Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate/High-Risk Myelofibrosis: Evidence to Date

Figures & data

Table 1 Summary of prognostic scores for therapeutic stratification in MF

Assigned number of points for individual risk factors, according to each risk score
Risk factors			IPSS^Citation15		DIPSS^Citation16		DIPSS-Plus^Citation17		MIPSS70^Citation18
Age >65 years			1		1		1		1.5§
Hemoglobin <100 g/L			1		2		1		0.5
Leukocyte count >25×10^9/L			1		1		1		NA
Circulating blasts ≥1%			1		1		1		NA
Presence of constitutional symptoms*			1		1		1		0.5
Unfavourable cytogenetics^#			NA		NA		1		NA
Red cell–transfusion need			NA		NA		1		NA
Platelet count <100×10^9/L			NA		NA		1		NA
Platelet count <200×10^9/L			NA		NA		NA		1
Triple negativity			NA		NA		NA		1.5
JAK2/MPL mutation			NA		NA		NA		0.5
ASXL1 mutation			NA		NA		NA		0.5
SRSF2 mutation			NA		NA		NA		0.5
Risk categorization and median survival
Risk	IPSS	Median survival	DIPSS	Median survival		DIPSS-plus	Median survival	MIPSS		Median survival
Low	0	11.3	0	NR		0	15.4	0–0.5		26.4
Int-1	1	7.9	1–2	14.2		1	6.5	1–1.5		9.7
Int-2	2	4	3–4	4		2–3	2.9	2–3.5		6.4
High	≥3	2.3	5–6	1.5		≥4	1.3	≥4		1.9

Notes: *Fever, night sweats, weight loss >10% from baseline; ^#+8, −7/7q–, i(17q), −5/5q–, 12p–, inv(3), 11q23 rearrangement; ^§age >60 years for MIPSS.

Abbreviations: Int-1, intermediate-1; Int-2, intermediate-2; NR, not reached.

Table 2 Summary of clinical trials using momelotinib in management of MF

Phase	Trial	Patients enrolled (n)	Description and objectives	Outcome measures	Outcomes	Ref
I/II	NCT00935987	166	Open-label, dose-escalation study evaluating the safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor	Primary Safety and tolerability (dose-limiting toxicities) and maximum tolerated dose up until 30 days after the last dose of CYT387 Objective response rate measured as complete response, partial response, or clinical improvement Pharmacokinetics of CYT387 (baseline to end of cycle 1) Secondary Effect of CYT387 on: Bone marrow or peripheral blood cytogenetics (assessed at the end of every third cycle) Peripheral blood–granulocyte JAK2^V617F- allele burden (assessed at the end of each cycle of therapy) Peripheral blood endogenous myeloid-colony formation (from baseline to study completion) Plasma levels of inflammatory fibrogenic and angiogenic cytokines (baseline to study completion) Pharmacodynamic correlates of CYT387 activity in patients with PMF or PET/PPV MF	Primary Dose-linear Cmax and exposure observed between the 150 and 300 mg/day doses, with mean elimination t½ 3.9–6.1 hours None of the patients had peripheral blood that qualified as complete response, so bone-marrow biopsies were not performed Secondary Change in IL1RA) and -1β associated with transfusion-independent response Spleen response was significantly associated with IL1RA, IL1β, IL2, bFGF, TNFα, MIP1β Treatment-associated decrease in cytokine levels associated with anemia ± spleen response Dominant cluster of overexpressed genes identified in anemia responders vs nonresponders	^Citation37
I/II	NCT00935987 7-year follow-up	100	Seven-year follow up of phase I/II study of patients with MF being treated with CYT387	Primary Effect of Mmb on overall and leukemia-free survival Secondary Impact of driver and other mutations on response rates, leukemia-free survival and relapse-free survival	Primary 73% of deaths occurred at a median of 2.5 years and 15% leukemic transformations occurred at median of 3.6 years At publication of results, 27% of patients were alive with median of 6.6 years from entering the study. Secondary Median treatment time with Mmb 1.4 years: clinical improvement in 57% of patients, with 43% achieving anemia response and 43% receiving spleen response Clinical improvement (CI) more likely to occur in ASXL1-unmutated patients and those with circulating blast count <2% CI not influenced by mutational status, DIPSS-plus risk, SRSF2 mutations, abnormal or unfavorable karyotype, prior JAK2-inhibitor therapy, leukocyte count, platelet count, or spleen size	^Citation39
