Selected JAKi trials in MF
| Agent . | Target(s) . | Clinical trial . | Numerosity and study-specific features . | Key results . | Toxicities . | Comments . |
|---|---|---|---|---|---|---|
| RUX | JAK1/2 | COMFORT-1,64 RUX vs PBO | RUX (n = 155), PBO (n = 154) | SVR ≥35% at 24 wk: 41.9% (RUX) vs 0.7% (PBO); reduction in TSS ≥50% at 24 wk: 45.9% (RUX) vs 5.3% (PBO); med. spleen response duration: 3.2 y (RUX); med. OS at 5 y: NR (RUX) vs 3.8 y (PBO) | G3/4 anemia, 45.2%; G3/4 thrombocytopenia, 12.9%; G3/4 neutropenia, 7.1% Rate of nonhematologic toxicities similar between RUX and PBO | 67%-75% of enrolled patients had failed HU prior to enrollment in COMFORT-1/-2 Led to FDA/EMA approval for MF |
| COMFORT-2,53 RUX vs BAT | RUX (n = 146), BAT (n = 73) | SVR ≥ 35% at 48 wk: 28% (RUX) vs 0% (BAT) (at 24 wk: 32% [RUX]); med. spleen response duration: 3.2 y (RUX); med. OS at 5 y: NR (RUX) vs 4.1 y (BAT) | Similar to COMFORT-1 Any grade diarrhea, 23% | |||
| FED | JAK2 | JAKARTA-1,28 FED vs PBO | FED 400 mg (n = 96), FED 500 mg (n = 97), PBO (n = 96), JAKi naive | SVR ≥ 35% at 24 wk: 36% (FED 400 mg) and 40% (FED 500 mg); reduction in TSS ≥ 50% at 24 wk: 36% (FED 400 mg) and 34% (FED 500 mg) | G3/4 anemia, 43% FED 400 mg, 60% FED 500 mg; G3/4 thrombocytopenia, 17% FED 400 mg, 27% FED 500 mg); G3/4 neutropenia, 8% FED 400 mg, 18% FED 500 mg; frequent GI toxicity (mostly G1/2) Frequent elevations of liver/pancreatic enzymes and creatinine (mostly G1/2) Encephalopathy in 4/97 patients in the FED 500 mg group | Suspected cases of Wernicke’s encephalopathy led to early study termination; recently, however, the FDA decided to lift the clinical hold based on updated clinical data98 |
| JAKARTA-2,29 single arm, phase 2 | FED 400 mg, RUX resistant/intolerant | SVR ≥35% at 24 wk: 55%; reduction in TSS ≥50% at 24 wk: 26% | G3/4 anemia, 38%; G3/4 thrombocytopenia, 22% | |||
| PAC | JAK2/FLT3 | PERSIST-130 PAC vs BAT (excl. JAKi) | PAC 400 mg QD (n = 220), BAT (n = 107), JAKi naïve No exclusions for cytopenias | SVR ≥35% at 24 wk: 19% (PAC) vs 5% (BAT); symptom response: no significant benefit of PAC (ITT); transfusion need: 25% of TD patients achieved transfusion-independence | G3/4 anemia, 17%; G3/4 thrombocytopenia, 12%; G3/4 diarrhea, 5%; heart failure, 2% | PAC was on full clinical hold Feb. 2016/Jan. 2017 for fatal toxicity concerns; further dose-finding studies are now ongoing. Overall, PAC seems potentially attractive for cytopenic MF patients. |
| PERSIST-2,31 PAC vs BAT (incl. RUX) | PAC 400 mg QD (n = 104), PAC 200 mg BID (n = 107), BAT (n = 100); previously treated or JAKi naive; PLT <100 × 109/L; 48% had prior RUX and BAT included RUX in 45% | SVR ≥35% at 24 wk: 18% (PAC) vs 3% (BAT); reduction in TSS ≥50% at 24 wk: 25% (PAC) vs 14% (BAT) | Toxicities less frequent in PAC BID dosing than QD dosing; cardiac AEs in 7% (PAC BID), 13% (PAC QD), and 9% (BAT); intracranial hemorrhage, 1% (PAC QD) | |||
| MMB | JAK1/2 | SIMPLIFY-1,32 MMB vs RUX | MMB (n = 215), RUX (n = 217), JAKi naive | SVR ≥35% at 24 wk: 26.9% (MMB) vs 29% (RUX); reduction in TSS ≥50% at 24 wk: MMB inferior to RUX; transfusion need: MMB associated with reduced transfusion requirement | G3/4 thrombocytopenia, 7%; G3/4 anemia, 6%; all grade PN 10% (MMB) vs 5% (RUX) | MMB seems attractive for anemic MF patients in need of spleen/symptom control; however, due the results of SIMPLIFY-1 and 2, MMB development has been discontinued. MMB improves anemia likely because of reduced hepcidin production by the liver. |
| SIMPLIFY-2,99 MMB vs BAT (incl. RUX) | MMB (n = 104), BAT (n = 52); previously treated with RUX; BAT included RUX in 88% | SVR ≥ 35% at 24 wk: MMB not superior to BAT (including RUX) in improving spleen size in patients previously treated with RUX; reduction in TSS ≥ 50% at 24 wk: MMB 26.2% (MMB) vs 5.9% (BAT); transfusion need: MMB associated with reduced transfusion requirement | G3/4 anemia, 13%; G3/4 thrombocytopenia, 7%; all-grade PN, 11% (MMB) vs 0% (BAT) |
| Agent . | Target(s) . | Clinical trial . | Numerosity and study-specific features . | Key results . | Toxicities . | Comments . |
