Editor's Note: The annual meeting of the European Hematology Association (EHA) is an international conference in the field of hematology, bringing together numerous experts and scholars from around the world to share and delve into innovative ideas and research progress, promoting continuous development in the field of hematology. This year, the research achievements of spleen tyrosine kinase (SYK) inhibitors attracted significant attention. HMPL-523 (Solepinib), the first SYK inhibitor from China to apply for market approval (*as of the press date), presented multiple research results at the EHA conference. In this issue, "Oncology Frontier - Hematology Frontier" invited Dr. Jing Sun from the Department of Hematology at Nanfang Hospital, Southern Medical University, to provide an in-depth interpretation of the ESLIM-01 study (NCT05029635) on Solepinib in the treatment of primary immune thrombocytopenia (ITP), aiming to offer clinical practice insights.

Current Status and New Paths in ITP Treatment

Oncology Frontier – Hematology Frontier: Could you share the current treatment landscape for ITP and the challenges faced in this field?

Dr. Jing Sun: Adult ITP is a complex autoimmune disease characterized by excessive destruction or insufficient production of platelets, leading to bleeding tendencies in patients. Currently, clinical guidelines recommend glucocorticoids and intravenous immunoglobulin (IVIG) as first-line treatments for adult ITP. For second-line treatments, the options are more diverse, including thrombopoietin (TPO)/thrombopoietin receptor agonists (TPO-RA), rituximab, and splenectomy.

One of the main challenges in treating adult ITP is its propensity for relapse, which impacts patients’ long-term health and quality of life. Additionally, the long-term use of certain therapeutic drugs can lead to side effects. Therefore, clinicians must consider individual patient differences, disease severity, and complication risks when formulating treatment strategies to balance benefits and risks.

The concept of personalized medicine is gaining importance in ITP treatment. By applying advanced technologies such as genomics and proteomics, we can gain a deeper understanding of ITP’s pathological mechanisms, providing more precise diagnostic and therapeutic methods for patients. The medical community is actively researching and developing new treatments, including SYK inhibitors, which hold the promise of offering more treatment options for ITP patients.

Dual Mechanisms Involving B Cells and Macrophages

Oncology Frontier – Hematology Frontier: What role does spleen tyrosine kinase play in the pathology of ITP, and what are Solepinib’s mechanisms in treating ITP?

Dr. Jing Sun: Spleen tyrosine kinase (SYK) is crucial in B cell receptor (BCR) signaling, playing a role in B cell activation and autoantibody production. Additionally, SYK functions downstream of Fcγ receptors, essential for phagocytosis mediation. Solepinib, a selective oral SYK inhibitor, operates through dual mechanisms. It inhibits SYK activity, interfering with BCR and Fcγ receptor signaling, thereby reducing immune responses, particularly involving B cells and macrophages.

Specifically, in the context of ITP, B cells are critical as they produce autoantibodies against platelets, marking them for destruction. SYK, a key enzyme in BCR signaling, is vital for B cell activation and antibody production. By blocking SYK activity, SYK inhibitors reduce BCR signaling, decreasing B cell activation and antibody production, subsequently reducing platelet-targeting autoantibodies and immune-mediated platelet destruction.

Regarding macrophages, they recognize antibody-marked platelets via surface Fcγ receptors, leading to phagocytosis and destruction. SYK is also pivotal in this process, mediating Fcγ receptor signaling and promoting macrophage phagocytic function. SYK inhibitors block this signaling pathway, reducing macrophage-mediated platelet phagocytosis and destruction, thus increasing platelet counts.

Overall, SYK plays a crucial role in the signaling pathways of immune cells like B cells and macrophages, making Solepinib a potentially valuable treatment for autoimmune diseases like ITP.

ESLIM-01 Study Subgroup Performance

Oncology Frontier – Hematology Frontier: Could you interpret the efficacy data from the ESLIM-01 study? Additionally, could you share your thoughts on the subgroup data concerning patients treated with recombinant human thrombopoietin and/or thrombopoietin receptor agonists and anti-CD20 monoclonal antibodies? How do you think these results will impact future clinical treatment strategies for ITP?

Dr. Jing Sun: The durable response rate (DRR) is a key indicator of ITP treatment efficacy and was the primary endpoint in the ESLIM-01 study, showing significant differences in the intent-to-treat (ITT) population. Specifically, compared to the placebo group, the Solepinib group achieved a DRR of 48.4%, while the placebo group had 0% (P < 0.0001). This result suggests that Solepinib may have a potential role in sustainably increasing platelet counts in patients.

