Ruxolitinib in Polycythemia Vera

Topic 05 · Myeloproliferative Neoplasms

Ashwin Kishtagari, MBBS, MSCI

Division of Hematology/Oncology, Vanderbilt University Medical Center

2026-08-18

Overview

Ruxolitinib for PV

Ruxolitinib is an oral JAK1/JAK2 inhibitor approved for adults with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

  • First targeted therapy approved in this second-line PV setting
  • Acts on the JAK-STAT pathway driving the PV clone
  • Original FDA approval: December 2014

Why a JAK inhibitor in PV

PV is driven by constitutive JAK-STAT signaling, most often through the JAK2 V617F mutation present in the large majority of patients.

  • Hydroxyurea is the usual first-line cytoreductive agent
  • A subset become resistant to or intolerant of hydroxyurea
  • This group has historically had limited options — the gap ruxolitinib was developed to fill

The Pivotal Trial: RESPONSE

RESPONSE — design

The approval was supported by the phase 3 RESPONSE trial.

  • Global, randomized, open-label study across 109 sites
  • 222 patients with PV, resistant to or intolerant of hydroxyurea
  • All had splenomegaly and were phlebotomy-dependent
  • Randomized 1:1: ruxolitinib 10 mg twice daily vs best available therapy (BAT)
  • BAT could cross over to ruxolitinib from week 32

RESPONSE — primary endpoint

A composite endpoint assessed at week 32:

Hematocrit control without phlebotomy (week 8–32) and a ≥35% reduction in spleen volume by imaging.

Designed to capture the two clinically meaningful goals of PV control at once: blood-count control and spleen reduction.

RESPONSE — primary result

Composite primary endpoint at week 32

  • Ruxolitinib: ~21% vs BAT: ~1% (P < 0.001)

Individual components

  • Hematocrit control without phlebotomy: 60% vs ~20%
  • ≥35% spleen volume reduction: 38% vs ~1%

Complete hematologic remission: ~24% vs ~9%

RESPONSE — durability

Responses proved durable with continued therapy.

  • Of patients meeting the primary endpoint at week 32, the large majority maintained response at later assessment
  • Long-term follow-up (80 weeks and beyond) confirmed durability
  • Most BAT patients crossed over to ruxolitinib at or soon after week 32

Note

Because nearly all BAT patients crossed over, long-term comparative survival contrasts are confounded — interpret beyond the primary timepoint with care.

Safety

Safety profile

Consistent with the known ruxolitinib profile.

  • Cytopenias: anemia, thrombocytopenia
  • Bruising, dizziness, headache, diarrhea
  • Serious infections and class-associated risks (e.g. non-melanoma skin cancer, herpes zoster) warrant monitoring

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.

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 indications include PV (post-hydroxyurea), unchanged in scope
  • Aimed at simplifying dosing, not expanding into 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 RESPONSE for PV.

Summary

  • Ruxolitinib is a JAK1/2 inhibitor for post-hydroxyurea PV
  • RESPONSE showed ~21% vs ~1% on the composite endpoint, driven by strong hematocrit control and spleen reduction
  • Responses were durable; safety dominated by cytopenias and infections
  • Jakafi XR (2026) adds a once-daily option via bioequivalence — same drug, simpler dosing