Results of selected studies of Jak inhibitors as monotherapy in MF
| Jak inhibitor/ targets . | Study/phase . | Population . | Treatment/ sample size . | Control/ sample size . | TSS50 at wk 24 . | SVR35 at wk 24 . | Anemia response . | Molecular responses/BMF reduction . | Relevant toxicities . |
|---|---|---|---|---|---|---|---|---|---|
| Ruxolitinib Jak1, Jak2 | COMFORT-1 phase 3 | Int-2/high-risk MF Platelets ≥100 × 109/L Intolerant/resistant to available therapy | 15 mg twice a day for platelets 100-200 × 109/L; 20 mg twice a day for platelets >200 × 109/L N = 155 | Placebo N = 154 | 45.9% | 41.9% | TI: 41% (14/34 TI patients) | JAK2 V617F VAF: 8% reduction at 24 wk; 17% at 48 wk BMF reduction: NR | Anemia, thrombocytopenia, headache, opportunistic infections |
| COMFORT-2 phase 3 | Int-2/high-risk MF Platelets ≥100 × 109/L | Same as COMFORT-1 N = 146 | BAT N = 73 | NR | 32% | NR | JAK2 V617F VAF: 38% with >20% reduction at 168 wk BMF reduction: 16% after median of 26 mo | ||
| Fedratinib Jak1, Jak2, Jak3, TYK3 | JAKARTA phase 3 | Int-2/high-risk MF Platelets ≥50 × 109/L Jak inhibitor naive | 400 mg or 500 mg/d N = 193 | Placebo N = 96 | 36% with 400 mg/d; 34% with 500 mg/d | 36% with 400 mg/d; 40% with 500 mg/d | TI: 88% (7/8 TD patients) | JAK2 V617F VAF: 0.4% increase at 24 wk/ BMF: NR | Anemia, thrombocytopenia, gastrointestinal toxicity, transaminitis, raised amylase and lipase, Wernicke's encephalopathy (black box warning) |
| JAKARTA-2 phase 2 | Int-1 MF with symptoms Int-2/high-risk MF Platelets ≥50 × 109/L Ruxolitinib failure/ intolerance | 400 mg/d N = 97 | NA | 26% | 55% | NR | NR | ||
| Pacritinib Jak2, FLT3,IRAK1, CSF1R, ACVR1 | PERSIST-1 phase 3 | Int-1/int-2/high-risk MF Any platelet count Jak inhibitor naive | 400 mg/d N = 220 | BAT N = 107 (excluded ruxolitinib) | 19% | 19% | TI: 25% (9/36 TD patients) | JAK2 V617F VAF: 15.8% reduction at 24 wk | Thrombocytopenia, anemia, diarrhea and gastrointestinal toxicity, fluid retention, heart failure, squamous cell skin cancer |
| PERSIST-2 phase 3 | Int-1/int-2/high-risk MF Platelets <100 × 109/L Jak inhibitor exposed or naive | 400 mg/d or 200 mg twice a day N = 211 | BAT N = 100 (45% on ruxolitinib) | 25% | 18% | TI ≥8 wk or ≥2 g/dL increase in Hb: 25% (11/44 with Hb <10 g/dL) | NR | ||
| PAC203 phase 2 | Int-1/int-2/high-risk MF Any platelet count Ruxolitinib failure/ intolerance | 100 mg/d or 100 mg twice a day or 200 mg twice a day N = 165 | NA | 7.5% | 9.3% for 200 mg twice a day; 1.8% for 100 mg twice a day; 0% for 100 mg/d | ≥1 g/dL increase in Hb: 10% (4/42 with Hb <10 g/dL) | NR | ||
| Momelotinib Jak1, Jak2, ACVR1 | SIMPLIFY-1 phase 3 | Int-1 MF with symptoms Int-2/high-risk MF Platelets ≥50 × 109/L Jak inhibitor naive | 200 mg/d N = 215 | Ruxolitinib N = 217 | 28.4% | 26.5% | TI at 24 wk: 66.5% | NR | Anemia, thrombocytopenia, neutropenia, transaminitis, raised amylase/lipase, peripheral neuropathy, first-dose effect (transient hypotension, flushing, dizziness, and nausea) |
| SIMPLIFY-2 phase 3 | Int-1 MF with symptoms Int-2/high-risk MF Any platelet count Suboptimal response/intolerance to ruxolitinib | 200 mg/d N = 104 | BAT N = 52 (89% ruxolitinib) | 26.2% | 7% | TI at 24 wk: 43% | NR | ||
| MOMENTUM phase 3 | Int-1/Int-2/high-risk MF with symptoms Platelets ≥25 × 109/L Hb <10 g/dL Jak inhibitor exposed | 200 mg/d N = 130 | Danazol N = 65 | 25% | 23% | TI at 24 wk: 31% | NR | ||
| Jaktinib Jak1, Jak2, ACVR1, TYK2 | NCT03886415 phase 2 | Int-1/Int-2/high-risk MF with symptoms Platelets ≥75 × 109/L | 100 mg twice a day or 200 mg/d N = 118 | NA | 69.6% with 100 mg twice a day; 57.5% with 200 mg/d | 54.8% with 100 mg twice a day; 31.3% with 200 mg/d | Hb increase: 36% (in patients with Hb <10 g/dL) | NR | Anemia, thrombocytopenia |
| Jak inhibitor/ targets . | Study/phase . | Population . | Treatment/ sample size . | Control/ sample size . | TSS50 at wk 24 . | SVR35 at wk 24 . | Anemia response . | Molecular responses/BMF reduction . | Relevant toxicities . |
