Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis

Figures & data

Table 1 Comparison of Selected Clinical Trials on JAK Inhibitors for Treatment of Myelofibrosis

Drug [TRIAL]	FED [JAKARTA 1]^Citation29	FED [JAKARTA 2]^Citation27	RUX [COMFORT 1]^Citation23	RUX [COMFORT 2]^Citation24	PAC [PERSIST 1]^Citation54	PAC [PERSIST 2]^Citation53	MOM [SIMPLIFY 1]^Citation47	MOM [SIMPLIFY 2]^Citation46
NCT-Identifier	NCT01437787	NCT01523171	NCT00952289	NCT00934544	NCT01773187	NCT02055781	NCT01969838	NCT02101268
Patient Population	FED (n=193) vs placebo (n=96); JAK inhibitor naïve	Single arm FED (n=97); RUX resistant/intolerant	RUX (n=155) vs placebo (n=154)	RUX (n=146) vs BAT (n=73)	PAC (n=220) vs BAT (n=107)	PAC (n=149) vs BAT including RUX (n=72)	MOM (n=215) vs RUX (n=217)	MOM (n=104) vs BAT (n=52)
Outcomes 1.) SVR ≥ 35% at 24 weeks (%) 2.) Reduction in TSS ≥ 50% at 24 weeks (%) 3.) Survival	1.) FED 400 mg = 36%; FED 500 mg = 40%; Placebo =1%; p<0.001 2.) FED 400 mg = 36%; FED 500 mg = 34%; Placebo= 7%; p<0.001 3.) Not reported	1.) RUX resistant= 53%; RUX intolerant=63% 2.) RUX resistant = 21%; RUX intolerant = 32% 3.) not reported	1.) RUX = 41.9; Placebo= 0.7; p<0.001 2.) RUX= 45.9; Placebo= 5.3; p<0.001 3.) HR for death: 0.50; 95% CI: 0.25–0.98; P=0.04 for RUX vs placebo	1.) RUX= 32; BAT= 0;p<0.001 2.) not reported 3.) HR for death: 0.70; 95% CI: 0.20–2.49 for RUX vs BAT	1.) PAC: 19%; BAT: 5%; p=0.0003 2.) 25% patients in PAC group vs 7% patients in BAT group, p<0·0001 3.) HR for death: 1.36 (95% CI: 0.89–2.09; p=0.16) PAC vs BAT	1.) PAC:18%; BAT: 3%; p=0.001 2.) 25% patients in PAC groupp vs 14% patients in BAT, p=0.08 3.) HR vs BAT for PAC once daily and twice daily: 1.18; 95% CI: 0.57–2.44 and 0.68; 95% CI: 0.30–1.53	1.) MOM: 27%; RUX: 29%; p=0.011 for non-inferiority 2.) MOM: 28%; RUX 42%; p=0.98 for non-inferiority 3.) Not reported	1.) MOM: 7%; BAT: 6%; p=0.9 2.) MOM: 26%; BAT:6% 3.) not reported
Adverse Events Grade ≥3	FED 400mg: 43% anemia, 21% lymphopenia, 17% thromboctyopenia FED 500mg: 60% anemia, 27% lymphopenia, 27% thrombocytopenia Placebo: 25% anemia, 21% lymphopenia, 9% thrombocytopenia 4 cases of Wernicke encephalopathy	38% anemia, 22% thrombocytopenia, 3% lymphopenia	45% anemia, 13% thrombocytopenia, 5% fatigue in RUX group vs 19% anemia, 12% abdominal pain, 7% fatigue in placebo group	5% anemia, 3% abdominal pain, 2% pyrexia in RUX group vs 5% pneumonia, 4% anemia, 4% dyspnea in BAT group	17% anemia, 12% thrombocytopenia, 5% diarrhea in PAC group vs 15% anemia, 11% thrombocytopenia, 3% dyspnea, 3% hypotension in BAT group	Thromobocytopenia: 31% (once daily PAC) 32% (twice daily PAC) vs BAT 18% Anemia:27% (once daily PAC), 22% (twice daily PAC), 14% (BAT)	MOM: 7% thrombocytopenia, 6% anemia, diarrhea, hypertension, neutropenia (2.8% each) RUX: 23% anemia, neutropenia and thrombocytopenia (4.6% each), hypertension (4.2%)	MOM: 14% anemia, 7% thrombocytopenia BAT: 14% anemia, 6% thrombocytopenia

Abbreviations: BAT, best available therapy; CI, confidence interval; FED, fedratinib; HR, hazard ratio; MOM, momelotinib; PAC, pacritinib; RUX, ruxolitinib; SVR, spleen volume reduction; TSS, total symptom score.

