Momelotinib‑Induced Peripheral Neuropathy in Myelofibrosis

Incidence and Clinical Characteristics

In patients with myelofibrosis receiving momelotinib, peripheral neuropathy occurs in approximately 44 % of treated individuals. 1
The median time to onset of neuropathy is 32 weeks (≈227 days) after therapy initiation. 1
Neuropathy is predominantly sensory and most cases are grade 1–2 in severity. 1
Once neuropathy develops, its average duration is about 11 months. 1
Only ~2 % of patients experience symptom improvement after dose reduction or drug discontinuation. 1
5–8 % of patients discontinue momelotinib because neuropathy becomes intolerable. 1

Lack of Dose‑Response Relationship

The occurrence of treatment‑emergent peripheral neuropathy does not correlate with the initial momelotinib dose. 1
No association is observed between neuropathy risk and the maximum dose achieved during therapy. 1
Prior exposure to thalidomide does not influence the likelihood of developing neuropathy on momelotinib. 1

Proposed Pathophysiologic Mechanisms

Momelotinib’s off‑target inhibition of kinases involved in neuronal signaling may contribute to neuropathy. 1
Disruption of cytokine and growth‑factor signaling pathways (mediated by JAK1/JAK2) that are essential for peripheral nerve maintenance is a plausible mechanism. 1
Pre‑clinical data suggest that similar JAK‑inhibitor effects on dorsal‑root‑ganglion neurons—analogous to the neurotoxic pattern seen with bortezomib—could underlie the sensory neuropathy. 4

Clinical Management Recommendations (NCCN Guidelines)

Eligibility: Exclude patients who have grade ≥ 2 peripheral neuropathy from initiating momelotinib therapy. 5
Monitoring: Perform a neurologic assessment before each treatment cycle to detect new symptoms such as numbness, tingling, or pain in the extremities. 7
Dose Modification: Recognize that dose reduction is unlikely to reverse neuropathy, given the low improvement rate (≈2 %). 1
Discontinuation: Consider stopping momelotinib if neuropathy becomes functionally limiting or intolerable, acknowledging that 5–8 % of patients require discontinuation for this reason. 1

Distinction from Conventional Chemotherapy‑Induced Peripheral Neuropathy

Unlike CIP‑related neuropathy, momelotinib‑associated neuropathy lacks a dose‑response relationship. 1
The onset is delayed (median 32 weeks) compared with typical CIPN, which often appears within the first 2 months of treatment. 8
Reversibility is poor; neuropathy often persists despite drug cessation, contrasting with some CIPN forms that improve after stopping the offending agent. 1

Evidence strength: The incidence and clinical data are derived from pooled analyses of phase 3 randomized trials (n ≈ 725), representing high‑quality evidence. The mechanistic insights are based on pre‑clinical and observational studies, constituting lower‑level evidence.