At present, the treatment of myelofibrosis (MF) continues to face significant challenges. A proportion of patients are intolerant of or develop resistance to existing JAK inhibitors, leaving limited subsequent therapeutic options. Against this background, a phase Ib/II study of the combination of the JAK/ROCK inhibitor rovadicitinib and the BET inhibitor TQB3617 has demonstrated encouraging efficacy, providing a promising foundation for the development of more effective and lower-toxicity treatment strategies. To elucidate the rationale, key findings, and clinical significance of this combination regimen, Hematology Frontier invited Professor Chang Chunkang from Shanghai Sixth People’s Hospital for an in-depth interpretation, highlighting how this strategy addresses unmet clinical needs and outlining expectations for future phase III studies to help optimize MF management.Hematology Frontier: Ruvadicitinib is a JAK/ROCK inhibitor, while TQB3617 is a BET inhibitor. What was the rationale for combining these two agents with distinct mechanisms of action to achieve synergistic anti–myelofibrosis effects? Which clinical challenges was this strategy designed to overcome?
Professor Chang Chunkang:
Ruxolitinib, as a classic JAK inhibitor, has been used clinically for many years. However, we have observed that some patients develop intolerance or resistance, and therapeutic options for these patients remain limited. At last year’s ASH meeting, we proposed a JAK/ROCK inhibitor monotherapy strategy with a mechanism distinct from traditional JAK inhibitors. Preliminary data showed that among eight evaluable patients, two who were previously intolerant of or resistant to ruxolitinib achieved meaningful responses again, providing an initial basis for further exploration.
In addition, dysregulation of bromodomain and extra-terminal (BET) proteins leads to abnormal histone acetylation and oncogene expression in malignant tumors. BET inhibitors, as key epigenetic agents, have demonstrated value across multiple malignancies, within the bone marrow microenvironment, and in inflammatory processes, with particularly well-defined inhibitory effects on inflammatory cytokines such as interleukin-6. The MANIFEST study previously showed that combining ruxolitinib with a BET inhibitor resulted in improved disease control in early treatment settings, while also highlighting the need for careful long-term safety monitoring.
Inflammation is now recognized as a core driver and biomarker of MF pathogenesis and progression. Numerous studies presented at recent ASH meetings suggest that enhancing suppression of early inflammatory responses through combination therapy is an important trend for delaying disease progression. Based on these considerations, we designed this original combination regimen to achieve better induction efficacy, particularly for patients intolerant of ruxolitinib or predicted to respond poorly to JAK inhibitor monotherapy. Preliminary observations from this year have provided initial validation of this concept.
Hematology Frontier: Phase II results showed that in JAK inhibitor–naïve patients, the combination achieved a striking 91.67% rate of ≥35% spleen volume reduction at 24 weeks. How do you interpret this level of efficacy? Beyond spleen reduction, improvements were also observed in symptom scores, anemia parameters, and even reversal of bone marrow fibrosis. What might these comprehensive benefits mean for long-term patient outcomes?
Professor Chang Chunkang:
This study primarily presents data on key efficacy endpoints and safety. Internationally, the core criteria for evaluating MF treatment response include spleen volume reduction of at least 35% (SVR35) and a ≥50% reduction in total symptom score (TSS50). In terms of efficacy, our data show that 91% of patients receiving the combination achieved SVR35, reaching 100% at best response—an outcome difficult to achieve with ruxolitinib monotherapy. Regarding symptom improvement, 67% of patients in the Ib phase achieved TSS50, and overall symptom scores declined to varying degrees, indicating that most patients experienced meaningful symptomatic benefit.
From a safety perspective, when combining a BET inhibitor, we paid particular attention to potential adverse events such as severe thrombocytopenia. Although grade ≥3 thrombocytopenia occurred in 13.7% of patients, no cases required platelet transfusion. Importantly, among patients with baseline anemia, we still observed significant spleen reduction, suggesting that this regimen remains effective in this subgroup.
Another critical concern is whether excessive suppression of inflammation might promote leukemic transformation. In the MANIFEST study, three cases of transformation were reported, although their relationship to treatment remains controversial. In our study, encouragingly, no leukemic transformation was observed among 51 patients. Dynamic monitoring of high-risk mutations such as ASXL1 showed stable expression before and after treatment, suggesting no clear signal of leukemic evolution in the context of improved MF. Nevertheless, given the relatively limited follow-up, these findings should be interpreted cautiously, and longer-term observation with larger cohorts is required to further confirm long-term safety.