III	SIMPLIFY-1 NCT01969838	432	An international randomized, double-blind, double-dummy, controlled study of Mmb versus Rux in subjects who were JAK kinase inhibitor–naïve with MF 215 patients received Mmb 217 patients received RUX	Primary Splenic response rate at 24 weeks: proportion of participants achieving ≥35% splenic volume reduction at week 24 on MRI or CT scan Secondary Response in TSS: proportion of patients achieving ≥50% reduction in TSS at week 24 Rate of RBC transfusion Average number of RBC units transfused per participant per month throughout 24-week period RBC-transfusion independence Proportion of patients transfusion-independent at week 24 (absence of RBC transfusions and no hemoglobin levels <8 g/dL in prior 12 weeks) RBC transfusion–dependence rate Proportion of patients transfusion-dependent at week 24 (defined as at least four units RBC transfusions, or hemoglobin <8g/dL in prior 8 weeks) In addition to above, SIMPLIFY-2 also assessed total spleen response as a fifth secondary outcome	Primary Mmb noninferior to Rux and spleen-response rate had 34% reduction from baseline Secondary Only 28.4% of patients taking Mmb reported a reduction in TSS score ≥50% from baseline compared to 42.2% of patients in Rux arm, so Mmb was inferior to Rux in symptom response Median rate of RBC transfusions at week 24 was 0 units/month in the Mmb group compared to 0.4 units/month in the Rux group 66.5% taking Mmb were transfusion-independent by week 24 compared to 29.3% taking Rux 30.2% of patients taking Mmb were transfusion-dependent by week 24 compared to 40.1% of patients taking Rux	^Citation40
III	SIMPLIFY-2 NCT02101268	156	International open-label randomized controlled trial comparing the efficacy of Mmb versus best-available therapy in anemic and thrombocytopenic patients with PMF or post-PV/ET MF treated with RUX 104 patients received Mmb 52 received BAT (ruxolitinib 89%)		Primary Mmb noninferior to Rux for reduction in spleen size by at least 35% from baseline via CT or MRI assessment Secondary 27 (26%) patients receiving Mmb had a total reduction in TSS ≥50% from baseline, compared to 3 (6%) on BAT (p=0.0006). Median rate of RBC transfusion was 0.5 units per month for Mmb group compared to 1.2 units in BAT group (P=0.39) 42 (40%) Mmb patients did not need transfusion during the 24 weeks compared with 14 (27%) patients receiving BAT 33 (64%) patients receiving Mmb were transfusion-dependent by week 24 compared with 52 (50%) receiving BAT (P=0.1)	^Citation41
III	MOMENTUM NCT04173494	180	A randomized, double-blind trial comparing Mmb to Danazol in symptomatic, anemic patients who had previously JAK inhibitor–treated PMF, P-PV/ET MF	Primary Proportion of patients achieving ≥50% reduction in TSS over the 28 days immediately prior to the end of week 24 compared to baseline Secondary Transfusion independence Proportion of patients transfusion-independent at week 24 (defined as not needing RBC transfusion for ≥12 weeks prior to the end of week 24 and Hb ≥8 g/dL Splenic response rate Proportion of patients with splenic reduction ≥25% from baseline at week 24	Study ongoing	NA

