Ten years after ruxolitinib approval for myelofibrosis: a review of clinical efficacy

Figures & data

Figure 1. Five-Year Overall Survival Data in the Pooled COMFORT-I and COMFORT-II studies. (A) Corrected for crossover with the RPSFT model. (B) Censored at crossover. HR: hazard ratio; NE: not evaluable; OS: overall survival; RPSFT: rank-preserving structural failure time. Reprinted with permission from Verstovsek et al. [21].

Table 1. Key Ruxolitinib-based clinical studies following the COMFORT trials.

Trial name	Study participants, N	Phase (NCT#)	Objective	Main inclusion criteria	Main efficacy results	Safety overview
REALISE [42]	Patients with anemia N = 51	2 (NCT02966353)	To assess a novel dosing strategy for RUX in patients with anemia	Age ≥18 y Palpable spleen Hb <10 g/dL ECOG PS 0–2 Peripheral blood blasts <10%	Week 24 PSL50, 56% Week 24 MF-SAF TSS, median change from BL, −55%	Hematologic grade ≥3 AEs: Thrombocytopenia, 20% Anemia, 31% Hb levels remained stable through study RBC transfusion requirement: RBC-TD at BL, decreased RBC-TI at BL, stable
JUMP [15,43]	Expanded access, including patients with PLT <100 × 10^9/L N = 2233	3b (NCT01493414)	To assess safety and efficacy of RUX, including in patients with low PLT counts	Age ≥18 y PLT, ≥50 × 10^9/L IPSS risk criteria: high, int-2, int-1 Int-1-risk: PS ≥5 cm from costal margin	Overall population
					Week 24 PSL50, 57% Week 96 OS, 87%	Hematologic grade ≥3 AEs: Thrombocytopenia, 19% Anemia, 35%
					PLT <100 × 10^9/L
					Week 24 PSL50, 38% Week 24 FACT-Lym TS response rate, 40% Week 24 FACIT-Fatigue scale response rate, 45% Week 96 OS, 75%	Thrombocytopenia, 54% Anemia, 36%
					PLT ≥100 × 10^9/L
					Week 24 PSL50, 57% Week 24 FACT-Lym TS response rate, 54% Week 24 FACIT-Fatigue scale response rate, 49% Week 96 OS, 90%	Thrombocytopenia, 17% Anemia, 35%
ROBUST [41]	Int-1 or higher-risk MF N = 48 (Int-1-risk, n = 14; int-2-risk, n = 13, High-risk, n = 21)	2 (NCT01558739)	To evaluate safety and efficacy of RUX, including in patients with int-1 risk disease	Age ≥18 y PLT, ≥100 × 10^9/L IPSS risk criteria: high, int-2, int-1 Int-1-risk: PS ≥5 cm from costal margin Peripheral blood blasts <10% ECOG PS 0–2	Week 24 treatment success^b rate: Overall, 54% Int-1-risk, 57% Int-2-risk, 31% High-risk, 67% Week 48, MF-SAF TSS response rate: Overall, 21% Int-1-risk, 21% Int-2-risk, 23% High-risk, 19%	Hematologic grade ≥3 AEs: Thrombocytopenia, 13% Anemia, 21%
EXPAND [44]	PLT ≤100 × 10^9/L S1, N = 44 S2, N = 25	Ib (NCT01317875)	To establish RUX MSSD in patients with low PLT	Age ≥18 y PLT: S1, ≤100 × 10^9/L and ≥75 × 10^9/L S2, ≤75 × 10^9/L and ≥50 × 10^9/L IPSS risk criteria: high, int-2, int-1 PS ≥5 cm from costal margin ECOG PS 0–2	MSSD established as RUX 10 mg bid Week 48, spleen response rate, S1, 33% S2, 30% Week 24 TSS mean change from BL, S1, −7.7 S2, −3.9	Hematologic grade ≥3 AEs: S1 Thrombocytopenia, 35% Anemia, 20% S2 Thrombocytopenia, 78% Anemia, 17%
[45]	Rechallenge N = 13 (2nd rechallenge: n = 4)	Retrospective case series	To assess if RUX rechallenge results in durable responses	RUX re-treatment at least once 2012–2017	Primary treatment	-
					Constitutional symptom^a improvement, 92% Spleen size reduction, 85% (mean reduction, 10.9 cm)
					1st rechallenge
					Constitutional symptom improvement, 92% Spleen size reduction, 69% (mean reduction, 7.1 cm)
					2nd rechallenge
					Constitutional symptom improvement, 100% Spleen size reduction, 100%
[46]	Rechallenge N = 26 (OPEN, n = 12; HIRE, n = 14)	Retrospective case series	To describe RUX treatment patterns and clinical outcomes with RUX rechallenge after interruption	MF diagnosis 2012–2016 (OPEN) or 2013–2017 (HIRE)	Symptom improvement, 46% (OPEN), 43% (HIRE) Spleen size reduction, 40% (OPEN), 33% (HIRE)	-