Hematology Frontier: You mentioned that, based on the positive Ib/II results, a phase III trial is being planned. If approved in the future, which patient populations do you think this combination therapy would be most suitable for? What are your main areas of focus for the upcoming phase III study?
Professor Chang Chunkang:
Given the impressive data observed thus far, particularly the SVR35 rate of 91%, the prospects for a phase III trial are promising. The primary goal is for this combination regimen to offer renewed clinical benefit to patients who are intolerant of or respond poorly to rovadicitinib monotherapy. Another important direction is improving predictive precision: for patients showing suboptimal responses during early induction with monotherapy, this combination may provide superior efficacy.
Long-term effects of combination therapy also warrant close attention, including potential impacts on leukemic transformation risk, infection prevention, and long-term management of adverse events such as thrombocytopenia. If these long-term safety concerns can be largely mitigated, the regimen could play a meaningful role in enhancing induction efficacy, improving quality of life, and extending survival in MF patients. We therefore look forward to advancing the phase III study and reporting further positive outcomes in due course.
Study Abstract
481: Safety and Efficacy of the JAK/ROCK Inhibitor Ruvadicitinib Combined with the BET Inhibitor TQB3617 in Patients with Myelofibrosis: A Phase Ib/II Clinical Trial
Ruvadicitinib (TQ05105) is a novel oral small-molecule dual JAK/ROCK inhibitor that has demonstrated significant clinical benefit in patients with myelofibrosis (MF). TQB3617 is an oral small-molecule BET family inhibitor that showed good tolerability and encouraging efficacy as monotherapy in prior phase I studies in lymphoma or MF. This report presents the primary results of a phase Ib/II trial evaluating ruvadicitinib in combination with TQB3617 in MF.
The phase Ib study used a 3+3 dose-escalation design in patients with poor response to prior JAK inhibitor therapy. The phase II study comprised three cohorts: cohort 1 and cohort 2 received combination therapy in JAK inhibitor–naïve patients and those with inadequate response to JAK inhibitors, respectively, while cohort 3 received TQB3617 monotherapy. Eligible patients were aged ≥18 years with primary MF, post–polycythemia vera MF, or post–essential thrombocythemia MF, intermediate- or high-risk by DIPSS, and palpable splenomegaly.
In phase Ib, no dose-limiting toxicities were observed. Based on safety and spleen response data, the recommended phase II dose was determined as ruvadicitinib 10 mg twice daily (21 days on/21 days) plus TQB3617 0.1 mg once daily (14 days on/21 days), with possible dose escalation of ruvadicitinib to 15 mg twice daily after six weeks. At 24 weeks, 50% of phase Ib patients achieved SVR35 and 67% achieved TSS50, with improvements in hemoglobin levels, reductions in JAK2 V617F allele burden, and improvement in bone marrow fibrosis grade in a subset of patients.
In phase II, at 24 weeks, 91.67% of JAK inhibitor–naïve patients achieved SVR35, while patients with inadequate JAK inhibitor response showed meaningful symptom improvement. Treatment-related adverse events were common but manageable, with grade ≥3 events primarily consisting of thrombocytopenia and anemia. No treatment-related deaths occurred.
Overall, ruvadicitinib combined with TQB3617 demonstrated good tolerability and significant clinical activity in both JAK inhibitor–naïve and refractory MF patients, supporting its potential as a novel therapeutic option. A phase III trial in patients with inadequate response to JAK inhibitors is currently being planned.
Expert Profile
Professor Chang Chunkang
Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University
Chief Physician, Professor, Doctoral Supervisor
Director, Department of Hematology, Shanghai Sixth People’s Hospital
Deputy Director, Shanghai Institute of Hematology
Vice President, Chinese Society of Geriatric Hematology
Chair, MDS Committee
Member, Chinese Society of Hematology Physicians
Member, Red Cell Group, Chinese Society of Hematology
Member, Hematology Society of the Medical Promotion Association
Deputy Leader, MDS/MPN Group, Chinese Anti-Cancer Association
Member, CSCO China Anti-Leukemia Alliance
Member, Chinese Society of Immunohematology
Member, China Rare Hematologic Diseases Working Group
Vice Chair, Shanghai Society of Hematology; Head, Red Cell Group
Board Member, Shanghai Anti-Cancer Association
Deputy Chair, Shanghai Hematologic Oncology Society
Shanghai Medical Leading Talent
Editorial Board Member, Chinese Journal of Hematology and Journal of Experimental Hematology
Author of more than 300 papers in domestic and international journals, including over 100 SCI-indexed articles in Nature Communications, Blood, PNAS, Hematologica, BJH, and others
