Momelotinib therapy for myelofibrosis: a 7-year follow-up

One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2–7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1–3.2) or SRSF2 (HR 2.4, 95% CI 1.3–4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3–16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9–32.1), and circulating blasts ≥2% (HR 3.9, 95% CI 1.4–11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.


Introduction
Momelotinib (MMB; GS-0387; CYT387) is a JAK1 and JAK2 inhibitor, with therapeutic activity in myelofibrosis (MF), in humans as well as in mice [1][2][3][4] . In a phase 1/ 2 study of MMB in patients with MF 1 , maximum tolerated dose was established at 300 mg/day and dose-limiting toxicity included grade 3 headache and hyperlipasemia. The particular phase 1/2 study included 166 patients treated at either 150 or 300 mg once-daily or 150 mg twice-daily for 9 months; 5 study patients were enrolled between November 2009 and August 2011 and 165 patients received at least one dose of study drug. The particular study included 14% of patients previously exposed to another JAK2 inhibitor therapy. After median (range) treatment duration of 15.3 months (0. 1-48.8), the overall response rate in the 166 patients multicenter study was 58% and included no complete remissions and only 1 partial remission and the drug did not affect the mutant JAK2 allele burden; anemia response was 59% and red cell transfusion-independency was achieved by 75% whereas palpable spleen response was reported at 40%. In terms of treatment-emergent drug toxicity, the most common grade 1/2 adverse events (AEs) included diarrhea, peripheral neuropathy and thrombocytopenia, and first-dose effect of hypotension, dizziness, nausea, headache, and flushing. The current study is limited to the subset of 100 patients treated with MMB at the Mayo Clinic; we provide a 7-year follow-up of patient data, which focuses on overall and leukemia-free survival, as well as the impact of driver and other mutations on response rates and overall, leukemia-free and relapse-free survival.

Methods
The current study was approved by the Mayo Clinic institutional review board and all patients provided informed written consent for clinical trial participation, study sample collection as well as permission for its use in research. Patient eligibility criteria, study design, treatment plan, study test schedule, and other protocol details have previously been reported 1 , and will not be reiterated here. The study population for the current study constitutes part of a larger phase 1/2 clinical trial (CCL09101; NCT00935987) using momelotinib for the treatment of MF; the results of which were recently communicated 5 . Toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Baseline transfusion status, anemia, and spleen responses were all defined according to the 2006 international working group for MPN research and treatment (IWG-MRT criteria) 6 . Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature and assignment as "unfavorable karyotype" was according to the previously established criteria 7 . Targeted next-generation sequencing was used to screen for prognostically relevant mutations 8,9 . Information on survival and leukemic transformation was updated in August 2017.
Statistical analyses considered clinical and laboratory parameters obtained at the time of MMB study entry. All statistical analyses considered clinical and laboratory parameters were obtained at the time of MMB study entry. Differences in the distribution of continuous variables between categories were analyzed by either Mann-Whitney or Kruskal-Wallis test. Patient groups with nominal variables were compared by chisquare test. Survival analysis was considered from the date of study entry to the date of death (uncensored) or last contact (censored). Patients receiving allogeneic stem cell transplant (ASCT) were censored at the time of their transplant for survival analysis. Leukemia-free survival calculations considered the transformation event as the uncensored variable. Survival curves were prepared by the Kaplan-Meier method and compared by the logrank test. The Cox proportional hazard regression model was used for multivariable analysis. p-Values less than 0.05 were considered significant. All analyses were conducted using the Stat View (SAS Institute, Cary, NC, USA). In order to obtain preliminary information regarding the impact of MMB therapy on survival, we recruited a retrospective cohort of JAK inhibitor treatment-naïve patients, from our institutional databases, matched for their dynamic international prognostic scoring system (DIPSS-plus) risk status 10 . All data were analyzed by the authors of the current document, without any influence from the sponsor.

Overall and leukemia-free survival analysis
To date, 73 (73%) deaths, occurring at a median of 2.5 years (range 0.06-6.9), and 15 (15%) leukemic transformations, occurring at a median of 3.6 years (range 0.12-7.2), have been recorded. Twenty-seven (27%) patients are currently alive and followed for a median of 6.6 years (range 5.5-7.2) from the time of study entry; among them, eight have received allogeneic stem cell transplant (ASCT) and were censored at the time of the procedure for survival analysis. Median survival from the time of study entry was 3.2 years with 5-year survival of 30%.

Discussion
It is now well-established that momelotinib treatment in MF provides relief from symptomatic splenomegaly and constitutional symptoms, and unlike most other JAK2 inhibitors, also improves anemia in a substantial fraction of patients 5 . The latter effect might be related to the drug's inhibitory activity on ALK2-mediated hepcidin expression 11 . Side effects of MMB, including thrombocytopenia and increased serum levels of liver and pancreas enzymes, can be monitored closely and might require drug dose adjustments. On the other hand, drug-induced peripheral neuropathy, which occurs in more than a third of the patients, might require earlier treatment discontinuation because of the possibility of irreversible damage 12 . Our long-term experience suggests that MMB is otherwise well tolerated and capable of inducing durable benefit, in a subset of molecularly appropriate patients, and without the unwanted side effect of druginduced anemia.
The pathway towards regulatory approval of MMB appears to be uncertain, judging from the underwhelming performance of the drug in two recent randomized studies. In JAK2 inhibitor-naïve patients 13 , MMB was compared to ruxolitinib and among patients completing 24 weeks of therapy, spleen response rates were similar (26.5% vs 29%) while anemia response rates were superior with MMB (transfusion-independence rate of 66.5% vs 49.3%) and symptoms response rates with ruxolitinib (42.2% vs 28.4%); grade 3/4 anemia occurred more frequently with ruxolitinib (23% vs 6%) while other AEs were reported to be similar. In the second phase 3 study of patients previously treated with ruxolitinib 14 , MMB was compared to best available therapy (BAT); among patients completing 24 weeks of treatment, spleen responses were not impressive in both arms of the study ( The palliative benefit of MMB and other JAK2 inhibitors comes at a cost to patients and this should be clearly communicated to them prior to starting treatment 15 . In this regard, the emphasis should be on peripheral neuropathy for MMB and anemia for ruxolitinib. Long-term use of ruxolitinib has also been associated with opportunistic infections, because of the immunosuppressive effects of the drug 16,17 . Patients should not be misled regarding the disease-modifying activity MMB or other JAK2 inhibitors, and there is no consistent evidence that these drugs can reverse MF or induce cytogenetic or molecular remissions; the mechanism of action for this class of drugs has been attributed to non-specific suppression of inflammatory cytokines, which explains their salutary activity in other unrelated conditions 18,19 . The current study underscores the transient nature of JAK2 inhibitor-induced palliation of symptoms in MF, as well as the limited effect on overall survival, which is instead primarily determined by the underlying molecular signature of the disease 20,21 . From a practical standpoint, these observations suggest that MF patients with SRSF2 or ASXL1 mutations or very high-risk karyotype might be better served by ASCT sooner than later. The use of JAK inhibitors in such cases is unlikely to modify the poor prognosis imparted by the associated adverse mutations and might compromise the sense of urgency for ASCT.