Table 2.
Description of JAK inhibitor trials.
| JAK inhibitors | Study ID | Phase | Patients (n) | Dose | Splenomegaly improvement | Transfusion independency | MF-related symptoms improvement | JAK2V617F allele burden decrease | Hematological SE | Nonhematological SE | Reduced dose/discontinued therapy |
|---|---|---|---|---|---|---|---|---|---|---|---|
| INCB018424 (Ruxolitinib) | Verstovsek et al. [2010] | I/II | 153 (81 PMF, 49 post-PV MF, 23 post-ET MF) | 20–100 mg daily | 44% (61/140); ≥50% reduction | – | 68.8% [75/109] according to MFSAF score | 14.7% (5/34) | Anemia (23%, new onset), thrombocytopenia (20%, Gr 3/4) | 49% Gr 1–4, 7% Gr 3/4 (the most common: diarrhea (5.9% Gr 1/2) and fatigue (4.3%; 1.3 Gr 3/4) | 75% were still taking the therapy at time of writing |
| Verstovsek et al. [2010] | II | 73 (34 PV, 39 ET) | PV: 10 mg BiD ET: 25 mg BiD | PV: 60% (13/21); all ≥50% reduction; 57%: nonpalpable spleen ET: 100% (4/4); all ≥50% reduction | phlebotomy independence among PV: 100% (24/24) | Marked improvement was noted in pruritus (100%) bone pain, night sweats, weakness and fever | – | PV versus ET: anemia (12% versus 18%, Gr ≥2), thrombocytopenia (6% versus 0%, Gr ≥2), neutropenia (0% versus 6%, Gr ≥2); all were reversible. | ET: gastrointestinal disorder (1 patient), and peripheral neuropathy (1 patient) | – | |
| Verstovsek et al. [2012] [COMFORT-I] | III | 309 with intermediate-2 to high risk MPN (ruxolitinib: 155; placebo: 154) | 15–20 mg BiD | Ruxolitinib: 41.9%; placebo: 0.7% (all ≥35% reduction) | – | Ruxolitinib: 45.9%; placebo: 5.3% (all ≥50% improvement) | – | Ruxolitinib versus placebo: grade 3/4 thrombocytopenia (12.9% versus 1.3%), grade 3/4 anemia (45.2% versus 19.2%) | Ruxolitinib versus placebo: abdominal pain (10.3% versus 41.1%), fatigue (25.2% versus 33.8%), diarrhea (23.2% versus 21.2%) and peripheral edema (18.7% versus 22.5%) | Ruxolitinib versus placebo: 11.0% versus 10.6% due to adverse events | |
| Harrison et al. [2012] [COMFORT-II] | III | 219 with intermediate-2 to high-risk MPN (ruxolitinib: 146; BAT: 73) | 15-20 mg BiD | Ruxolitinib: 28%; placebo: 0% (all ≥35% reduction) | – | At week 48, patients receiving ruxolitinib had marked reductions in myelofibrosis-associated symptoms, including appetite loss, dyspnea, fatigue, insomnia, and pain, whereas patients receiving the BAT had worsening symptoms | – | Thrombocytopenia and anemia occurred more frequently in the patients receiving ruxolitinib than in those receiving BAT | Ruxolitinib versus BAT: diarrhea (24.0% versus 12.0%), and peripheral edema (22% versus 26.0%) | Discontinuation of treatment owing to adverse events (8% in the ruxolitinib group versus 5% in the BAT group) | |
| Verstovsek, NCT01243944 [RESPONSE] | III (ongoing) | Enrolling PV patients resistant/intolerant to hydroxyurea | – | – | – | – | – | – | – | – | |
| CEP701 (Lestaurtinib) | Moliterno et al. [2009] | I/II | 39 ( 27 PV and 12 ET) | 80-120 mg BiD | 83% (15/18); all had >5 cm reduction in spleen volume | – | – | 20% (3/15) | Thrombotic events (13%) | Gastrointestinal (constitutional in nature) | 13% discontinued therapy (1: disease progression; 1: leg cramps; 3: GI SE) |
