From December 7 to 10, 2024, the 66th American Society of Hematology (ASH) Annual Meeting took place in San Diego, USA, bringing together global experts to discuss the latest advancements in hematology. During this prestigious event, Dr. Minghui Duan from Peking Union Medical College Hospital presented his team’s latest findings on myelofibrosis (MF) treatment (Abstract #1002), offering new perspectives for future therapeutic strategies. To provide deeper insights, Hematology Frontier invited Professor Duan for an in-depth discussion on his research.

Hematology Frontier: Myelofibrosis treatment options are limited, particularly for patients with inadequate response or intolerance to ruxolitinib. Could you elaborate on the rationale behind this study and the advantages of combining selinexor with ruxolitinib over ruxolitinib monotherapy?

Dr. Minghui Duan: Myelofibrosis is undoubtedly a complex and challenging hematologic malignancy. Ruxolitinib, as a targeted therapy, has been widely used for years and has demonstrated significant efficacy in alleviating splenomegaly. However, as the disease progresses, the underlying oncogenic signaling pathways become increasingly intricate. Beyond the JAK-STAT pathway, multiple alternative pathways become activated, leading to treatment resistance and eventual loss of efficacy. In some cases, these alternative signaling pathways contribute to severe adverse effects, rendering ruxolitinib intolerable for certain patients.

To address these challenges, it is crucial not only to adjust ruxolitinib dosing for optimal outcomes but also to explore novel therapeutic agents that target additional dysregulated pathways. One pathway that has garnered significant attention is XPO1, which plays a crucial role in tumor cell survival and proliferation. Inhibiting XPO1 has demonstrated broad anti-tumor effects across various malignancies. Selinexor, a representative XPO1 inhibitor, has been extensively used in multiple myeloma treatment and was approved in China in July 2024 for diffuse large B-cell lymphoma. Its efficacy across different cancer types is well established.

In myelofibrosis, selinexor has shown strong potential both as monotherapy and in combination with other agents. Preclinical studies have demonstrated its effectiveness in reducing tumor burden, including significant spleen shrinkage in myelofibrosis mouse models. Early-phase clinical trials indicated that for treatment-naïve patients, selinexor plus ruxolitinib resulted in SVR35 rates exceeding 90%, an extremely promising outcome. In ruxolitinib-resistant cases, selinexor monotherapy achieved SVR35 in approximately 40% of patients. However, monotherapy required relatively high doses (80 mg weekly), which increased the risk of side effects and financial burden for Chinese patients.

Given this, our research team chose not to discontinue ruxolitinib in patients with inadequate response or intolerance but rather to introduce selinexor at lower doses (40–60 mg weekly) as a combination therapy. This approach yielded satisfactory outcomes, with approximately 40% of patients achieving SVR35 and several experiencing significant symptom relief, including reduced transfusion frequency and improved hemoglobin levels. Importantly, the combination regimen resulted in milder and more manageable gastrointestinal adverse effects compared to selinexor monotherapy.

This study holds particular significance for Chinese myelofibrosis patients, as it not only enhances treatment efficacy while maintaining manageable safety but also reduces the financial burden by lowering the required selinexor dosage. We believe this study will provide a more accessible and effective treatment option, benefiting a broader patient population.

Hematology Frontier: What insights does this study provide for future treatment strategies in myelofibrosis? What are the next steps in advancing myelofibrosis research?

Dr. Minghui Duan: Looking ahead, the combination of ruxolitinib and selinexor is likely to become a key therapeutic option for myelofibrosis patients. Currently, late-stage myelofibrosis patients often require hematopoietic stem cell transplantation (HSCT) as a curative approach. For these patients, effective pre-transplant bridging therapy is essential to reduce spleen size and optimize transplant outcomes. In this context, the ruxolitinib-selinexor combination represents a promising strategy that warrants further investigation.

For patients who do not require immediate transplantation, the efficacy of ruxolitinib monotherapy remains limited, especially in intermediate- and high-risk MF patients, where treatment outcomes remain suboptimal. While our current study focuses on ruxolitinib-refractory and intolerant cases, our long-term goal is to evaluate this combination as a frontline treatment to expand its benefits to a broader patient population.

Furthermore, an ongoing international Phase III randomized controlled trial is actively comparing ruxolitinib monotherapy versus ruxolitinib plus selinexor in first-line myelofibrosis treatment. If this study yields positive results, it will provide strong evidence supporting the integration of selinexor into first-line therapy. Ultimately, should the findings confirm superior efficacy, all myelofibrosis patients receiving ruxolitinib could benefit from selinexor combination therapy as an initial treatment approach, ensuring optimal therapeutic outcomes.

About Dr. Minghui Duan

Dr. Minghui Duan is a Chief Physician in the Department of Hematology at Peking Union Medical College Hospital. He serves as Vice Chair of the First Youth Committee of the Beijing Medical Association Hematology Branch and is a committee member of multiple national and international hematology and oncology associations. His expertise spans hematopoietic stem cell transplantation, lymphoma, leukemia, myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). He specializes in the diagnosis and treatment of rare and complex hematologic disorders.