AE: adverse event; bid: twice daily; BL: baseline; ECOG PS: Eastern Cooperative Oncology Group performance status; FACIT-Fatigue: Functional Assessment of Chronic Illness Therapy–Fatigue scale; FACT-Lym TS: Functional Assessment of Cancer Therapy–Lymphoma total score; Hb: hemoglobin; HIRE: HealthCore Integrated Research Environment claims and provider data repository; int: intermediate; IPSS: International Prognostic Scoring System; MF: myelofibrosis; MF-SAF TSS: MF-Symptom Assessment Form Total Symptom Score; MSSD: maximum safe starting dose; OPEN: Cardinal Health Oncology Provider Extended Network; OS: overall survival; PLT: platelet count; PS: palpable splenomegaly; PSL50; ≥50% reduction in palpable spleen length; RBC: red blood cell; RUX: ruxolitinib; S1: stratum 1; S2: stratum 2; TD: transfusion dependent; TI: transfusion-independent; TSS: Total Symptom Score.

^aUnexplained fever, night sweats, fatigue, and weight loss; ^b Defined as the proportion of patients achieving ≥50% reduction in spleen length and/or a ≥ 50% decrease in the MF-SAF TSS.

Table 2. Ruxolitinib dosing guidance based on baseline platelet counts, renal or hepatic insufficiency, coadministration with strong CYP3A4 inhibitors, or anemia.

Parameter	Recommended ruxolitinib starting dose
Prescribing information recommendations
PLT count^a: >200 × 10^9/L 100 to 200 × 10^9/L 50 to <100 × 10^9/L	20 mg bid 15 mg bid 5 mg bid
Moderate/severe renal or mild/moderate/severe hepatic impairment with PLT: >150 × 10^9/L 100 to 150 × 10^9/L 50 to <100 × 10^9/L	No dose adjustment 10 mg bid 5 mg qd
End-stage renal disease with PLT: >200 × 10^9/L 100 to 200 × 10^9/L	20 mg once after dialysis session 15 mg once after dialysis session
Coadministration with strong CYP3A4 inhibitors and PLT: ≥100 × 10^9/L 50 to <100 × 10^9/L	• 10 mg bid 5 mg qd
REALISE Study [42]
Anemia	10 mg bid for 12 wk regardless of baseline PLT count; patients with ANC >0.5 × 10^9/L and Hb ≥6.5 g/dL were eligible for dose increases after 12 wk 15 mg bid from wk 12 if PLT 100 to ≤200 × 10^9/L 20 mg bid from wk 16 if PLT ≥200 × 10^9/L 25 mg bid from wk 20 if PLT ≥200 × 10^9/L and patients did not achieve 50% reduction in palpable spleen length

ANC: absolute neutrophil count; bid: twice daily; CYP3A4: cytochrome P450 3A4; Hb: hemoglobin; PLT: platelet; qd: once daily.

^aDoses may be titrated in individual patients based on safety and efficacy outcomes.

