Table 3.

Results of clinical trials with JAKis in MF

Agent and primary targets	Clinical trial and numerosity	Key inclusion criteria	SVR ≥35% at 24 wk	Symptom reduction	Relevant toxicities with agent on study	Comments
RUX JAK1/2	COMFORT-1 phase 3 RUX (n = 155) vs PBO (n = 154) RUX 15 mg BID (PLT 100 × 109/L-200 × 109/L) or RUX 20 mg BID (PLT >200 × 109/L)	≥Int-2 MF PLT ≥100 × 109/L Intolerant or refractory to other available therapies	41.9% (RUX) vs 0.7% (PBO)	≥50% MFSAF TSS v2.0 at 24 wk: 45.9% (RUX) vs 5.3% (PBO)	G3/4 anemia: 45.2% G3/4 thrombocytopenia: 12.9% G3/4 neutropenia: 7.1% Rate of nonhematological toxicities and discontinuation for AEs: (11%) like PBO	Median OS in pooled analysis: 5.3 y (RUX) vs 3.8 y (PBO/BAT)
	COMFORT-2 phase 3 RUX (n = 146) vs BAT (n = 73) RUX initial doses as in COMFORT-1	≥Int-2 MF PLT ≥100 × 109/L	32% (RUX) vs 0% (BAT)	EORTC QLQ-C30 mean change from BL: +9.1 (RUX) vs +3.4 (BAT) FACT-Lym score mean change from BL: +11.3 (RUX) vs −0.9 (BAT)	G3/4 anemia: 42% G3/4 thrombocytopenia: 8% Any grade diarrhea: 23% Discontinuation for AEs 8% (RUX) vs 5% (BAT)
FEDR JAK2 JAK1 TYK2 JAK3	JAKARTA phase 3 FEDR (n = 193) vs PBO (n = 96) FEDR 400 or 500 mg QD	≥Int-2 MF PLT ≥50 × 109/L JAKI-naïve	36% (FEDR 400 mg with 4 wk later confirmation) and 40% (FEDR 500 mg) vs 1% (PBO)	≥50% modified MFSAF TSS at 24 wk: 36% (FEDR 400 mg) and 34% (FEDR 500 mg) vs 7% (PBO)	G3/4 anemia: 43% (FEDR 400 mg); 60% (FEDR 500 mg) G3/4 thrombocytopenia: 17% (FEDR 400 mg); 27% (FEDR 500 mg) G3/4 neutropenia: 8% (FEDR 400 mg); 18% (FEDR 500 mg) Frequent GI toxicity (mostly G1/2) Encephalopathy in 4 of 97 patients in the FEDR 500 mg group	Suspected cases of Wernicke encephalopathy (WE) led to early study termination; in 2017, however, the FDA decided to lift the clinical hold based on updated clinical data
	JAKARTA-2 phase 2 FEDR (n = 97) FEDR 400 mg QD	Int-1 with symptoms, Int-2 or high-risk MF PLT ≥50 × 109/L RUX resistant, intolerant	55% (30% with stringent RUX failure criteria)	≥50% modified MFSAF TSS at 24 wk: 26%	G3/4 anemia: 38% G3/4 thrombocytopenia: 22% Frequent GI toxicity (mostly G1/2)
	FREEDOM NCT03755518 phase 3b FEDR (estimated n = 110) FEDR 400 mg QD	Int/high-risk MF PLT ≥50 × 109/L RUX exposed	Primary end point	Secondary end point	Out of n = 34 evaluable patients G3/4 anemia: 21% G3/4 thrombocytopenia: 6% Modest GI toxicity (mostly G1/2)	These studies included prospective strategies for preventing or mitigating GI AEs, thiamine level decreases, and potential WE Ongoing
	FREEDOM 2 NCT03952039 phase 3 FEDR vs BAT (estimated n = 192) FEDR 400 mg QD	≥Int-2 MF PLT ≥50 × 109/L RUX refractory, resistant or intolerant	Primary end point	Secondary end point	Secondary end point
