Ruxolitinib in Myelofibrosis

Topic 07 · Myeloproliferative Neoplasms

Ashwin Kishtagari, MBBS, MSCI

Division of Hematology/Oncology, Vanderbilt University Medical Center

2026-08-18

Overview

Ruxolitinib for MF

Ruxolitinib is an oral JAK1/JAK2 inhibitor and was the first drug approved for myelofibrosis (MF).

  • Approved for intermediate- or high-risk MF
  • Covers primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF
  • Original FDA approval: November 2011

Why a JAK inhibitor in MF

MF is characterized by dysregulated JAK-STAT signaling, marrow fibrosis, splenomegaly, and a heavy symptom burden.

  • Massive splenomegaly causes pain and early satiety
  • Constitutional symptoms: fatigue, night sweats, weight loss, pruritus
  • Reduced quality of life and shortened survival in higher-risk disease

Ruxolitinib targets the signaling that drives both splenomegaly and symptoms.

The Pivotal Trials: COMFORT

The COMFORT program

Approval was supported by two phase 3 trials: COMFORT-I and COMFORT-II.

  • Enrolled patients with intermediate-2 or high-risk MF
  • Primary endpoint in both: ≥35% reduction in spleen volume by imaging
  • Different comparators and timepoints, consistent results
  • COMFORT-I: vs placebo, spleen response at week 24
  • COMFORT-II: vs best available therapy (BAT), spleen response at week 48

COMFORT-I — design & result

Randomized, double-blind, placebo-controlled study in 309 patients.

Primary endpoint (≥35% spleen volume reduction at week 24):

  • Ruxolitinib ~42% vs placebo <1% (P < 0.001)

Symptoms — a key secondary endpoint:

  • ~46% of ruxolitinib patients achieved a ≥50% reduction in total symptom score, vs a low single-digit rate on placebo

COMFORT-II — design & result

Randomized 2:1, open-label study vs BAT in 219 patients.

Primary endpoint (≥35% spleen volume reduction at week 48):

  • Ruxolitinib ~28% vs BAT 0% (P < 0.001)

Mean spleen volume reduction was similar across both trials at week 24 (~32% in COMFORT-I, ~29% in COMFORT-II).

COMFORT — durability & survival

Benefits were sustained, with signals of a survival advantage.

  • Spleen responses maintained for years with continued therapy (median response duration ~3 years)
  • Pooled long-term follow-up suggested an overall survival benefit favoring ruxolitinib
  • Survival contrasts are confounded by crossover from the control arms

Note

Because control-arm patients could cross over, long-term comparative survival estimates should be read with that caveat in mind.

Safety

Safety profile

Dominated by on-target cytopenias.

  • Thrombocytopenia and anemia are the most common, dose-related effects
  • Risk of serious infections
  • Class-associated risks (e.g. non-melanoma skin cancer, herpes zoster)
  • Avoid abrupt discontinuation (risk of symptom rebound)

Warning

This deck summarizes published trial findings for educational use. Verify all figures, indications, and safety details against the current prescribing information and guidelines before any teaching or clinical use.

RR6 model

A New Formulation: Jakafi XR

Ruxolitinib XR (Jakafi XR)

In May 2026, the FDA approved a once-daily, extended-release tablet formulation of ruxolitinib — Jakafi XR.

  • Same active drug, once daily instead of twice daily
  • Approved for the same MF indications (intermediate-/high-risk, including post-PV and post-ET MF)
  • Goal is dosing simplification, not new disease territory

How XR was approved

No new efficacy trial — approval rested on bioequivalence.

  • Open-label, randomized, 2-period crossover study in healthy adults
  • Once-daily XR 55 mg shown bioequivalent to twice-daily IR 25 mg
  • Comparable steady-state exposure across the day

The efficacy and safety case carries over from the established immediate-release studies, including the COMFORT trials for MF.

Summary

  • Ruxolitinib was the first approved therapy for intermediate-/high-risk MF
  • COMFORT-I (vs placebo) and COMFORT-II (vs BAT) both met the ≥35% spleen reduction endpoint, with marked symptom improvement
  • Benefits were durable, with a probable survival signal (crossover-confounded)
  • Jakafi XR (2026) adds a once-daily option via bioequivalence — same drug, simpler dosing