Phase 3 trials of JAK2 inhibitors in JAK2 inhibitor–naïve patients with MPNs
| Drug . | Trial . | Reference . | Patient population studied . | No. of patients . | Comparator . | Efficacy . | Safety . |
|---|---|---|---|---|---|---|---|
| Ruxolitinib | COMFORT-1 | 21 | Adults with intermediate-2/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, platelets ≥100 × 109/L, and <10% circulating blasts | 309 | Placebo (1:1) | ≥35% SVR (41.9% vs 0.7%); ≥50% TSS reduction (45.9% vs 5.3%), both at 24 weeks; overall survival advantage for ruxolitinib | Anemia, thrombocytopenia, ecchymoses, dizziness, headache more frequent with ruxolitinib |
| Ruxolitinib | COMFORT-2 | 22 | Adults with intermediate-2/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, platelets ≥100 × 109/L, and <10% circulating blasts | 219 | BAT (2:1) | ≥35% SVR (28% at 48 weeks and 32% at 24 weeks) in ruxolitinib arm; 0% and 0% in best available therapy arm; ↑ EORTC QLQ-C30 and FACT-Lymphoma scores with ruxolitinib, ↓ with B; overall survival benefit for ruxolitinib emerged at 3 years23 | Anemia, thrombocytopenia, diarrhea, abdominal pain, weight gain more frequent with ruxolitinib |
| Pacritinib | PERSIST-1 | 24 | Symptomatic* adults with intermediate-/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, absolute neutrophil count >0.5 × 109/L, and <10% circulating blasts | 327 | BAT excluding JAK2 inhibitors (2:1) | ≥35% SVR (19% vs 5% at 24 weeks); ≥50% TSS reduction (no difference at 24 weeks; did emerge at 48 weeks in intention-to-treat population but 36% vs 14% in evaluable population); 25% vs 0% achieved transfusion independence | Diarrhea, nausea, vomiting more frequent in pacritinib group |
| Momelotinib | SIMPLIFY-1 | 25 | Adults with intermediate-2/high-risk† PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, platelets ≥50 × 109/L, absolute neutrophil count ≥0.75 × 109/L, <10% circulating blasts, and no grade ≥2 peripheral neuropathy | 432 | Ruxolitinib (1:1) | ≥35% SVR (26.5% [momelotinib] vs 29% [ruxolitinib]); ≥50% TSS reduction (28.4% [momelotinib] vs 42.2% [ruxolitinib]); transfusion independence rate, 66.5% (momelotinib) vs 49.3% (ruxolitinib); transfusion dependence rate, 30.2% (momelotinib) vs 40.1% (ruxolitinib) | Thrombocytopenia, diarrhea, headache, dizziness frequent in both arms; also nausea with momelotinib and anemia with ruxolitinib; peripheral neuropathy reported by 10% of momelotinib and 5% of ruxolitinib patients |
| Fedratinib | JAKARTA | 18 | Adults with intermediate-2/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM and platelets ≥50 × 109/L | 289 | Placebo (1:1:1); 2 fedratinib doses were compared (400 and 500 mg) | ≥35% SVR (36%, 40%, and 1%); ≥50% TSS reduction (36%, 34%, and 7%, all at 24 weeks) | Anemia, thrombocytopenia, leukopenia, neutropenia, diarrhea, nausea, vomiting, elevated AST/ALT more frequent with fedratinib than placebo |
| Ruxolitinib | RESPONSE | 26 | Adults with PV requiring phlebotomy, spleen volume ≥450 cm3 and resistance or intolerance to HU27 | 222 | Standard therapy (1:1) | Composite 1º end point (hematocrit control + ≥35% SVR), 20.9% vs 0.9%; hematocrit control, 60% vs 19.6%; ≥35% SVR, 38.2% vs 0.9%; complete hematologic response, 23.6% vs 8.9%; ≥50% TSS reduction, 49% vs. 5%; all at 32 weeks | Higher rates of herpes zoster and nonmelanoma skin cancers in ruxolitinib group |
| Ruxolitinib | RESPONSE-2 | 28 | Adults with PV requiring phlebotomy, no palpable splenomegaly, and resistance or intolerance to HU27 | 149 | Standard therapy (1:1) | Hematocrit control, 62% vs 19%; complete hematologic response, 23% vs 5%; ≥50% TSS reduction, 45% vs 23%, all at 28 weeks | Headache, constipation, hypertension, weight gain, and anemia common in ruxolitinib group |
| Drug . | Trial . | Reference . | Patient population studied . | No. of patients . | Comparator . | Efficacy . | Safety . |
|---|---|---|---|---|---|---|---|
