Current and emerging Jak inhibitor landscape for cytopenic MF
| Jak inhibitor . | Approved agents . | Investigational agents . | ||||
|---|---|---|---|---|---|---|
| Ruxolitinib . | Fedratinib . | Pacritinib . | Momelotinib . | Ilginatinib . | Itacitinib . | |
| Targets | Jak1, Jak2 | Jak2, Jak1, FLT3, BRD4, TYK2, many others | Jak2, IRAK1, FLT3 | Jak1, Jak2, ACVR | Jak2 | Jak1 |
| Indications | Symptomatic MF with platelets ≥50 × 109/L | Symptomatic MF with platelets ≥50 × 109/L | Symptomatic MF with platelets <50 × 109/L | In development for MF with anemia | In development for MF with thrombocytopenia | In development for MF with anemia |
| Key data in cytopenic MF | Phase 2 study of rux in setting of platelets 50-100 × 109/L, starting at 5 mg twice daily and escalating as tolerated. Median SVR 25% in those escalated to 10 mg twice daily vs 13% on lower doses.17 JUMP: phase 3B study of rux in the setting of platelets 50-100 × 109/L, in which 56% of patients had a ≥50% spleen length reduction by palpation, and favorable safety profile.18 EXPAND: phase 1B dose-finding study in setting of platelets 50-100 × 109/L, demonstrated rux 10 mg twice daily as safe starting dose.19 | Subgroup analysis study pooled data from JAKARTA and JAKARTA2 treated with full-dose fedratinib and compared group with platelets 50-100 × 109/L to >100 × 109/L and reported no difference in spleen responses (36% vs 49% in JAKARTA and 36% vs 28% in JAKARTA2). Symptom responses were also similar between groups. No serious bleeding events occurred.25 | PERSIST-1: phase 3 study of up-front treatment with Pac vs BAT, SVR35 in 19% on Pac vs 5% on BAT. Responses similar for those with thrombocytopenia.27 PERSIST-2: in those with platelets <100 × 109/L, SVR10 79% (vs 36% on BAT) and SVR35 18% (vs 3%), in those with platelets <50 × 109/L, SVR35 in 29% on Pac 200 mg twice daily vs 3% on BAT.28 PAC203: dose- finding study with enhanced inclusion/exclusion criteria, establishing Pac dose as 200 mg twice daily.29 PACIFICA: ongoing study of Pac vs physician's choice (including other JAKis) in those with platelets ≤50 × 109/L (NCT03165734). | MOMENTUM: ongoing phase 3 study of momelotinib vs danazol for MF with anemia and prior JAKi treatment, interim data report improved symptom response, spleen response, and anemia parameters among the momelotinib group.34 | Phase 2 study of ilginatinib vs BAT in those with platelets ≤50 × 109/L is ongoing (NCT04854096). | Phase 2 study of itacitinib in those previously treated with JAKi with adequate platelet counts of >50 × 109/L—results awaited (NCT04629508). |
| Clinical practice points | Starting dose based on platelet count and escalate as able. Early anemia is common, with gradual improvement (so dose adjustments not indicated for early anemia). | No starting dose reductions needed for moderate thrombocytopenia, but dose reduce for worsening platelets. Early nausea or diarrhea are common. Monitor thiamine and for signs of encephalopathy. Monitor renal function and liver function. | Less myelosuppression. Early nausea/diarrhea are common and generally improve with supportive care. Caution in those with CV disease or recent hemorrhage. Monitor QTc. Monitor for bleeding. | Rare peripheral neuropathy risk. | TBD | TBD |
| Jak inhibitor . | Approved agents . | Investigational agents . | ||||
|---|---|---|---|---|---|---|
| Ruxolitinib . | Fedratinib . | Pacritinib . | Momelotinib . | Ilginatinib . | Itacitinib . | |
| Targets | Jak1, Jak2 | Jak2, Jak1, FLT3, BRD4, TYK2, many others | Jak2, IRAK1, FLT3 | Jak1, Jak2, ACVR | Jak2 | Jak1 |
| Indications | Symptomatic MF with platelets ≥50 × 109/L | Symptomatic MF with platelets ≥50 × 109/L | Symptomatic MF with platelets <50 × 109/L | In development for MF with anemia | In development for MF with thrombocytopenia | In development for MF with anemia |
| Key data in cytopenic MF | Phase 2 study of rux in setting of platelets 50-100 × 109/L, starting at 5 mg twice daily and escalating as tolerated. Median SVR 25% in those escalated to 10 mg twice daily vs 13% on lower doses.17 JUMP: phase 3B study of rux in the setting of platelets 50-100 × 109/L, in which 56% of patients had a ≥50% spleen length reduction by palpation, and favorable safety profile.18 EXPAND: phase 1B dose-finding study in setting of platelets 50-100 × 109/L, demonstrated rux 10 mg twice daily as safe starting dose.19 | Subgroup analysis study pooled data from JAKARTA and JAKARTA2 treated with full-dose fedratinib and compared group with platelets 50-100 × 109/L to >100 × 109/L and reported no difference in spleen responses (36% vs 49% in JAKARTA and 36% vs 28% in JAKARTA2). Symptom responses were also similar between groups. No serious bleeding events occurred.25 | PERSIST-1: phase 3 study of up-front treatment with Pac vs BAT, SVR35 in 19% on Pac vs 5% on BAT. Responses similar for those with thrombocytopenia.27 PERSIST-2: in those with platelets <100 × 109/L, SVR10 79% (vs 36% on BAT) and SVR35 18% (vs 3%), in those with platelets <50 × 109/L, SVR35 in 29% on Pac 200 mg twice daily vs 3% on BAT.28 PAC203: dose- finding study with enhanced inclusion/exclusion criteria, establishing Pac dose as 200 mg twice daily.29 PACIFICA: ongoing study of Pac vs physician's choice (including other JAKis) in those with platelets ≤50 × 109/L (NCT03165734). | MOMENTUM: ongoing phase 3 study of momelotinib vs danazol for MF with anemia and prior JAKi treatment, interim data report improved symptom response, spleen response, and anemia parameters among the momelotinib group.34 | Phase 2 study of ilginatinib vs BAT in those with platelets ≤50 × 109/L is ongoing (NCT04854096). | Phase 2 study of itacitinib in those previously treated with JAKi with adequate platelet counts of >50 × 109/L—results awaited (NCT04629508). |
| Clinical practice points | Starting dose based on platelet count and escalate as able. Early anemia is common, with gradual improvement (so dose adjustments not indicated for early anemia). | No starting dose reductions needed for moderate thrombocytopenia, but dose reduce for worsening platelets. Early nausea or diarrhea are common. Monitor thiamine and for signs of encephalopathy. Monitor renal function and liver function. | Less myelosuppression. Early nausea/diarrhea are common and generally improve with supportive care. Caution in those with CV disease or recent hemorrhage. Monitor QTc. Monitor for bleeding. | Rare peripheral neuropathy risk. | TBD | TBD |
CV, cardiovascular; Pac, pacritinib; Rux, ruxolitinib; TBD, to be determined.