 24, 95.2% of patients did not require transfusions, reducing the risks associated with transfusions. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale, used to assess the degree of patient fatigue, showed that higher scores indicate lower fatigue levels and higher quality of life. At the 8-week and 24-week evaluations, patients in the Sovleplenib group showed improvements in FACIT-F scores compared to baseline, unlike the placebo group.

Summary

The results of the ESLIM-02 study provide evidence for the potential application of Sovleplenib in the future treatment of wAIHA. We look forward to more research results on Sovleplenib to further enrich the treatment options for wAIHA patients.

Dr. Bing Han

• Chief Physician, Doctoral Supervisor at Peking Union Medical College Hospital Hematology Department
• Head of the Red Blood Cell Disease Group, Peking Union Medical College Hospital Hematology Department
• Core member of the International IPIG Working Group
• Deputy Director of the Red Blood Cell Disease Group, Chinese Medical Association Hematology Branch
• Head of the PNH Group, Rare Diseases Group, Chinese Medical Association Hematology Branch
• Deputy Director of the Red Blood Cell Disease Academic Working Committee, Second Committee of the Hematology Branch of the Chinese Medical Association Geriatrics Society
• Deputy Head of the Second Committee of the MDS and MPN Working Group, Hematology Oncology Professional Committee, Chinese Anti-Cancer Association (CACA)
• Deputy Head of the MDS Disease Group, Chinese Female Physicians Association
• Deputy Director of the Red Blood Cell Committee, Beijing Cancer Prevention Society
• Deputy Director of the Cell Morphology Professional Committee, Laboratory Medicine Branch, Bethune Spirit Research Association
• Deputy Director of the Red Blood Cell Disease Diagnosis Committee, Laboratory Medicine Branch, Chinese Medical Doctor Association
• Standing Member of the Chinese Medical Association Geriatric Hematology Branch
• Executive Director of the World Federation of Traditional Chinese Medicine
• Member of the Beijing Rare Disease Society