| Santos et al. [2010] | II | 22 (15 PMF, 4 post-PV MF, 3 post-ET MF) | 80 mg BiD | 18%; 13.6% response according to IWG criteria | 9.1% | – | None | Anemia (14%, all Gr 3/4); thrombocytopenia (23%) | Diarrhea (72%; 9% Gr 3/4,); nausea (50%, all Gr 1,2); vomiting (37%, all Gr 1,2) | – | |
| SB1518 | Verstovsek et al. [2009] | I | 43 (36 MF, 7 AML) | 100-600 mg daily | 28% (7/25); all had ≥50% reduction, and a clinical improvement according to IWG | – | – | – | Thrombocytopenia (4%, all Gr 3/4) | Diarrhea (30%; 7% Gr 3), nausea (12%, all Gr 1/2) | 37% discontinued therapy (7: disease progression; 4: toxicity; 5: other reasons) |
| Seymour et al. [2010] | I | 20 (85% were JAK2 positive) | 100-600 mg daily | Confirmed clinical improvement (rate not mentioned) | Confirmed improvement | – | – | – | Diarrhea (89%; 11% Gr 3); nausea and vomiting (39%; 6% Gr 3 nausea; all Gr 1/2 vomiting), abdominal pain (22%), fatigue (22%), dysgeusia and rash (17%; all Grade 1/2) | 30% discontinued therapy | |
| Komrokji 2011 | II | 34 (PMF, post-ET and post-PV MF) | 400 mg/day | 88% had reduction in palpable splenomegaly; 32% had a ≥35% reduction in splenic volume | 1 patient | Significant improvement (>2 points) in: abdominal pain, bone pain, early satiety, worst fatigue, inactivity, night sweats and pruritus | – | – | Increased bilirubin, allergic reaction and intermittent nausea | 50% discontinued therapy; 29% required dose reduction for SE | |
| Deeg 2011 | II | 33 with MF | Dose given QD | 96.7%; 56.7%: ≥25% reduction; 39%: ≥50% reduction; 23%: 100% reduction | – | 40-65% | – | – | Diarrhea (81%; 6% Gr 3), nausea (41%; all Gr 1/2), vomiting (22%; all Gr 1/2), and fatigue (9%; all Gr 1/2) | 24% reduced the dose; 64% remained on therapy at 6 months | |
| CYT387 | Pardanani et al. [2011a] | I/II | 166 (106 PMF, 24 post-ET MF, 36 post-PV MF) | 150 or 300 mg QD or 150 mg BiD | 31% improvement according to IWG-MRT criteria | 54% | Most patients had clinical improvement of constitutional symptoms | – | Thrombocytopenia (17%; Gr 3/4) | Dizziness, flushing and hypotension after the first dose (20% of patients) | 32(19%) during the core study and 16 (21%) during extension phase |
| SAR302503 | Pardanani et al. [2011b] | I/II | 59 (44 PMF, 12 post-PV MF, 3 post-ET MF) | 680 mg/dl | 6 cycles: 39%; 12 cycles: 47% (all ≥ 50% reduction) | – | Improvement in early satiety, night sweats, fatigue, pruritus, and cough. | 86% (38% had >20% decrease) | Anemia and thrombocytopenia | Increased amylase/lipase (DLT), nausea/vomiting, diarrhea, increased transaminases | 23% stopped by the sixth cycle |
| AZD1480 | Verstovsek, NCT00910728 | I/II (ongoing) | Enrolling patients with PMF, post-PV MF, post-ET MF | 2.5 mg, 10 mg, 100 mg | – | – | – | – | – | – | – |
| XL019 | Shah et al. [2008] | I/II | 30 (17 PMF, 13 post-PV/ET MF) | 25–50 mg QD, 25 mg three times per week | 100% [12/12] (42% had ≥50% reduction) | – | 90% [10/11] improvements in constitutional symptoms (pruritus/ fatigue) | – | – | peripheral neuropathy (23%, Gr 1/2; in 7 receiving ≥100 mg daily) | 70% discontinued XL019 due to neurotoxicity |
AML, acute myelogenous leukemia; BAT, best available therapy; DLT, dose-limiting toxicity; ET, essential thrombocythemia; Gr, grade; MF, myelofibrosis; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera; SE, side effects.