|---|---|---|---|---|---|---|---|---|---|
| Ruxolitinib Jak1, Jak2 | COMFORT-1 phase 3 | Int-2/high-risk MF Platelets ≥100 × 109/L Intolerant/resistant to available therapy | 15 mg twice a day for platelets 100-200 × 109/L; 20 mg twice a day for platelets >200 × 109/L N = 155 | Placebo N = 154 | 45.9% | 41.9% | TI: 41% (14/34 TI patients) | JAK2 V617F VAF: 8% reduction at 24 wk; 17% at 48 wk BMF reduction: NR | Anemia, thrombocytopenia, headache, opportunistic infections |
| COMFORT-2 phase 3 | Int-2/high-risk MF Platelets ≥100 × 109/L | Same as COMFORT-1 N = 146 | BAT N = 73 | NR | 32% | NR | JAK2 V617F VAF: 38% with >20% reduction at 168 wk BMF reduction: 16% after median of 26 mo | ||
| Fedratinib Jak1, Jak2, Jak3, TYK3 | JAKARTA phase 3 | Int-2/high-risk MF Platelets ≥50 × 109/L Jak inhibitor naive | 400 mg or 500 mg/d N = 193 | Placebo N = 96 | 36% with 400 mg/d; 34% with 500 mg/d | 36% with 400 mg/d; 40% with 500 mg/d | TI: 88% (7/8 TD patients) | JAK2 V617F VAF: 0.4% increase at 24 wk/ BMF: NR | Anemia, thrombocytopenia, gastrointestinal toxicity, transaminitis, raised amylase and lipase, Wernicke's encephalopathy (black box warning) |
| JAKARTA-2 phase 2 | Int-1 MF with symptoms Int-2/high-risk MF Platelets ≥50 × 109/L Ruxolitinib failure/ intolerance | 400 mg/d N = 97 | NA | 26% | 55% | NR | NR | ||
| Pacritinib Jak2, FLT3,IRAK1, CSF1R, ACVR1 | PERSIST-1 phase 3 | Int-1/int-2/high-risk MF Any platelet count Jak inhibitor naive | 400 mg/d N = 220 | BAT N = 107 (excluded ruxolitinib) | 19% | 19% | TI: 25% (9/36 TD patients) | JAK2 V617F VAF: 15.8% reduction at 24 wk | Thrombocytopenia, anemia, diarrhea and gastrointestinal toxicity, fluid retention, heart failure, squamous cell skin cancer |
| PERSIST-2 phase 3 | Int-1/int-2/high-risk MF Platelets <100 × 109/L Jak inhibitor exposed or naive | 400 mg/d or 200 mg twice a day N = 211 | BAT N = 100 (45% on ruxolitinib) | 25% | 18% | TI ≥8 wk or ≥2 g/dL increase in Hb: 25% (11/44 with Hb <10 g/dL) | NR | ||
| PAC203 phase 2 | Int-1/int-2/high-risk MF Any platelet count Ruxolitinib failure/ intolerance | 100 mg/d or 100 mg twice a day or 200 mg twice a day N = 165 | NA | 7.5% | 9.3% for 200 mg twice a day; 1.8% for 100 mg twice a day; 0% for 100 mg/d | ≥1 g/dL increase in Hb: 10% (4/42 with Hb <10 g/dL) | NR | ||
| Momelotinib Jak1, Jak2, ACVR1 | SIMPLIFY-1 phase 3 | Int-1 MF with symptoms Int-2/high-risk MF Platelets ≥50 × 109/L Jak inhibitor naive | 200 mg/d N = 215 | Ruxolitinib N = 217 | 28.4% | 26.5% | TI at 24 wk: 66.5% | NR | Anemia, thrombocytopenia, neutropenia, transaminitis, raised amylase/lipase, peripheral neuropathy, first-dose effect (transient hypotension, flushing, dizziness, and nausea) |
| SIMPLIFY-2 phase 3 | Int-1 MF with symptoms Int-2/high-risk MF Any platelet count Suboptimal response/intolerance to ruxolitinib | 200 mg/d N = 104 | BAT N = 52 (89% ruxolitinib) | 26.2% | 7% | TI at 24 wk: 43% | NR | ||
| MOMENTUM phase 3 | Int-1/Int-2/high-risk MF with symptoms Platelets ≥25 × 109/L Hb <10 g/dL Jak inhibitor exposed | 200 mg/d N = 130 | Danazol N = 65 | 25% | 23% | TI at 24 wk: 31% | NR | ||
| Jaktinib Jak1, Jak2, ACVR1, TYK2 | NCT03886415 phase 2 | Int-1/Int-2/high-risk MF with symptoms Platelets ≥75 × 109/L | 100 mg twice a day or 200 mg/d N = 118 | NA | 69.6% with 100 mg twice a day; 57.5% with 200 mg/d | 54.8% with 100 mg twice a day; 31.3% with 200 mg/d | Hb increase: 36% (in patients with Hb <10 g/dL) | NR | Anemia, thrombocytopenia |
CSF1R, colony stimulating factor 1 receptor; Int-1, intermediate-1 risk by Dynamic International Prognostic Scoring System; Int-2, intermediate-2 risk by Dynamic International Prognostic Scoring System; IRAK1, interleukin 1 receptor associated kinase 1; NA, not available; NR, not reported.
Data compiled from Verstovsek et al2 ; Mascarenhas et al4 ; Pardanani et al8 ; Harrison et al9 ; Mesa et al12 ; Harrison et al13 ; Verstovsek et al14 ; Zhang et al.32