| Ruxolitinib | COMFORT-1 | 21 | Adults with intermediate-2/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, platelets ≥100 × 109/L, and <10% circulating blasts | 309 | Placebo (1:1) | ≥35% SVR (41.9% vs 0.7%); ≥50% TSS reduction (45.9% vs 5.3%), both at 24 weeks; overall survival advantage for ruxolitinib | Anemia, thrombocytopenia, ecchymoses, dizziness, headache more frequent with ruxolitinib |
| Ruxolitinib | COMFORT-2 | 22 | Adults with intermediate-2/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, platelets ≥100 × 109/L, and <10% circulating blasts | 219 | BAT (2:1) | ≥35% SVR (28% at 48 weeks and 32% at 24 weeks) in ruxolitinib arm; 0% and 0% in best available therapy arm; ↑ EORTC QLQ-C30 and FACT-Lymphoma scores with ruxolitinib, ↓ with B; overall survival benefit for ruxolitinib emerged at 3 years23 | Anemia, thrombocytopenia, diarrhea, abdominal pain, weight gain more frequent with ruxolitinib |
| Pacritinib | PERSIST-1 | 24 | Symptomatic* adults with intermediate-/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, absolute neutrophil count >0.5 × 109/L, and <10% circulating blasts | 327 | BAT excluding JAK2 inhibitors (2:1) | ≥35% SVR (19% vs 5% at 24 weeks); ≥50% TSS reduction (no difference at 24 weeks; did emerge at 48 weeks in intention-to-treat population but 36% vs 14% in evaluable population); 25% vs 0% achieved transfusion independence | Diarrhea, nausea, vomiting more frequent in pacritinib group |
| Momelotinib | SIMPLIFY-1 | 25 | Adults with intermediate-2/high-risk† PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM, platelets ≥50 × 109/L, absolute neutrophil count ≥0.75 × 109/L, <10% circulating blasts, and no grade ≥2 peripheral neuropathy | 432 | Ruxolitinib (1:1) | ≥35% SVR (26.5% [momelotinib] vs 29% [ruxolitinib]); ≥50% TSS reduction (28.4% [momelotinib] vs 42.2% [ruxolitinib]); transfusion independence rate, 66.5% (momelotinib) vs 49.3% (ruxolitinib); transfusion dependence rate, 30.2% (momelotinib) vs 40.1% (ruxolitinib) | Thrombocytopenia, diarrhea, headache, dizziness frequent in both arms; also nausea with momelotinib and anemia with ruxolitinib; peripheral neuropathy reported by 10% of momelotinib and 5% of ruxolitinib patients |
| Fedratinib | JAKARTA | 18 | Adults with intermediate-2/high-risk PMF or post-PV/ET MF with palpable splenomegaly ≥5 cm below LCM and platelets ≥50 × 109/L | 289 | Placebo (1:1:1); 2 fedratinib doses were compared (400 and 500 mg) | ≥35% SVR (36%, 40%, and 1%); ≥50% TSS reduction (36%, 34%, and 7%, all at 24 weeks) | Anemia, thrombocytopenia, leukopenia, neutropenia, diarrhea, nausea, vomiting, elevated AST/ALT more frequent with fedratinib than placebo |
| Ruxolitinib | RESPONSE | 26 | Adults with PV requiring phlebotomy, spleen volume ≥450 cm3 and resistance or intolerance to HU27 | 222 | Standard therapy (1:1) | Composite 1º end point (hematocrit control + ≥35% SVR), 20.9% vs 0.9%; hematocrit control, 60% vs 19.6%; ≥35% SVR, 38.2% vs 0.9%; complete hematologic response, 23.6% vs 8.9%; ≥50% TSS reduction, 49% vs. 5%; all at 32 weeks | Higher rates of herpes zoster and nonmelanoma skin cancers in ruxolitinib group |
| Ruxolitinib | RESPONSE-2 | 28 | Adults with PV requiring phlebotomy, no palpable splenomegaly, and resistance or intolerance to HU27 | 149 | Standard therapy (1:1) | Hematocrit control, 62% vs 19%; complete hematologic response, 23% vs 5%; ≥50% TSS reduction, 45% vs 23%, all at 28 weeks | Headache, constipation, hypertension, weight gain, and anemia common in ruxolitinib group |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; FACT-Lymphoma, Functional Assessment of Cancer Therapy-Lymphoma; LCM, left costal margin.
Defined as a score ≥3 for at least 2 symptoms or a score >4 for at least 1 symptom other than fatigue on the original MPN-Symptom Assessment Form (MPN-SAF) TSS, or a TSS ≥13 on the MPN-SAF TSS 2.0.
Patients with intermediate-1 risk were eligible if they had symptomatic hepatomegaly, splenomegaly, or anemia and/or were unresponsive to available therapy.