Momelotinib Treatment-Associated Neuropathy: Prevalence, Risk Factors and Outcome in 100 Patients with Myelofibrosis

Background: Momelotinib (a JAK1 and JAK2 inhibitor) induces both anemia and spleen response in patients with myelofibrosis (MF) (Leukemia 2013;27:1322). The favorable effect on anemia was a distinguishing feature for momelotinib, compared to other JAK inhibitors, but the drug was also associated with treatment-emergent peripheral neuropathy (TE-PN). We examined the natural history and risk factors of momelotinib-associated peripheral neuropathy.

Methods: The study patients constitute part of a larger phase-1/2 clinical trial (CCL09101; NCT00935987) using momelotinib for the treatment MF. Toxicity grading was according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.03. Momelotinib capsules (as opposed to the newer tablet formulation used in the currently ongoing phase-3 study) were used in the current study, which represents a sponsor-independent analysis.

Results: 100 patients with MF (median age 66 years; 58% males) were treated at the Mayo Clinic between 11/20/09 and 11/10/10. DIPSS-plus (JCO. 2011;29:392) risk distribution was 63% high, 36% intermediate-2 and 1% intermediate-1. 75% of the patients harbored JAK2V617F and 50% abnormal karyotype. Previous treatment included other JAK inhibitors in 21 patients, thalidomide/lenalidomide/pomalidomide in 31 and hydroxyurea or other cytoreductive agents in 55. History of diabetes was documented in 7% of the patients at baseline and 14 (14%) of the patients had symptoms of PN before starting treatment with momelotinib, all of which were grade-1.

Momelotinib was initiated at 100 mg/day in 3 patients, 150 mg/day in 21, 150 mg twice-daily in 20, 200 mg/day in 3, 300 mg/day in 47 and 400 mg/day in 6. The maximum momelotinib dose was 150 mg/day in 6 patients, 150 mg twice-daily in 20, 300 mg/day in 68 and 400 mg/day in 6. Treatment duration was <6 months in 12 patients, 6-12 months in 22, 12-24 months in 19 and >24 months in 47.

Median follow-up after the institution of protocol drug therapy was 35 months (range 1-49). During this period, TE-PN was documented in 44 (44%) patients; of these, 42 were in patients without baseline neuropathy. TE-PN involved the feet only in 28 patients, hands only in one patient and both feet and hands in 15 patients. Median (range) for the time of onset of TE-PN was 32 weeks (1-132) and duration of TE-PN 11 months (0-40). All 42 newly-emergent PN were grade-1 sensory while the two patients with grade-1 baseline PN progressed to grade-2. Formal neurological evaluation, which was performed in 9 patients, mostly showed length-dependent sensory-motor large and small fiber neuropathy with axonal features.

TE-PN resulted in drug discontinuation in 7 patients and reduction in drug dose in 28 patients. Improvement after drug dose reduction was documented in only one patient and in none of those with drug discontinuation. Progression to grade-2 PN was documented in 3 patients.

TE- PN was significantly associated with clinical improvement (CI) with 54% incidence in responders vs 30% in non-responders (p=0.02); however, longer treatment duration was also associated with higher prevalence of TE-PN (p=0.03). In univariate analysis, patients with TE-PN lived longer than those without TE-PN (p=0.048); however, significance was lost during multivariable analysis that included either achievement of CI or treatment duration.

Neither the initial (p=0.53) nor maximum (p=0.37) momelotinib dose was correlated with TE-PN, which was also not influenced by JAK2V617F (p>0.99), karyotype (p=0.26), history of diabetes (p=0.39) or previous treatment with JAK inhibitor therapy (p=0.7), thalidomide (p=0.24), lenalidomide (p=0.59), pomalidomide (p=0.63) or hydroxyurea (p=0.56). There were no correlations between TE-PN and age (p=0.37), sex (p=0.37), type of MF (p=0.98), DIPSS-plus score (p=0.07), baseline transfusion dependency (p=0.15), constitutional symptoms (p=0.83) or spleen size (p=0.53). TE-PN did not correlate with hematologic (p=0.14) or extramedullary toxicity other than PN (p=0.41) or lipase/amylase abnormalities (p=0.35).

Conclusions: Momelotinib-associated neuropathy in MF might not be reversible in the majority of cases but also does not appear to be progressive. We were not able to identify risk factors for TE-PN, other than duration of treatment, which also explains its apparent association with response/survival. We are currently looking into possible correlations with serum thiamine levels.