PAC JAK2 FLT3 IRAK1 CSF1R ACVR1	PERSIST-1 phase 3 PAC (n = 220) vs BAT (n = 107, excl. JAKi) PAC 400 mg QD	≥Int-1 risk MF JAKi-naïve No exclusions for cytopenia	19% (PAC) vs 5% (BAT)	≥50% MPNSAF TSS at 24 wk: no significant benefit vs BAT	G3/4 anemia: 17% G3/4 thrombocytopenia: 12% G3/4 diarrhea: 5% Heart failure: 2%	PERSIST-1: 25% of TD patients achieved TI Full clinical hold Feb2016/Jan2017 for fatal hemorrhagic and cardiac toxicity concerns, lifted after updated clinical data
	PERSIST-2 phase 3 PAC (n = 211) vs BAT (n = 100, including RUX) PAC 400 mg QD or 200 mg BID	≥Int-1 risk MF PLT <100 × 109/L Previously treated or JAKi-naïve 48% had prior RUX and BAT included RUX in 45%	18% (PAC) vs 3% (BAT) 22%, if PAC at 200 mg BID	≥50% MPNSAF TSS at 24 wk: 25% (PAC) vs 14% (BAT) 32%, if PAC at 200 mg BID	Toxicities less frequent in PAC BID dosing compared with QD Cardiac AEs: 7% at PAC 200 mg BID and 13% at PAC 400 mg QD Intracranial hemorrhage: 1% (PAC QD)
	PAC203 phase 2 PAC (n = 165) PAC 100 mg QD or 100 mg BID or 200 mg BID	≥Int-1 risk MF Any PLT count RUX failure or intolerance	9.3% (PAC 200 mg BID) vs 1.8% (100 mg BID) vs 0% (100 mg QD) 16.7%, if PAC at 200 mg BID and BL PLT <50 × 109/L	≥50% MPNSAF TSS at 24 wk: similar among arms (around 7.5%)	G3/4 anemia: 20.4% at 200 mg BID G3/4 thrombocytopenia: 33.3% at 200 mg BID Common GI toxicity, mostly G1/2 at PAC 200 mg BID Uncommon severe cardiac events and bleedings
	PACIFICA NCT03165734 phase 3 PAC 200 mg BID vs physician’s choice (estimated n = 348)	≥Int-1 risk MF PLT <50 × 109/L No or limited exposure to any JAKi	Primary end point	Primary end point	Secondary end point	Ongoing
MMB JAK1 JAK2 ACVR1	SIMPLIFY-1 phase 3 MMB (n = 215) vs RUX (n = 217) MMB 200 mg QD	Int-1 with symptoms, Int-2 or high-risk MF PLT ≥50 × 109/L JAKi naïve	MMB not inferior to RUX (26.5% vs 29%)	≥50% MPNSAF TSS at 24 wk: MMB inferior to RUX (28.4% vs 42.2%)	G3/4 anemia: 6% G3/4 thrombocytopenia: 7% All grade PN: 10%	TI at 24 wk: MMB associated with significantly reduced RBC transfusions needs Correlation between TI at 24 wk and OS (trend in SIMPLIFY-2)
	SIMPLIFY-2 phase 3 MMB (n = 104) vs BAT (n = 52, 89% RUX) MMB 200 mg QD	Int-1 with symptoms, Int-2 or high-risk MF Any PLT count Suboptimal response, intolerance to RUX	MMB not superior to BAT (around 7% in both arms)	≥50% MPNSAF TSS at 24 wk: 26.2% (MMB) vs 5.9% (BAT)	G3/4 anemia: 14% G3/4 thrombocytopenia: 7% All grade PN: 11%
	MOMENTUM phase 3 MMB (n = 130) vs Danazol (DAN, n = 65) MMB 200 mg QD, DAN 600 mg QD	Int/high-risk symptomatic MF Hb <10 g/dL PLT ≥25 × 109/L Previous exposure to any JAKi	23% (MMB) vs 3% (DAN)	MFSAF TSS at 24 wk: 32% (MMB) vs 6% (DAN)	G3/4 anemia: 61% G3/4 thrombocytopenia: 28%	TI at 24 wk: 31% (MMB) vs 20% (DAN)