Table 3. Mechanism of action and pharmacokinetics of JAK inhibitors for MF.

Agent	Target	Pharmacokinetics	Pharmacodynamics	Week 24 efficacy
Ruxolitinib	JAK1/JAK2 [78]	Half-life: 3 h [79] Cmax: 649–4780 nM^a AUC: 2610–16,600 nM·h^a	Maximum pSTAT3 inhibition, 72–95%^a	COMFORT-I [11] SVR35, 42% TSS50, 46% COMFORT-II [12] SVR35, 32%
Momelotinib	JAK1/JAK2 ALK2 [80]	Half-life: 3.7 h^b [81] Cmax: 768 nM^b AUC: 4049 ng·h/mL^b	—	SIMPLIFY-1 [82] SVR35 MMB, 27% RUX, 29% TSS50 MMB, 28% RUX, 42% SIMPLIFY-2 [83] SVR35 MMB, 7% TSS50 MMB, 26% MOMENTUM [39] SVR35 MMB, 23% TSS50 MMB, 25%
Fedratinib	JAK2, FLT3 [66]	Half-life: 14.3–62.1 h^c [68] Cmax: 5.0–1760 nM^c AUC: 70.0–29,300 ng·h/mL^c	Mean pSTAT3 inhibition, −24% to +58%^d	JAKARTA [84] SVR35, 36% (400 mg) and 40% (500 mg) TSS50, 36% (400 mg) and 34% (500 mg)
Pacritinib	JAK2, IRAK1, CSF1R, FLT3, ALK2 [69,85,86]	Half-life: 1–4 days [87] Cmax: 6.9–7.9 nM^e AUC: 133–177 μg·h/mL^e	Maximum pSTAT3 inhibition, 32%–53%^f	PERSIST-1 [61] SVR35, 19% TSS50, 19% PERSIST-2 [88] SVR35, 18% TSS50, 25% PAC203 [89] SVR35, 9% (200 mg bid), 2% (100 mg bid), and 0% (100 mg qd) TSS50, 7% (200 mg bid), 7% (100 mg bid), and 8% (100 mg qd)

ALK2: activin receptor-like kinase-2; AUC: area under the curve; bid: twice per day; C_max: maximum plasma concentration; FLT3: Fms-like tyrosine kinase 3; JAK: Janus kinase; MMB: momelotinib; qd: once per day; RUX: ruxolitinib; SVR35: ≥35% spleen volume reduction from baseline; TSS50: ≥50% reduction in Total Symptom Score from baseline.

^aSteady-state parameters in healthy participants from a dose range 15 mg every 12 h to 100 mg every 24 h.

^bSingle 200 mg dose in healthy participants.

^cAscending single dose range 10–680 mg in healthy participants.

^dAscending single dose range 10–680 mg in healthy participants; PD assessments at 3 h post dose, mean pSTAT3 inhibition calculated as 100 – mean percentage of pSTAT3 remaining.

^eDay 15 assessments for dose range 100–300 mg in patients with lymphoma.

^fDay 1 assessments for dose range 100–600 mg in patients with relapsed lymphoma.

Table 4. Key clinical trials of ruxolitinib-based combination therapies.

