Recent progress of JAK inhibitors for hematological disorders

Figures & data

Table 1. Effects of ruxolitinib on MF.

Category		Details of response	References
Molecular response		Approximately 20% reduction of JAK2V617F allele burden 6/236 cases reached complete molecular response	[11,17]
Pathological improvement		15% of patients showed reduction of fibrosis levels at two years	[18]
Clinical benefit	Spleen volume reduction	41.9% patients had SVR > 35% at 24 weeks 32% patients had SVR > 35% at 24 weeks	[6,7]
	Symptom improvement	45.9% patients had improvement of TSS < 50% at 24 weeks	[6]
Survival benefit		Risk of death was reduced by 30% Median OS 7.7 years in ruxolitinib-treated patients vs. 3.4 years in patients treated with HU	[12,13]

Note: SVR: spleen volume reduction; TSS: total symptom score; HU: hydroxyurea.

Table 2. Factors associated with the response to ruxolitinib.

Response	Factors	Impact	References
Spleen response	DIPSS; high/intermeidate-2	Negative	[20]
	Base line spleen size more than 10cm below LCM	Neagtive
	Platelet counts <200 × 109/L	Negative
	Time between MF diagnosis and start of ruxolitinib >2 years	Negative
	Transfusion dependency	Negative
	Average ruxolitinib dose lower than 10mg BID	Negative
	DIPSS; low/intermediate-1	Positive	[19]
	Use as first line therapy	Positive
	Daily dose at 12 weeks >20 mg/day	Positive
	JAK2V617F allele burden ≧50%	Positive	[23]
	Having three more gene mutations	Negative	[24]
Survival benefit	Spleen response at six months (reduction of spleen length ≧25%)	Positive	[21]
	Ruxolitinib dose at baseline, 3M and 6M< 20mg twice daily	Negative	[22]
	Spleen response at three and six months ≦ 30% from base line	Negative
	Needed red blood cell transfusion at base line, three and six months	Negative
	Mutation of ASXL1 or EZH2	Negative	[25]

Note: LCM: left costal margin; BID: bis in die.

Table 3. Phase II/III clinical trials with fedratinib, pacritinib and momelotinib.

		Study population				Key results
	Name of the study (reference)	Number of patients	DIPSS score	Status of JAK inhibitor use	Treatment arm	Spleen response (SVR35)	Symptom improvement (TSS50)	Other
Fedratinib	JAKARTA	289	INT-2, high	JAKi naïve	Fedratinib (400 mg or 500 mg) vs. placebo	36%, 39% VS 1%	36%, 34% VS 7%
	JAKARTA-2	97	INT-1, INT-2, high	Ruxolitinib resistant or intolerant	Fedratinib (400 mg) (single arm)	55% in initial analysis 30% in stringent criteria cohort	27%
Pacritinib	PERSIST-1	327	INT-1, INT-2 high	JAKi naïve (no exclusion criteria for cytopenia)	Pacritinib VS BAT (excluding JAKi)	19% VS 5% (p = .0003)	25% VS 7% (p < .0001)
	PERSIST-2	311	INT-1, INT-2 high	Previous JAKi treatment allowed Platelet count <100 × 109	Pacritinib (400 mg once daily or 200 mg twice daily VS BAT(including ruxolitinib)	18% VS 3% (p = .001)	32% VS 14% (p = .01)
Momelotinib	SIMPLIFY-1	432	INT-2, high	JAKi naïve	Momelotinib VS ruxolitinib	26.5% VS 29% (p = .011)	28.4% VS 42.2%
	SIMPLIFY-2	156	INT-1, INT-2 high	Previously treated with ruxolitinib and suboptimal response/hemtological toxicity required RBC transfusion dose reduction >20mg BID by anemia grade 3 thrombocytopenia grade3 bleeding	Momelotinib VS BAT (including ruxolitinib)	7% VS 6% (p = .9)	26% VS 6%	Transfusion independence 43% VS 21%

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