In subgroup analyses, the study evaluated whether patients with different characteristics exhibited significant differences in response to Solepinib. The results showed a consistent trend of treatment response across various subgroups. For instance, in patients treated with TPO and/or TPO-RA, the DRR was 46.8% compared to 53.1% in untreated patients. In patients treated with anti-CD20 antibodies, the DRR was 50%, compared to 48.1% in untreated patients. These subgroup data indicate that Solepinib’s treatment response may be consistent across different therapeutic backgrounds.

Baseline characteristics showed that, compared to the control group, patients in the Solepinib group had poorer performance status (ECOG PS=1, 21% vs. 13%), higher bleeding risk (WHO bleeding score=1, 69% vs. 53%), and a higher proportion of prior TPO/TPO-RA treatment (75% vs. 65%). Despite these differences, Solepinib showed potential in DRR, overall response rate (ORR), and quality of life improvement.

Based on the ESLIM-01 study results, there is hope that future ITP treatment guidelines and recommendations will consider including Solepinib as a clinical treatment option. We look forward to further research data on Solepinib, which could impact the ITP treatment landscape, potentially being considered for first-line therapy and for patients with poor response to traditional treatments.

Overall Adverse Reactions in ITP Treatment

Oncology Frontier – Hematology Frontier: How would you evaluate the overall adverse reactions of Solepinib in treating ITP?

Dr. Jing Sun: In the context of COVID-19 and the higher dropout rate in the placebo group due to non-response, the Solepinib group’s drug exposure time was almost double that of the control group (24.1 weeks vs. 12.1 weeks). The incidence of grade ≥3 treatment-emergent adverse events (TEAEs) (25.4% vs. 24.2%) and serious TEAEs (20.6% vs. 17.7%) in the Solepinib group was similar to the placebo group, with no deaths reported as of the analysis.

Common TEAEs during the study included upper respiratory tract infection (29%), COVID-19 infection (24%), and increased blood lactate dehydrogenase (24%). Gastrointestinal toxicity and hypertension incidence remained low, and no thromboembolic events were observed as of the analysis.

Clinical Performance in Onset Time and Treatment Stability

Oncology Frontier – Hematology Frontier: Based on Solepinib’s clinical performance in onset time and treatment stability in the ESLIM-01 study, what impact do you think this could have on ITP patients’ treatment and quality of life?

Dr. Jing Sun: In ITP treatment, rapidly increasing platelet counts is crucial for effectively reducing bleeding risk and improving clinical symptoms. In patients treated with Solepinib, platelet counts could rise to ≥50×10⁹/L within about one week (8 days). For patients with a sustained response to Solepinib, platelet counts could stabilize within the range of 80-100×10⁹/L, reducing the risk of bleeding events. During six follow-ups over 14-24 weeks, 84% (51/61) of patients met the response criteria five times, and 64% (39/51) showed a response at all six follow-ups. This indicates that Solepinib may provide stability in treatment, supporting long-term management and reducing the need for emergency interventions for ITP patients.

If patients observe symptom improvement early in the treatment, they are more likely to adhere to the long-term treatment plan. Treatment stability and sustained platelet counts within a safe range help patients carry out normal daily activities and may reduce the need for emergency treatments and hospitalizations.

In summary, the ESLIM-01 study results suggest that Solepinib may have potential applications in ITP treatment. With deeper understanding of ITP’s pathological mechanisms and continued innovation in treatment methods, we hope to provide more personalized and precise treatment options for ITP patients, enhancing their health and quality of life.

Dr. Jing Sun

• Professor and Chief Physician, Department of Hematology, Nanfang Hospital, Southern Medical University
• Member, Rare Disease Branch, Chinese Medical Association
• Member, Hemostasis and Thrombosis Group, Hematology Branch, Chinese Medical Association
• Member, Expert Committee of China Marrow Donor Program
• Chair, Rare Disease Committee, Guangdong Pharmaceutical Association
• Vice Chair, Rare Disease Branch, Guangdong Medical Association
• Standing Committee Member and Head of the Hemostasis Group, Hematology Branch, Guangdong Medical Association (10th Session)
• Vice Chair and Head of the Hemostasis Group, Hematology Branch, Guangdong Medical Doctor Association (2nd Session)
• Director, Guangdong Hemophilia Diagnosis and Management Center
• Member, Asia-Pacific Hemophilia Working Group