Agent (class) Study participants, N	Phase (NCT#)	Main inclusion criteria	Main efficacy results	Safety overview
RUX + pelabresib [103] (BET inhibitor) JAKi-experienced: N = 86 JAKi-naive: N = 84	2 (NCT02158858; MANIFEST)	Age ≥18 y Peripheral blood blasts <10% ECOG PS ≤2 DIPSS ≥ int-2 ANC ≥1 × 10^9/L JAKi-experienced: PLT, ≥75 × 10^9/L JAKi-naive: • PLT, ≥100 × 10^9/L	JAKi-experienced
			Week 24 SVR35, 20%^a Week 24 TSS50, 37% Conversion from TD to TI, 16%	Hematologic grade ≥3 AEs: Thrombocytopenia, 33% Anemia, 19%
			JAKi-naive
			Week 24 SVR35, 68% Week 24 TSS50, 56%	Hematologic grade ≥3 AEs: Thrombocytopenia, 12% Anemia, 35%
RUX + parsaclisib [104] (PI3Kδ inhibitor) N = 74	2 (NCT02718300)	Age ≥18 y Peripheral blood blasts ≤10% ECOG PS ≤2 Suboptimal response to RUX ANC ≥0.5 × 10^9/L PLT, ≥50 × 10^9/L	Week 12 SVR35, 0% (qd/qw) and 6% (qd) Week 12 spleen volume reduction ≥10%, 33% (qd/qw) and 59% (qd)	Dose interruptions due to AEs: Parsaclisib, 18/33 and 10/20 patients in qd/qw and qd RUX, 4/33 and 4/20
RUX + azacitidine [105] (hypomethylating agent) N = 46	2 (NCT01787487)	Age ≥18 y DIPSS int-1 or -2 ECOG PS ≤2 ANC ≥1 × 10^9/L PLT, ≥50 × 10^9/L	ORR, 33/46 (72%) (IWG-MRT criteria) 7/33 responders (21%) achieved response after AZA addition Patients with BL splenomegaly >5 cm BCM Week 24 > 50% reduction in spleen length, 62% (21/34) Improvement in BM at Month 24 (n = 14): Reticulin fibrosis, 8 (57%) Collagen, 7 (50%) Osteosclerosis, 4 (29%)	Hematologic grade ≥3 AEs: Anemia (46%) Thrombocytopenia (30%) Neutropenia (14%) 8% discontinued because of drug-related toxicity (neutropenia, n = 2; anemia, n = 1; thrombocytopenia, n = 1)
RUX + navitoclax [106] (BCL inhibitor) N = 34 (combination treatment cohort)	2 (NCT03222609; REFINE)	Age ≥18 y Peripheral blood blasts ≤10% ECOG PS ≤2 DIPSS: int or high-risk MF Suboptimal response to RUX PLT, ≥100 × 10^9/L	Week 24 SVR35, 26.5% Week 24 TSS50, 30% BMF improved by 1–2 grades in 33% OS not reached at median follow-up of 21.6 mo	Hematologic grade ≥3 AEs: Thrombocytopenia, 56% Anemia, 32% Discontinuations due to AEs: Navitoclax, 5 patients (15%) RUX, 2 (6%) patients
RUX + danazol [107] (androgen) N = 14	2 (NCT01732445)	Age ≥18 y ECOG PS ≤2 Anemia (Hb <10 g/dL) ANC ≥1 × 10^9/L PLT, ≥50 × 10^9/L	IWG-MRT clinical improvement, 21.4% ORR, 7.1% 4/5 (80%) JAKi-naive patients had stable or increasing Hb Of 9 patients who had received JAKi, 5 (56%) had stable or increasing Hb and 8 (89%) had stable or increasing PLT	Hematologic grade ≥3 AEs: 71% (n = 10) Nonhematologic grade ≥3 AEs: 14% (n = 2)
RUX + luspatercept [108,109] (TGFβ superfamily receptor ligand trap) N = 79	2 (NCT03194542)	Age ≥18 y ECOG PS ≤2 Anemia ANC ≥1 × 10^9/L PLT, ≥50 × 10^9/L	Mean Hb increase ≥1.5 g/dL from BL: NTD, no RUX = 3/20 (15%); NTD + RUX = 8/14 (57%) RBC-TI ≥12 weeks during study: TD no RUX = 4/21(19%); TD + RUX = 8/22 (36%) ≥50% reduction in RBC transfusion burden: TD, no RUX = 8/21 (38%), TD + RUX = 10/22 (46%)	TRAEs in ≥5% of patients: Hypertension, 13% Bone pain, 9% Diarrhea, 5% 10% discontinued because of drug-related toxicity
RUX + sotatercept [109] (TGFβ superfamily receptor ligand trap) Combination cohort: n = 9 (sotatercept monotherapy: n = 24)	2 (NCT01712308)	Age ≥18 y Hb <10 g/dL Sporadic RBC transfusions, or TD	ORR = TI + Hb increase ≥1.5 g/dL from BL for ≥12 consecutive weeks without RBC transfusion 6/17 (35%) in sotatercept monotherapy cohort	TRAEs: Grade 2 bilateral lower limb pain, n = 2 (1 patient in each cohort) Hypertension, n = 1
		RUX combination cohort
		≥6 months RUX with stable dose for ≥2 months	Response in 1/8 (12.5%)
RUX + thalidomide [110] (immunomodulatory agent) N = 23 (n = 15 evaluated)	2 (NCT03069326)	Age ≥18 y ECOG PS ≤2 ANC ≥1 × 10^9/L PLT, ≥50 × 10^9/L Suboptimal response, or refractory to RUX single-agent therapy RUX treatment for ≥3 months, and stable dose for ≥4 weeks before enrollment	Cycle 3: Significant increase from BL in PLT Significant increase in PLT in patients with thrombocytopenia at BL Trend toward increase in Hb over time Spleen volume reduction in 6/11 (55%) ORR, 9/15 (60%) ClinImp, 7/15 (46.6%) PLT response, 6/8 (75%) with thrombocytopenia at BL	Nonhematologic grade ≥3 AEs: Limb edema, diverticulitis, hypertension, syncope (n = 1 each) Thromboembolic event and grade 3 neutropenia, n = 1
RUX + prednisone, thalidomide, and danazol [111] N = 72 (n = 53 in combination therapy group)	Pilot study (ChiCTR1900025219)	Age ≥18 y SV ≥450 cm^3 Peripheral blood blasts <10% ECOG PS ≤2 DIPSS: int-1, int-2, or high-risk ANC ≥1 × 10^9/L PLT, ≥50 × 10^9/L	Combo therapy group: Spleen reductions ≥50%, 44.9% Symptom response, 41.7%	20.8% had new or worsening anemia (grade ≥3, 13%) 18.9% had new or worsening thrombocytopenia (grade ≥3, 1.8%)
RUX + selinexor [112] (Nuclear export inhibitor) N = 10 (n = 3 in selinexor 40 mg qw + RUX group, n = 7 in selinexor 60 mg qw + RUX group)	1/2 (NCT04562389)	Age ≥18 y Peripheral blasts ≤5% and bone marrow blasts ≤10% ECOG PS ≤2 DIPSS: int-1, int-2, or high-risk ANC ≥1.5 × 10^9/L PLT, ≥100 × 10^9/L	Week 12 SVR35, 4/5 evaluable patients	No dose-limiting TEAEs No grade ≥3 neutropenia or thrombocytopenia

