Tips on using ruxolitinib in everyday practice Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas, USA 1

3-Year Update From COMFORT-I Ruxolitinib (n = 155) Placebo (n = 151) Placebo Ruxolitinib (n = 111) Median exposure, weeks 145 37 105 Still on treatment, n (%) 77 (49.7) 57 (51.4) Crossed over, n (%) 111 (73.5) Discontinued, n (%) 78 (50.3) 40 (26.5) 54 (48.6) Primary reasons for discontinuation, n (%)* Death 15 (19.2) 7 (17.5) 11 (20.4) Adverse event 9 (22.5) 8 (14.8) Consent withdrawn 12 (15.4) Disease progression 18 (23.1) 13 (32.5) 15 (27.8) All patients originally randomized to placebo crossed over or discontinued within 3 months of the primary analysis Median time to crossover: 41.1 weeks * Percentages are calculated based on the number of patients who discontinued within the respective treatment group.

Spleen Volume Response: Ruxolitinib vs. BAT 132 (97%) 35 (56%) ↑ Spleen volume 4 (3%) 28 (44%)

Reduction in MF-Related Symptoms by Spleen Volume Reduction at Week 24 Total Symptom Score Mean % Change From Baseline ± SEM 70 30 -10 -50 -70 50 10 -30 n = 99 n = 20 P = .0004 n = 46 P<.0001 n = 60 P<.0001 All Placebo Ruxolitinib Spleen Volume Reduction <10% 10 to <35% ≥35% Improvement Worsening P value vs all placebo.

Durability of Spleen Volume Reduction 1.0 ≥10% reduction (n = 90) 0.8 0.6 Probability ≥35% reduction 0.4 0.2 8 16 24 32 40 48 56 64 72 80 88 96 104 112 No. at risk Weeks From Onset 90 84 75 72 63 57 52 47 43 41 35 4 4 4 90/155 (58%) had a 35% reduction at any time point during the study 64% maintained a ≥35% reduction for at least 2 years

Improvement in Symptoms Worsening Improvement * Fatigue * Dyspnea * Appetite loss * Insomnia * Pain * Diarrhea Nausea/vomiting Constipation Financial impact Overall Adjusted Mean Change From Baseline Score Ruxolitinib BAT

Duration of Symptom Improvement Global Health Status/QoL Mean Change From Baseline BL 12 24 36 48 60 72 84 96 Weeks 20 10 -5 -10 -15 15 5 Fatigue BL 12 24 36 48 60 72 84 96 10 -10 -15 -20 -25 5 -5 Weeks Ruxolitinib Placebo Role Functioning Physical Functioning 15 15 10 10 5 5 Mean Change From Baseline -5 -10 -5 -15 -20 BL 12 24 36 48 60 72 96 84 Weeks -10 BL 12 24 36 48 60 72 96 84 Weeks Arrows indicate improvement.

Improved Exercise Capacity and Body Weight 6-minute walk test (6MWT) is well established measure of exercise capacity MF patients walk 60-90 meters less than age-matched healthy volunteers 28 56 84 112 140 168 -9.5 -7.5 -5.5 -3.5 -1.5 0.5 2.5 4.5 6.5 8.5 10.5 12.5 Mean Lowest Quartile Days on Study Change in Body Weight, kg Ruxolitinib phase I/II

Efficacy of ruxolitinib in patients with MF without clinically significant splenomegaly Fatigue improved 6 Resolution of night sweats 2 Itching Weight gain (up to 17%) 5 Improved performance status Reduction of liver size 50-68% 3 of 3 All pts were symptomatic Ruxolitinib was administered at the dose of 25mg BID Benjamini et. al., Blood 2012; 120:2768-2769

Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time Ruxolitinib Grade 4 Ruxolitinib Grade 3 Placebo Grade 3 Placebo Grade 4 Anemia Thrombocytopenia 9.9 2.9 0.7 All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0–<6 months only

Mean Platelet Count and Hemoglobin Level Over Time 370 115 Ruxolitinib Placebo Ruxolitinib Placebo 110 320 105 270 Mean platelets (x109/L) Mean hemoglobin (g/L) 100 220 95 170 90 120 85 12 24 36 48 60 72 84 96 108 120 132 144 12 24 36 48 60 72 84 96 108 120 132 144 Weeks Weeks Number of patients Number of patients RUX 155 144 143 136 124 112 110 107 104 100 94 88 79 155 145 143 136 124 113 110 107 104 100 94 88 79 PBO 151 128 112 82 37 151 132 113 83 37

Development of Anemia Does not Affect Response to Ruxolitinib Treatment

Mean Daily Dose of Ruxolitinib Over Time 25 20 mg BID starting dose 15 mg BID starting dose 20 15 Mean Daily Dose (mg, BID) ± SEM 10 5 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 98 62 20 mg BID 49 20 15 mg BID Number of patients 100 55 77 69 33 26 73 30 93 35 Weeks Approximately 70% of patients had dose adjustments during the first 12 weeks of therapy By week 24, patients originally randomized to RUX 15 mg BID and 20 mg BID were titrated to a mean dose of ~10 mg BID and 15-20 mg BID, respectively

Optimizing Dose Titration of Ruxolitinib: The COMFORT-I Experience Baseline platelet count of less than 150 × 109/L was highly predictive of titration to a dosage of ≤10 mg BID within the first 8 weeks of ruxolitinib therapy Baseline hemoglobin value of less than 10 g/dL was highly predictive of an anemia event (developed grade ≥3 anemia or required RBC transfusion) within the first 12 weeks of ruxolitinib therapy Dose titration is a key!!!