Jaktinib (JAKT) JAK2 JAK1 ACVR1 TYK2	NCT03886415 phase 2 JAKT 100 mg BID vs 200 mg QD (n = 118)	≥Int-1 risk symptomatic MF PLT ≥75 × 109/L	54.8% (JAKT 100 mg BID), 31.3% (JAKT 200 mg QD)	≥50% MFSAF TSS at 24 wk: 69.6% (JAKT 100 mg BID), 57.5% (JAKT 200 mg QD)	G3/4 anemia: ∼25% G3/4 thrombocytopenia: ∼15%	Increased Hb levels in 36% of patients with baseline Hb ≤10 g/dL
	NCT04217993 phase 2b JAKT 100 mg BID (estimated n = 43 in the extended research part)	≥Int-1 risk symptomatic MF PLT >30 × 109/L Intolerant to RUX	Primary end point	Secondary end point	Secondary end point	Ongoing
	NCT04851535 phase 2 JAKT 100 mg BID (estimated n = 30)	≥Int-1 risk symptomatic MF PLT ≥75 × 109/L Relapsed, refractory to RUX	Primary end point	Secondary end point		Ongoing
	NCT04617028 phase 3 JAKT + PBO vs HU + PBO (estimated n = 105)	≥Int-2 MF JAKi naïve	Primary end point			Ongoing
TQ05105 (TQ) JAK2	NCT05020652 phase 2 TQ + HU blank tablets vs TQ blank tablets + HU	≥Int-1 risk MF PLT ≥100 × 109/L JAKi-naïve	Primary end point	Secondary end point	Secondary end point	Ongoing
Itacitinib (ITA) JAK1	NCT01633372 phase 2 ITA (n = 87) ITA 100 mg BID vs 200 mg BID vs 600 mg QD	≥Int-1 risk symptomatic MF PLT ≥50 × 109/L Prior JAKi not excluded	17% (across doses)	≥50% MFSAF TSS at 24 wk: 20% (100 mg BID) vs 29% (200 mg BID) vs 35% (600 mg QD)	G3/4 anemia: 25%-38% G3/4 thrombocytopenia: 15%-44% Fatigue: 28.7%
	LIMBER-213 NCT04629508 phase 2 Immediate release ITA (RP2D)	≥Int-1 risk MF PLT ≥50 × 109/L Previous RUX and/or FEDR	Primary end point	Secondary end point	Secondary end point	Ongoing
	NCT03144687 phase 2 Cohort A: ITA 200 mg QD + ongoing RUX at <10 mg BID (estimated n = 21) Cohort B: ITA 600 mg QD (estimated n = 21)	PLT ≥50 × 109/L Cohort A: patients already on RUX <10 mg BID Cohort B: RUX failure or intolerance	Primary end point	Secondary end point	Secondary end point	Ongoing

AE, adverse event; BAT, best available therapy; BID, twice daily; EORTC QLQ, European Organization for the research and treatment of cancer quality of life questionnaire; FACT-Lym, Functional Assessment of cancer therapy-lymphoma; FDA, Food and Drug Administration; G, grade; GI, gastrointestinal; Hb, hemoglobin; HU, hydroxyurea; JAKi, JAK inhibitor; MF, myelofibrosis; MFSAF, Myelofibrosis Symptom Assessment Form; MPNSAF, Myeloproliferative Neoplasm Symptom Assessment Form; OS, overall survival; PBO, placebo; PLT, platelets; PN, peripheral neuropathy; QD, once daily; RBC, red blood cells; RP2D, recommended phase 2 dose; SVR35, spleen volume reduction of 35%; TD, transfusion-dependent; TI, transfusion-independent; TSS, total symptom score.