From September 13 to 17, 2024, the European Society for Medical Oncology (ESMO) Annual Meeting is being held in Barcelona, Spain. As one of the top international oncology conferences, the event gathers experts and scholars from around the world to share cutting-edge research and discuss future developments. In the Mini Oral Session on Hematologic Malignancies, Dr. Ling Pan from West China Hospital, Sichuan University, presented a pivotal phase II study comparing rovatirelinib with hydroxyurea for the treatment of intermediate and high-risk myelofibrosis (MF). The results demonstrated significant benefits in both efficacy and safety for rovatirelinib, offering a new potential treatment option for MF patients. Hematology Frontier invited Dr. Ling Pan to discuss the current landscape and challenges in the diagnosis and treatment of MF, provide insights into this pivotal study, and share her experiences at the ESMO conference.

Hematology Frontier: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis. Could you briefly explain the current status of MF diagnosis and treatment, as well as the unmet needs?

Dr. Ling Pan: Myelofibrosis (MF) is one of the myeloproliferative neoplasms, a diffuse bone marrow fibrosis disorder that includes primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF). MF eventually progresses to bone marrow failure or transforms into acute leukemia. In September 2023, PMF was included in the second list of rare diseases in China. The main clinical symptoms of MF include spleen and liver enlargement, anemia, fatigue, early satiety, abnormal blood counts, and significant weight loss, with an overall poor prognosis for patients.

Currently, MF remains incurable, and treatment is largely determined by prognosis and clinical symptoms, but available options are limited. Before the advent of JAK inhibitors, clinicians primarily used symptomatic treatments like hydroxyurea, corticosteroids, androgens (such as danazol), and immunomodulators (such as thalidomide and lenalidomide), but these provided limited relief from splenomegaly and constitutional symptoms. While the exact mechanism of MF remains unclear, it is believed to be related to mutations in JAK2, MPL, and CALR genes, which cause hyperactivation of the JAK/STAT signaling pathway. The introduction of JAK inhibitors has offered better treatment options and moved MF therapy into the targeted drug era.

However, the only JAK inhibitor approved in China is the imported drug ruxolitinib, which is expensive, adding a significant financial burden to patients. Thus, there are still unmet clinical needs for MF treatment, particularly affordable and effective therapies.

Hematology Frontier: At this ESMO meeting, you presented the results of a phase II study comparing rovatirelinib and hydroxyurea in MF treatment. Could you explain the study and its significance?

Dr. Ling Pan: This was a multicenter, randomized, double-blind, positive-controlled pivotal phase II registration study. Professor Zhijian Xiao from the Institute of Hematology, Chinese Academy of Medical Sciences, and I were the lead investigators, with participation from 37 centers nationwide. The study included patients with intermediate-2 or high-risk MF who had splenomegaly symptoms and had not been treated with JAK inhibitors. After successful screening, patients were stratified by risk level and randomly assigned 2:1 to the treatment or control group.

A total of 107 patients were enrolled, with the primary endpoint being the proportion of patients who achieved a ≥35% reduction in spleen volume (SVR35) from baseline at week 24. As of October 15, 2023, the SVR35 rate was 58.33% in the treatment group and 22.86% in the control group, with a statistically significant difference between the two groups (P=0.0006). The best spleen response rate (the proportion of patients achieving ≥35% reduction in spleen volume at any time) was 63.89% in the treatment group and 31.43% in the control group, also showing significant statistical difference (P=0.0017).

Subgroup analysis based on age, gender, MF type, JAK2 mutation status, MF grade, DIPSS score, baseline hemoglobin, spleen volume, and symptom scores all favored the treatment group. In terms of symptom improvement, the proportion of patients with a ≥50% reduction in total symptom score (TSS50) from baseline at week 24 was 61.11% in the treatment group versus 45.71% in the control group, without significant statistical difference. However, the best overall symptom improvement rate (TSS reduction ≥50% at any time) was 77.78% in the treatment group and 54.29% in the control group, showing a significant statistical difference (P=0.0136). This indicates that rovatirelinib can effectively improve patients’ constitutional symptoms.

Regarding safety, the most common ≥grade 3 hematological toxicities included anemia (28.89% vs. 60.00%), thrombocytopenia (20.00% vs. 17.14%), lymphopenia (7.78% vs. 11.43%), leukopenia (4.44% vs. 17.14%), and neutropenia (4.44% vs. 17.14%). Non-hematological toxicities included hyperuricemia (26.67% vs. 17.14%), weight gain (26.67% vs. 14.29%), and elevated creatinine (17.78% vs. 2.86%), most of which were grade 1–2. No drug-related deaths occurred during the study, and no new safety signals were observed, with safety outcomes consistent with other drugs targeting the same pathway.

