1. Verstovsek S et al. Proc ASCO 2011;Abstract 6500.
Results of COMFORT-I, a Randomized Double-Blind, Phase III Trial of JAK1/JAK2 Inhibitor Ruxolitinib (INCB18424) vs Placebo for Patients with Myelofibrosis
Verstovsek S et al.
Proc ASCO 2011;Abstract 6500.

2. Introduction
Myelofibrosis (MF) is characterized by splenomegaly, debilatating symptoms, cytopenias and shortened survival.
MF manifests as primary myelofibrosis (PMF), post-essential thrombocythemia MF (PET-MF) or post-polycythemia vera MF (PPV-MF).
Treatment of MF with conventional drugs provides only palliative benefits (Curr Opin Hematol 2006;13:87).
The JAK2 V617F mutation is found in about 50% of patients with MF and is associated with certain clinical signs such as splenomegaly (Blood 2007;110:4030).
Selective JAK1/JAK2 inhibitor ruxolitinib (INCB018424) has been shown to be effective in preclinical models of myeloproliferative neoplasms (Blood 2010;115:3109).
Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

3. JAK2 Signaling Pathway Ligand Receptor Phosphorylation Ruxolitinib
Transcription

4. COMFORT-I: A Phase III Trial of the JAK1/JAK2 Inhibitor Ruxolitinib
Eligibility
PMF or PPV-MF or PET-MF
Intermediate-2 or high risk by IWG-MRT criteria
Palpable spleen ≥5 cm
Platelet count ≥100 x 109/L
JAK2 V617F positive or negative
Ruxolitinib
15 or 20 mg BID R
Placebo*
* Crossover to ruxolitinib arm allowed
Ruxolitinib dose dependent upon starting platelet count:
15 mg BID if platelet count x 109/L
20 mg BID if platelet count >200 x 109/L
Spleen volume measured by MRI every 12 weeks
Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

5. Primary Endpoint: Patients with ≥35% Decrease in Spleen Volume (Week 24)
Odds ratio 134.4; 95% CI ( ,005)
41.9
Responders (%)
0.7
Ruxolitinib (n = 155)
Placebo (n = 153)
Patients discontinuing prior to week 24 or who crossed over prior to week 24 were considered nonresponders.
With permission from Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

6. Mean Percent Change from Baseline in Spleen Size Over Time
Spleen Volume (MRI or CT)
Palpable Spleen Length
Mean % Change ± SEM
Ruxolitinib
Placebo
With permission from Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

7. Percent of Patients with ≥50% Symptom Score Decrease (Week 24) — ITT
OR 15.28; 95% CI ( )
45.9
% of Patients
5.3
Ruxolitinib (n = 148)
Placebo (n = 152)
Symptom score = sum of scores for itching, night sweats, bone/muscle pain, abdominal discomfort, pain under the left ribs, and early satiety
With permission from Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

8. Probability of Survival
Overall Survival
Ruxolitinib Placebo
10 (6.5) (9.1)
Number (%) of Events
Probability of Survival
Hazard Ratio = 0.67 LogRank P value =
Weeks
With permission from Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

9. Hematology Laboratory Values (Worst Grade on Study*)
Ruxolitinib, n = 155
Placebo, n = 151
Grade 3 %
Grade 4 %
Hemoglobin
34.2
11.0
15.9
3.3
Platelets
9.0
3.9
1.3
Neutrophils
5.2
1.9
0.7
* Patients are included at their worst on-study grade regardless of whether this represents a change from their baseline.
Grade 3/4 anemia and thrombocytopenia were more common in those with higher baseline grade.
Discontinuation of treatment because of anemia and thrombocytopenia was rare (1 patient in each treatment group for each event).
Verstovsek S et al. Proc ASCO 2011;Abstract 6500.

10. Conclusions
Ruxolitinib demonstrated marked and sustained clinical benefits in spleen size.
Symptomatic burden was reduced in patients treated with ruxolitinib.
Thrombocytopenia and anemia were among the most common adverse events associated with ruxolitinib, though they rarely led to treatment discontinuation.
The results of this study, combined with those of the COMFORT-II trial (Proc ASCO 2011;Abstract LBA6501), demonstrate that ruxolitinib may become a treatment option for patients with MF.
Verstovsek S et al. Proc ASCO 2011;Abstract 6500.