Abbreviations: JAK, janus kinase; Mmb, momelotinib; Rux, ruxolitinib; RBC, red blood cell; PMF, primary MF; PV, polycythemia vera; ET, essential thrombocythemia; TSS, total symptom score; BAT, best alternative therapy; MRI, magnetic resonance imaging.

Table 3 Summary of momelotinib safety from clinical trials

	Trials
	NCT00935987	7-year follow-up NCT00935987	SIMPLIFY-1 NCT01969838	SIMPLIFY-2 NCT02101268
≥ Grade 3 hematologic adverse event	Thrombocytopenia (32%) Neutropenia (3%) Anemia (3%)	Thrombocytopenia (24%) Neutropenia (9%) Anemia (5%)	Mmb vs Rux Thrombocytopenia (7% vs 4.6%) Anemia (5.6% vs 23.1%) Neutropenia (2.8% vs 4.6%)	Mmb VS BAT Thrombocytopenia Seven (7%) vs three (6%) Anemia 14 (14%) vs seven (14%)
≥ Grade 3 nonhematologic adverse event	Hyperlipasemia (5%) Increased ALT (3%) Increased AST (3%) Headache (3%)	Hyperlipasemia (7%) Increased ALT (4%) Increased AST (2%) Headache (2%) Increased ALP (2%)	Hypertension (2.8% vs 4.2%)	Mmb vs BAT Abdominal pain One (1%) vs 3 (6%)
Gastrointestinal side effects	Most commonly noted: Nausea (18%) Diarrhea (13%) Severity grade 1–2 and self-limiting, not requiring dose reduction or discontinuation	All grade 1 or 2: Nausea (23%) Diarrhea (20%) Increased amylase (17%)	4.6% of patients had at least grade 3 diarrhea Treatment-emergent adverse events occurring in >10% included nausea (34%), abdominal pain (22%)	Mmb vs BAT Diarrhea 32 (31%) grade 1/2, two (2%) grade 3 vs 7 (14%) grade 1/2, one (2%) grade 3 Nausea 18 (17%) grade 1/2, two (2%) grade 3 vs four (8%) grade 1/2, one (2%) grade 3 Abdominal pain 15 (14%) grade 1/2 and one (1%) grade 3 vs five (10%) grade 1/2 and three (6%) grade 3 Constipation 12 (12%) vs two (5%), both grade 1/2
Peripheral neuropathy (PN)	27% reported peripheral neuropathy (mostly grade 1), with 13 patients reporting it as new and three patients reporting it as worsening or preexisting symptoms. Six of these (38%) had previous exposure to immunomodulators or JAK-inhibitor treatment. Median time to onset of symptoms was 141 days. Eight (50%) had complete resolution of symptoms by the end of the trial, despite continuing CYT387.	Seven patients (15%) 47% had grade 1 or 2 peripheral neuropathy	Mmb arm: PN noted in 22 patients (10.3%) with 28 adverse events compared to ten patients (4.6%) with eleven adverse events in Rux arm. Two patients receiving Mmb reported PN at baseline compared to one patient receiving Rux. All adverse events were grade 1–2, except for one episode of peripheral sensory neuropathy in Rux arm. PN did not lead to discontinuation of treatment. PN was most commonly reported as peripheral sensory neuropathy, with peripheral motor neuropathy occurring only with Mmb.	15 events of peripheral neuropathy reported in eleven (11%) of patients, all grade 1 or 2 except one case of grade 3 in patients receiving Mmb, two of whom had PN at baseline, compared to 0 patients in BAT group. Three (3%) patients discontinued Mmb due to PN (one resolved case of sensory neuropathy, one ongoing case of peripheral sensorimotor neuropathy, and one case of polyneuropathy).
Dose reductions	16 patients (33%) needed dose reduction, occurring more frequently in patients receiving 300mg than those receiving 150mg. Five patients needed dose reductions due to peripheral neuropathy. There was no clear pattern identified during analysis of adverse events for the remainder.	Not discussed in study	26% Mmb arm compared to 56% Rux arm needed dose reductions or interruptions (most commonly for adverse events — 17.3% and 25.6%, respectively).	60 (58%) patients receiving Mmb required dose reduction. Discontinuation of BAT was inconsistently reported, due to changes in therapy or intentional no therapy options available for this group.
Dose-limiting toxicities	Grade 3 headache (n=1) Grade 3 hyperlipasemia (n=1) Both reversible on drug discontinuation	Grade 3 headache Grade 3 hyperlipasemia	Reported for 17.8% in Mmb arm and 36.6% in Rux arm	17 (16%) patients receiving Mmb needed dose reduction. Nine (17%) PN patients receiving BAT needed dose reduction due to adverse events.
Acute leukemic transformation	Not discussed in study	On study: three leukemic transformations During 7-year follow-up, 15 patients had leukemic transformations occurring at median of 3.6 years	Mmb: one patient (grade 4) Rux: two patients (grades 3 and 5)	Mmb: two patients grade 5, one patient grade 4 BAT: one patient grade 1
Death	Total five deaths, none related to CYT387	On-study deaths: 15 patients During 7-year follow-up: 73 deaths occurring at median of 2.5 years ian survival from time of study is 3.2 years, with 5-r survival of 30%	At reported follow-up: Mmb: seven deaths (3.3%) Rux: seven deaths (3.2%)	At reported follow-up: Mmb group: six patients (6%) had died, with two possibly related to Mmb therapy Rux arm: four patients (7%) had died, not related to treatment
Reference	37	39	40	42

Abbreviations: JAK, janus kinase; Mmb, momelotinib; RBC, red blood cell; BAT, best alternative therapy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; PN, peripheral neuropathy.

Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895–2901. doi:10.1182/blood-2008-07-170449

 PubMed Web of Science ®Google Scholar

Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703–1708. doi:10.1182/blood-2009-09-245837

 PubMed Web of Science ®Google Scholar

Gangat N, Caramazza D, Vaidya R, et al. DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. JCO. 2011;29(4):392–397. doi:10.1200/JCO.2010.32.2446

 PubMed Web of Science ®Google Scholar

Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia. 2018;32(7):1631–1642. doi:10.1038/s41375-018-0107-z

 PubMed Web of Science ®Google Scholar

Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;27(6):1322–1327. doi:10.1038/leu.2013.71

 PubMed Web of Science ®Google Scholar

Tefferi A, Barraco D, Lasho TL, et al. Momelotinib therapy for myelofibrosis: a 7-year follow-up. Blood Cancer J. 2018;8(3):29. doi:10.1038/s41408-018-0067-6

 PubMed Web of Science ®Google Scholar

Mesa RA, Kiladjian -J-J, Catalano JV, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis. J Clin Oncol. 2017;35(34):3844–3850. doi:10.1200/JCO.2017.73.4418

 PubMed Web of Science ®Google Scholar

Mesa RA, Catalano J, Cervantes F, et al. Dynamic and time-to-event analyses demonstrate marked reduction in transfusion requirements for janus kinase inhibitor-naïve myelofibrosis patients treated with momelotinib compared head to head with ruxolitinib. 2019 ASH Annual Meeting & Exposition. 2019.

 Google Scholar