This study demonstrated that rovatirelinib offers superior clinical efficacy in treating intermediate and high-risk MF patients who have not previously received JAK inhibitors. It effectively reduces spleen size and improves clinical symptoms with manageable safety. Coupled with positive data from other clinical trials, rovatirelinib may become a new treatment option for MF patients in China.

Hematology Frontier: Based on the results of this study, how do you see the future application of rovatirelinib in MF treatment? Are there plans for further large-scale clinical trials to validate its long-term efficacy and safety?

Dr. Ling Pan: Rovatirelinib is an innovative drug independently developed in China. Preclinical studies showed that it effectively inhibits JAK family kinases and ROCK kinase activity, significantly reducing the phosphorylation of STAT3 and STAT5, thereby inhibiting the JAK/STAT signaling pathway and exhibiting anti-tumor activity.

At the 2023 American Society of Hematology (ASH) Annual Meeting, phase I data of rovatirelinib in myeloproliferative neoplasms (MPN) were presented, demonstrating favorable pharmacokinetics and tolerability, with a best spleen response rate of 63.79% and a best symptom improvement rate of 87.50%, comparable to the data reported in this ESMO study. The pivotal phase II study comparing rovatirelinib and hydroxyurea reported at ESMO was essentially a phase III trial. Based on the positive results, the China National Medical Products Administration accepted rovatirelinib’s new drug application in July this year, and it is currently under review. We plan to continue following up with study participants to obtain long-term efficacy and safety data.

Additionally, rovatirelinib has shown potential in patients with poor response or intolerance to ruxolitinib, and the company is accelerating research into other indications, such as combining rovatirelinib with BET inhibitor TQB3617 or BCL-2 inhibitor TQB3909 for treatment-naive or JAK-inhibitor-refractory intermediate to high-risk MF patients. Globally, positive results have been reported in the MANFIST-2 and TRANSFORM-1 trials, highlighting the potential of combining JAK inhibitors with other agents. We expect that large-scale studies will be conducted in the future to allow more patients to benefit from rovatirelinib.

Hematology Frontier: Lastly, could you share your experiences attending the ESMO meeting and any impressive research findings in hematologic malignancies?

Dr. Ling Pan: As one of the world’s largest and most prestigious oncology conferences, ESMO brings together numerous experts and scholars to showcase the latest research, promoting global progress in oncology. This year, over 30 experts from China presented their innovative research, which is truly inspiring.

In the field of hematologic malignancies, at least 10 clinical studies received oral presentations, covering topics like MF, non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), adult chronic myelomonocytic leukemia, classical Hodgkin lymphoma, peripheral T-cell lymphoma, NK/T-cell lymphoma, and marginal zone lymphoma. This reflects international recognition of China’s academic achievements in hematologic oncology.

One particularly impressive study was presented by Professor Junyuan Qi from the Institute of Hematology, Chinese Academy of Medical Sciences, on the phase I results of BCL-2 inhibitor TQB3909 in relapsed or refractory NHL and AML. The study aimed to evaluate the safety and efficacy

Dr. Ling Pan Professor of Hematology, Chief Physician, and Master’s Supervisor at West China Hospital, Sichuan University.

Formerly served as the Director of the Hematology Department, Professor, and Doctoral Supervisor at the Second Hospital of Hebei Medical University. Member of the Hematology Physicians Branch of the Chinese Medical Doctor Association and former Chair of the Hematology Committee of the Hebei Medical Association. Currently serves as a member of the second MDS-MPN study group of the Hematological Oncology Division of the Chinese Anti-Cancer Association. Standing Committee Member of the Hematology Branch of the Sichuan Provincial Medical Women’s Association and the second Hematology Branch of the Chinese Society of Geriatrics. Advisor to the Hematological Oncology Committee of the Sichuan Provincial Anti-Cancer Association.

Professor Pan is also a reviewer or editorial board member for several academic journals, including Chinese Journal of Hematology, International Journal of Blood Transfusion and Hematology, Lymphoma & Leukemia, Journal of Clinical Hematology, and Chinese Journal of Blood Transfusion.

Her primary research interests focus on chronic myeloproliferative neoplasms, chronic lymphocytic leukemia, and multiple myeloma diagnosis and treatment. She has published 103 articles in Chinese and English journals and has authored or co-authored six books.