Efficacy by Titrated Dose n=101 n=24 n=26 n=23 n=39 n=21 Spleen Volume n=103 n=22 n=38 n=20 Total Symptom Score n=35 n=28 n=31 n=17 Week 24 Week 48 Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment.

Consideration in everyday practice 1 Consideration in everyday practice 1. addition of an “Anemia Drug” to a JAK2 inhibitor for patients who are already seriously anemic or become anemic Danazol Erythropoietin Low dose thalidomide 2. start with the lower dose (same as for patients with low platelets): 5mg BID or 10mg BID, and increase in monthly increments

Ruxolitinib in Patients With Low Platelet Counts starting dose of ruxolitinib 5 mg twice daily, with escalations to maximum 15 mg twice daily in patients with MF and platelets 50- 100 x 109/L Pts with IPSS int-1/2 or high risk MF (evaluable N = 41) At 24 wks, most pts optimized to ruxolitinib dose 10 mg BID or higher; spleen volume reduction and TSS reduction consistent with data reported in COMFORT-I  

Modified Dose Escalation of Ruxolitinib: A Feasible Therapeutic Approach 26 patients received dose escalation approach: Starting with 5 mg BID and escalating monthly 16 received standard dose: Starting with 15 or 20 mg BID “A dose escalation approach for ruxolitinib therapy is better tolerated and with preserved clinical responses compared to the standard dosing regimen in patients with myelofibrosis” Tabarroki A, et al. Blood. 2013;122: Abstract 1586.

COMFORT-I: Incidence of new onset nonhematologic adverse events over time regardless of causality Percent of patients 0–<6 months 6–<12 months 12–<18 months 18–<24 months ≥24 months RUX PBO Fatigue 25.7 31.9 5.8 7.9 8.4 5.4 Diarrhea 23.2 22.9 5.7 3.4 10.3 Ecchymosis 18.1 9.2 5.5 4.3 1.6 Dyspnea 16.8 16.1 4.5 6.4 4.8 4.9 Peripheral edema 16.7 5.3 6.3 5.1 Headache 15.5 5.0 0.9 2.1 1.5 Dizziness 14.2 6.5 3.2 Nausea 12.8 17.0 5.2 3.0 8.0 Constipation 12.0 12.1 4.2 5.9 8.7 Vomiting 10.8 2.5 1.0 4.0 Pain in extremity 11.4 10.7 8.5 Pyrexia 11.3 2.4 3.7 6.7 8.2 Insomnia 2.0 2.8 4.1 Abdominal pain 10.1 40.7 Arthralgia 4.4

What happens if therapy with ruxolitinib is interrupted? Number of patients: 34 33 33 34 34 33 33 33 36 37 39 40 40 40 34 29 26 23 24 24 22 22 22 20 21 20 18 17 15 Days Around Dose Change Return of the symptoms within 7 days: AVOID INTERRUPTIONS!!!

Additional Safety Findings: COMFORT-I AML After 3 years of follow up: 4 cases in patients originally randomized to ruxolitinib and 4 in patients originally randomized to placebo Rate of leukemic transformation per person year of ruxolitinib exposure Originally randomized to ruxolitinib: 0.0121/person- year Originally randomized to placebo: 0.0233/person-year Historical control: 0.038/person-year No evidence of an increased risk of leukemic transformation

COMFORT-I: Reduction of JAK2V617F Allele Burden on Ruxolitinib Median variation on placebo + 3.5% at week 24 + 6.3% at week 48 Median variation on ruxolitinib: - 10.9% at week 24 - 21.5% at week 48

Effects of Five Years of Ruxolitinib Therapy on Bone Marrow Morphology in Patients With Myelofibrosis and Comparison With Best Available Therapy Kvasnicka HM, et al. Blood. 2013;122: Abstract 4055.

Recent publications of interest Ruxolitinib leads to improvement of pulmonary hypertension in patients with myelofibrosis. Tabarroki A, et al. Leukemia. 2014 Jan 10. [Epub ahead of print] Restoration of response to ruxolitinib upon brief withdrawal in two patients with myelofibrosis. Gisslinger H, et al. Am J Hematol. 2013 Nov 25. [Epub ahead of print]

Overall Survival: ruxolitinib vs. BAT (int-2/high risk MF) 52% reduction in risk of death in the ruxolitinib arm compared to BAT arm (HR = 0.48; 95% CI, 0.28-0.85; log-rank P = .009)

Impact Of Ruxolitinib On The Natural History Of Patients With Primary Myelofibrosis Patients who introduced ruxolitinib at some point during their disease history (COMFORT-2) had a better survival when compared to those who continued standard treatments for the whole follow-up (DIPSS).

Impact Of Ruxolitinib On The Natural History Of Patients With Primary Myelofibrosis

Overall survival of patients by degree of spleen length reduction

WHAT IS NEXT: combination trials with JAK2 inhibitors To increase benefits seen with JAK2 inhibitors (splenomegaly, symptoms) as well as to bring additional benefits (anemia, BM fibrosis, clone elimination) To reduce unwanted side effects (anemia, thrombocytopenia) but maintain clinical benefits MOST IMPORTANTLY: To improve stem cell transplant result

THANK YOU sverstov@mdanderson.org