Table 2 Ongoing Clinical Trials of JAK Inhibitors in Myelofibrosis

Agent(s)/Regimen	NCT Identifier	Targets	Phase	Population
Ruxolitinib Monotherapy
Ruxolitinib doses calculated with platelets count and P450 cytochrome inhibitor HSCT for patients with donor	NCT01795677	JAK1-/JAK2-inhibitor	II	Primary or secondary myelofibrosis prior to allogeneic hematopoietic stem cell transplantation
Ruxolitinib Pre-, During- and Post-HSCT for Patients with Primary or Secondary Myelofibrosis	NCT03427866	JAK1-/JAK2-inhibitor	II	Primary or secondary myelofibrosis prior to allogeneic hematopoietic stem cell transplantation
Ruxolitinib vs Allogeneic SCT for Patients with Myelofibrosis According to Donor Availability	NCT03333187	JAK1-/JAK2-inhibitor	II	Primary or secondary myelofibrosis
Ruxolitinib before and after Reduced Intensity Donor Stem Cell Transplant	NCT02917096	JAK1-/JAK2-inhibitor	I	Primary or secondary myelofibrosis prior to allogeneic hematopoietic stem cell transplantation
Ruxolitinib (dose escalation)	NCT01317875	JAK1-/JAK2-inhibitor	I	Myelofibrosis
Ruxolitinib Combinations
Ruxolitinib + thalidomide	NCT03069326	JAK1-/JAK2-inhibitor + immunomodulator	II	Primary or secondary myelofibrosis
Ruxolitinib + pomalidomide	NCT01644110	JAK1-/JAK2-inhibitor + immunomodulator	I/II	Primary or secondary myelofibrosis
PIM447 (pan-pim inhibitor) + ruxolitinib (doublet), LEE011 (CDK4/6 inhibitor) + ruxolitinib (doublet), PIM447 + ruxolitinib + LEE 011 (triple combination)	NCT02370706	JAK1-/JAK2-inhibitor + pan-pim inhibitor or CDK4/6 inhibitor	Ib	JAK2V617F-positive primary or secondary MF
Open-Label of Navitoclax (ABT-263) Alone or in Combination With Ruxolitinib	NCT03222609	Bcl-2 inhibitor ± JAK1-/JAK2-inhibitor	II	Intermediate or high-risk primary Myelofibrosis, post polycythemia Vera Myelofibrosis or post-essential thrombocythemia myelofibrosis
Pevonedistat (MLN4924) + ruxolitinib	NCT03386214	NEDD8 inhibitor ± JAK1-/JAK2-inhibitor	I	Primary or secondary myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by IPSS; tolerating 3 months of ruxolitinib before enrolment
Itacitinib (INCB039110) in Combination With Low-Dose Ruxolitinib or Itacitinib Alone	NCT03144687	JAK1 inhibitor ± JAK1-/JAK2-inhibitor	II	Primary or secondary myelofibrosis, tolerating 2 months of and response to ruxolitinib before enrolment
Ruxolitinib + azacytidine SC or IV for 5 days for up to 15 28-day cycles	NCT01787487	JAK1-/JAK2-inhibitor + hypomethylating agent	II	Patients with myelofibrosis, myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, myelodysplastic syndromes/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U)
Panobinostat (3 times a week, every other week in 28-day cycles; LBH589) + ruxolitinib	NCT01433445	Histone deacetylase inhibitor + JAK1-/JAK2-inhibitor	I	Primary or secondary myelofibrosis
CPI-0610 + ruxolitinib	NCT02158858	BET inhibitor ± JAK1/JAK2-inhibitor	I/II	Myelofibrosis with or without prior JAK inhibitor therapy
Ruxolitinib + Peg-interferon Alpha-2a	NCT02742324	JAK1/JAK2-inhibitor + IFN	I/II	Primary or secondary myelofibrosis, age 18–65 years
Parsaclisib (INCB050465) + ruxolitinib	NCT02718300	PIK3 inhibitor + JAK1/JAK2-inhibitor	II	Primary or secondary myelofibrosis
TGR-1202 (umbralisib) + Ruxolitinib	NCT02493530	PIK3 inhibitor + JAK1/JAK2-inhibitor	I	Primary or secondary myelofibrosis, MDS/MPN or Polycythemia Vera Resistant to Hydroxyurea
PU-H71 + ruxolitinib	NCT03373877	HSP90 inhibitor + JAK1/JAK2-inhibitor	I	Primary or secondary myelofibrosis
PU-H71 + ruxolitinib	NCT03935555	HSP90 inhibitor + JAK1/JAK2-inhibitor	I	Primary or secondary myelofibrosis
Fedratinib
Fedratinib vs best available therapy [FREEDOM-2]	NCT03952039	JAK2-inhibitor	III	Primary or secondary myelofibrosis previously treated with ruxolitinib
Fedratinib (single- arm) [FREEDOM]	NCT03755518	JAK2-inhibitor	III	Primary or secondary myelofibrosis previously treated with ruxolitinib
Pacritinib
Pacritinib	NCT03165734	JAK2/IRAK1-inhibitor	II	Primary or secondary myelofibrosis previously treated with ruxolitinib

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