Two patients treated with the venetoclax+ruxolitinib combination. (A) Patient A (top): the curve shows the evolution of white blood cell (WBC) count during treatment with the venetoclax+ruxolitinib combination. The 2 histogram graphs show the daily doses of venetoclax and ruxolitinib received. The combination was started with ruxolitinib 15 mg twice daily and venetoclax 2 days later with a daily ramp-up from 20 to 800 mg over 6 days. Adverse events (AEs): (1) grade 3 urinary infection; (2) grade 3 thrombocytopenia; (3) grade 3 exacerbation of COPD; and (4) grade 3 pneumonia. Because of the repeated infectious AEs and thrombocytopenia, the schedule was modified to an intermittent one, with ruxolitinib 15 mg twice daily given together with venetoclax 400 mg daily for 5 days, at 4-week intervals. (B) Same data for patient B: venetoclax was started first with a daily ramp-up from 20 mg to 800 mg over 6 days. After 2 months of slow progression, ruxolitinib was added at 10 mg/d and then increased to 10 mg twice daily. AE 1: grade 2 thrombocytopenia. (C) A computed tomographic scan of patient A showing the spleen at baseline (largest dimension measured, 168.3 mm) and 1 month after the beginning of treatment with ruxolitinib+venetoclax (largest dimension measured, 110 mm). (D) The proposed mechanism underlying our main findings. At baseline, BCL-2 and MCL-1 are molecular vulnerabilities in T-PLL. JAK/STAT pathway inhibition through JAK1 inhibition selectively increases BCL-2–dependent apoptotic priming and the activity of venetoclax.