COMFORT Trials: Applying Evidence to Intermediate-Risk Myelofibrosis
Panelists discuss how clinical trial data from the COMFORT studies supports using Janus kinase (JAK) inhibitors such as ruxolitinib for myelofibrosis patients beyond the original high-risk study population, with experts noting they often treat intermediate-1-risk patients based on symptomatic burden and splenomegaly rather than risk stratification alone to achieve meaningful spleen volume reduction and symptom improvement.
Summary of Ruxolitinib Efficacy Data and Clinical Application in Myelofibrosis
COMFORT Trials: Foundation for JAK Inhibitor Therapy
- COMFORT-1 and COMFORT-2 were pivotal randomized phase 3 trials leading to ruxolitinib approval
- Primary end point achievements:
- COMFORT-1: 42% vs <1% achieved ≥35% spleen volume reduction (SVR35) at week 24
- COMFORT-2: 28% vs 0% achieved SVR35 at week 48
- Survival benefit demonstrated in both trials:
- Hazard ratios of 0.69 and 0.70 respectively
- Confirmed by pooled analyses and large database studies from US and Europe
- Primary end point achievements:
Clinical Application Beyond Trial Parameters
- Real-world spleen response considerations:
- Most patients experience some degree of spleen volume reduction even if not achieving formal SVR35 threshold
- Waterfall plots show nearly all patients have some decrease in spleen size
- Cross-trial comparisons between JAK inhibitors are difficult to interpret
- Application to intermediate-1-risk patients:
- Despite COMFORT trials enrolling only intermediate-2 and high-risk patients, clinicians routinely use ruxolitinib for intermediate-1 risk patients
- Treatment decisions should be based on:
- Symptom burden (often underrecognized)
- Spleen-related issues
- Not solely on risk stratification scores
- Rationale for treating intermediate-1-risk patients:
- Earlier intervention may prevent disease progression
- May achieve spleen reduction more readily when treated earlier
- European label for ruxolitinib is symptom/spleen-based rather than risk-based
- Risk stratification primarily guides prognosis and transplant decisions, not JAK inhibitor use
The panel emphasized that formal risk classification should guide prognosis and transplant timing, while symptom burden and spleen-related issues should drive JAK inhibitor treatment decisions across all risk categories.
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