BCL-2 inhibitor TQB3909 combined with JAK inhibitors in patients with intermediate- or high-risk myelofibrosis: A two-cohort, open-label, Phase ib/II, multicenter study

Abstract Introduction: Overexpression of anti-apoptotic proteins BCL-2 and BCL-XL has been observed in tumor cells of myelofibrosis (MF) patients (pts). JAK inhibitors (JAKi) suppress BCL-XL and MCL-1 transcription, reducing their protein levels, while BCL-2 inhibitors directly inhibit BCL-2/BCL-XL function. The combination is hypothesized to enhance apoptosis of malignant cells and restore sensitivity to JAK2 inhibition. Previous studies of BCL-2 inhibitor plus ruxolitinib (RUX) have shown improved efficacy compared to JAKi monotherapy. TQB3909 is a novel BCL-2 inhibitor currently under investigation. Here, we present the exploratory signal from a phase Ib/II study of TQB3909 in combination with JAKi in MF pts. Methods:This is a multicenter, open-label, phase Ib/II trial (NCT06245941) conducted at 5 sites in China. Eligible pts was ≥18 years old, diagnosed with MF (DIPSS intermediate-1 or higher), either JAKi-naïve or resistant. Palpable splenomegaly (≥5 cm below LCM) or spleen volume ≥450 cm³ (MRI/CT) was required. Pts received either RUX or rovadicitinib (ROV) combined with TQB3909 based on investigator discretion. Dose escalation of TQB3909 (100 mg, 200 mg, 300 mg QD) was first explored in the RUX cohort, followed by a 3+3 dose-escalation design in the ROV cohort (10mg, 15 mg bid). The study is ongoing at the dose-escalation stage. This report summarizes spleen size reduction (assessed by spleen length or imaging), total symptom score (TSS) reduction during the study period, hemoglobin (HB) and platelet (PLT) dynamics, and adverse events (AEs). Results: Between May 13, 2024, and April 22, 2025, 16 pts were enrolled (11 PMF, 4 PPV-MF, 1 PET-MF): 7 (43.8%) in the RUX+TQB3909 cohort and 9 (56.3%) in the ROV+TQB3909 cohort. JAK2 mutations were found in 13 pts (81.3%). Seven pts (43.8%) were classified as intermediate-1, eight (50.0%) as intermediate-2, and one (6.3%) as high-risk according to DIPSS. Five pts (31.3%) were JAKi-naïve, while 11 (68.8%) were resistant to RUX monotherapy. In the RUX cohort (n=7), TQB3909 was administered at 100 mg (n=2), 200 mg (n=2), and 300 mg (n=3) per day. In the ROV cohort (n=9), TQB3909 was fixed at 200 mg QD. Among 11 evaluable pts, spleen size reduction was observed in 9 (81.8%), with 6 pts (54.5%) achieving 20% reduction. Notably, spleen size reduction 35% was achieved in 66.7% pts (4/6) in the ROV cohort, compared to 20.0% (1/5) in the RUX cohort, suggesting a potential advantage of the TQB3909+ROV combination. TSS reduction was observed in all evaluable pts (12/12, 100%), and TSS50 was achieved in 75.0% pts (9/12). HB improvement (≥15 g/L increase from baseline) occurred in 50.0% (8/16), including 42.9% (3/7) in the RUX cohort and 55.6% (5/9) in the ROV cohort. PLT and HB levels showed more favorable dynamics in the ROV cohort compared to RUX. The ROV cohort maintained higher PLT counts (nadir median 150 x10⁹/L) and HB levels (nadir 94 g/L with sustained recovery), while the RUX cohort exhibited lower nadirs. In the RUX cohort, one pt (14.3%) discontinued early due to RUX withdrawal syndrome, one pt discontinued due to Grade 3 cryptococcal infection, and another due to Grade 3 lymphopenia. At ROV 10 mg bid, one pt experienced a dose-limiting toxicity (DLT) of Grade 4 thrombocytopenia, and 1 discontinued due to RUX withdrawal syndrome. Subsequently, four additional pts were enrolled at this dose with no further DLTs. The ROV 15 mg cohort (n=3) reported 1 DLT (33.3%) of Grade 4 thrombocytopenia. DLT observation is ongoing. Excluding 2 pts who discontinued due to RUX withdrawal syndrome, Grade ≥3 TEAEs were reported in 10 of 14 pts (71.4%). The most common Grade ≥3 TEAEs included lymphopenia (5/14, 35.7%), anemia (4/14, 28.6%), thrombocytopenia (2/14, 14.3%), and diarrhea (2/14, 14.3%). Conclusions: TQB3909 combined with JAKi demonstrated meaningful clinical activity in MF pts, particularly in combination with ROV, showing spleen reduction, symptom improvement, and potential anemia benefit. However, TQB3909+ROV is associated with hematologic toxicities, and dose optimization is ongoing to balance efficacy and tolerability. Acknowledgement: This research was funded by the Zhejiang Provincial Health High-level Innovative Talent Project (2022-2026).