|---|---|---|---|---|---|---|
| RUX | JAK1/2 | COMFORT-1,64 RUX vs PBO | RUX (n = 155), PBO (n = 154) | SVR ≥35% at 24 wk: 41.9% (RUX) vs 0.7% (PBO); reduction in TSS ≥50% at 24 wk: 45.9% (RUX) vs 5.3% (PBO); med. spleen response duration: 3.2 y (RUX); med. OS at 5 y: NR (RUX) vs 3.8 y (PBO) | G3/4 anemia, 45.2%; G3/4 thrombocytopenia, 12.9%; G3/4 neutropenia, 7.1% Rate of nonhematologic toxicities similar between RUX and PBO | 67%-75% of enrolled patients had failed HU prior to enrollment in COMFORT-1/-2 Led to FDA/EMA approval for MF |
| COMFORT-2,53 RUX vs BAT | RUX (n = 146), BAT (n = 73) | SVR ≥ 35% at 48 wk: 28% (RUX) vs 0% (BAT) (at 24 wk: 32% [RUX]); med. spleen response duration: 3.2 y (RUX); med. OS at 5 y: NR (RUX) vs 4.1 y (BAT) | Similar to COMFORT-1 Any grade diarrhea, 23% | |||
| FED | JAK2 | JAKARTA-1,28 FED vs PBO | FED 400 mg (n = 96), FED 500 mg (n = 97), PBO (n = 96), JAKi naive | SVR ≥ 35% at 24 wk: 36% (FED 400 mg) and 40% (FED 500 mg); reduction in TSS ≥ 50% at 24 wk: 36% (FED 400 mg) and 34% (FED 500 mg) | G3/4 anemia, 43% FED 400 mg, 60% FED 500 mg; G3/4 thrombocytopenia, 17% FED 400 mg, 27% FED 500 mg); G3/4 neutropenia, 8% FED 400 mg, 18% FED 500 mg; frequent GI toxicity (mostly G1/2) Frequent elevations of liver/pancreatic enzymes and creatinine (mostly G1/2) Encephalopathy in 4/97 patients in the FED 500 mg group | Suspected cases of Wernicke’s encephalopathy led to early study termination; recently, however, the FDA decided to lift the clinical hold based on updated clinical data98 |
| JAKARTA-2,29 single arm, phase 2 | FED 400 mg, RUX resistant/intolerant | SVR ≥35% at 24 wk: 55%; reduction in TSS ≥50% at 24 wk: 26% | G3/4 anemia, 38%; G3/4 thrombocytopenia, 22% | |||
| PAC | JAK2/FLT3 | PERSIST-130 PAC vs BAT (excl. JAKi) | PAC 400 mg QD (n = 220), BAT (n = 107), JAKi naïve No exclusions for cytopenias | SVR ≥35% at 24 wk: 19% (PAC) vs 5% (BAT); symptom response: no significant benefit of PAC (ITT); transfusion need: 25% of TD patients achieved transfusion-independence | G3/4 anemia, 17%; G3/4 thrombocytopenia, 12%; G3/4 diarrhea, 5%; heart failure, 2% | PAC was on full clinical hold Feb. 2016/Jan. 2017 for fatal toxicity concerns; further dose-finding studies are now ongoing. Overall, PAC seems potentially attractive for cytopenic MF patients. |
| PERSIST-2,31 PAC vs BAT (incl. RUX) | PAC 400 mg QD (n = 104), PAC 200 mg BID (n = 107), BAT (n = 100); previously treated or JAKi naive; PLT <100 × 109/L; 48% had prior RUX and BAT included RUX in 45% | SVR ≥35% at 24 wk: 18% (PAC) vs 3% (BAT); reduction in TSS ≥50% at 24 wk: 25% (PAC) vs 14% (BAT) | Toxicities less frequent in PAC BID dosing than QD dosing; cardiac AEs in 7% (PAC BID), 13% (PAC QD), and 9% (BAT); intracranial hemorrhage, 1% (PAC QD) | |||
| MMB | JAK1/2 | SIMPLIFY-1,32 MMB vs RUX | MMB (n = 215), RUX (n = 217), JAKi naive | SVR ≥35% at 24 wk: 26.9% (MMB) vs 29% (RUX); reduction in TSS ≥50% at 24 wk: MMB inferior to RUX; transfusion need: MMB associated with reduced transfusion requirement | G3/4 thrombocytopenia, 7%; G3/4 anemia, 6%; all grade PN 10% (MMB) vs 5% (RUX) | MMB seems attractive for anemic MF patients in need of spleen/symptom control; however, due the results of SIMPLIFY-1 and 2, MMB development has been discontinued. MMB improves anemia likely because of reduced hepcidin production by the liver. |
| SIMPLIFY-2,99 MMB vs BAT (incl. RUX) | MMB (n = 104), BAT (n = 52); previously treated with RUX; BAT included RUX in 88% | SVR ≥ 35% at 24 wk: MMB not superior to BAT (including RUX) in improving spleen size in patients previously treated with RUX; reduction in TSS ≥ 50% at 24 wk: MMB 26.2% (MMB) vs 5.9% (BAT); transfusion need: MMB associated with reduced transfusion requirement | G3/4 anemia, 13%; G3/4 thrombocytopenia, 7%; all-grade PN, 11% (MMB) vs 0% (BAT) |
AE, adverse event; BAT, best-available therapy; BID, twice daily; EMA, European Medicines Agency; G, grade; ITT, intention-to-treat analysis; med., median; NR, not reached; OS, overall survival; PBO, placebo; PLT, platelets; PN, peripheral neuropathy; QD, once daily; TD, transfusion dependence; TSS, total symptom score.