1. Ponatinib as Initial Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Cortes JE et al. Proc ASH 2013;Abstract 1483.

2. Background Ponatinib is an oral, pan-BCR-ABL tyrosine kinase inhibitor (TKI) approved for patients with CML that is resistant or intolerant to previous TKI therapy. In vitro, ponatinib at clinically relevant concentrations (40 nM) is able to prevent the emergence of drug-resistant CML clones (Cancer Cell 2009;16:401). Use of ponatinib as front-line therapy may therefore result in high rates of early responses and prevent drug resistance in patients with CML. Study objective: To assess the efficacy and safety of single-agent ponatinib as initial therapy for patients with CML-CP. Cortes JE et al. Proc ASH 2013;Abstract 1483.

3. Phase II Trial Design Eligibility CML-CP with no or minimal prior therapy Primary endpoint: Complete cytogenetic response (CCyR) rate at 6 months Patients were followed with cytogenetic analysis and PCR every 3 months for the first 12 months, then every 6 months (data cutoff October 1, 2013). Ponatinib 45 mg PO daily* n = 51 † * Trial amendment changed starting dose from 45 mg daily to 30 mg daily (July 2013): 43 patients enrolled at 45 mg daily and 8 enrolled at 30 mg daily starting doses † Accrual suspended in October 2013 because of increased cumulative incidence of serious arteriothrombotic events Cortes JE et al. Proc ASH 2013;Abstract 1483.

4. Overall Response Response parameter n (%) Complete hematologic response (CHR)*43/48 (90%) CCyR † 41/42 (98%) Major molecular response (MMR)34/42 (81%) Complete molecular response11/42 (26%) * Only patients not in CHR at start of treatment † Patients with at least 3 months follow-up and evaluable karyotype Cortes JE et al. Proc ASH 2013;Abstract 1483.

5. Cytogenetic Response Over Time Cortes JE et al. Proc ASH 2013;Abstract 1483. Patient group3 months6 months9 months 12 months Best response Inevaluable00010 No cytogenetic response 11000 Partial cytogenetic response 31211 CCyR3832251741

6. Select Grade 3/4 Treatment- Emergent Adverse Events Hematologic n Neutropenia6 Thrombocytopenia5 Anemia2 Nonhematologic n (%) Elevated serum lipase23 (45%) Pancreatitis*10 (20%) Abdominal pain4 (8%) Elevated amylase level4 (8%) * 10/23 patients had symptomatic Grade 3 pancreatitis, and of these 9/10 had CT/ultrasound findings of pancreatitis; 13/23 had chemical pancreatitis; 2/23 had a repeated episode of pancreatitis. Cortes JE et al. Proc ASH 2013;Abstract 1483.

7. Cardiac and Vascular Adverse Events Cortes JE et al. Proc ASH 2013;Abstract 1483. Adverse events Any gradeGrade 3/4 n (%) Hypertension*11 (22%)4 (8%) Chest pain † 7 (14%)0 Acute coronary syndrome1 (2%) Raynaud syndrome2 (4%)0 Transient ischemic attack1 (2%)0 Peripheral vascular disease1 (2%)0 Palpitations1 (2%)0 Prolonged QTc interval1 (2%)0 Pericarditis1 (2%)0 * 3 patients had new onset hypertension (HTN) and 8 had preexisting HTN (5 had worsening of HTN, 3 stable HTN); 2 patients with Grade 3 HTN were receiving 45 mg and 2 were receiving 30 mg † 1 due to Grade 2 pericarditis and 6 patients had negative EKG and cardiac enzymes

8. Author Conclusions Ponatinib induces a high rate of early CCyR and MMR in patients with newly diagnosed CML-CP. With a dose of 45 mg daily most patients require dose reductions, most frequently because of elevation of lipase with or without pancreatitis. Hypertension occurs frequently in patients who receive ponatinib in this setting. Possible arteriovascular thrombotic events occur in nearly 20% of patients. Because of safety concerns related to increased cumulative incidence of arteriovascular thrombotic events in Phase I and Phase II studies for patients previously treated with other agents, enrollment to this study has ended. Cortes JE et al. Proc ASH 2013;Abstract 1483.

9. Single-Agent Ponatinib as Initial Therapy for CML-CP This was a single-arm, single-institution study with about 50 patients, and we reported that response rates with ponatinib at 3 months are excellent. At 3 months, more than 80% of patients have a complete cytogenetic response and we observe a high rate of major molecular response. The patients respond well to ponatinib and respond quickly. We did have a number of patients for whom we had to lower the dose of ponatinib. This was mainly due to the presence of elevated lipase levels, which was frequently asymptomatic. We also observed pancreatitis, but only occasionally was it regarded as true pancreatitis. Although most patients began the study at a dose of 45 mg, the median dose of ponatinib in the study was 30 mg daily. We did not have a control arm in this study. We do, however, have historical data with imatinib, and the results we observed with ponatinib look better than what we would expect with imatinib. Interview with Jorge E Cortes, MD, January 24, 2014