AE: adverse event; ANC: absolute neutrophil count; AZA: azacitidine; BCL: B-cell lymphoma; BCM: below costal margin; BET: bromodomain and extra-terminal; BL: baseline; BM: bone marrow; BMF: bone marrow fibrosis; ClinImp: clinical improvement; DIPSS: Dynamic International Prognostic Scoring System; ECOG PS: Eastern Cooperative Oncology Group performance status; Hb: hemoglobin; int: intermediate; IWG-MRT: International Working Group for Myelofibrosis Research and Treatment; JAKi: Janus kinase inhibitor; MF: myelofibrosis; NTD: non-transfusion dependence; ORR: overall response rate; OS: overall survival; PI3K: phosphoinositide 3 kinase; PLT: platelet; qd: once daily; qw: once weekly; RBC: red blood cell; RUX: ruxolitinib; SV: spleen volume; SVR35: ≥35% SV reduction from baseline; TD: transfusion dependent; TEAE: treatment-emergent adverse event; TGF: transforming growth factor; TI: transfusion independence; TRAE: treatment-related adverse event; TSS50: ≥50% reduction in Total Symptom Score from baseline.

^aFor SVR35 rates at Week 24, discontinued patients were included as nonresponders, and ongoing patients that had not yet reached Week 24 were excluded.

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