Great Debates and Updates in Hematologic Malignancies 2014 Q: What is the optimal therapeutic choice for CML refractory to first- and second-generation TKIs? A: Stem Cell Transplant Michael J. Mauro, MD Leader, Myeloproliferative Disorders Program Memorial Sloan Kettering Cancer Center, New York, NY

Point 1: Prior response may very well predict subsequent response Both TKI and SCT salvage

Hammersmith score: How things went with Imatinib predict success or failure with 2G TGIs ; Might this be true for 3rd line? Good risk, <1.5 (n=24) 3 factors comprising the score: best cytogenetic response on imatinib: complete cytogenetic response, 0 points; 1-94% Ph-positive metaphases, 1 point; 95% or more Ph-positive metaphases, 3 points Sokal risk group: low, 0 points; intermediate or high, 0.5 points neutropenia: no neutropenia, 0 points; recurrent episodes of grade III-IV neutropenia during imatinib therapy that required dose reduction, 1 point. Intermediate risk, ≥1.5 and ≤2.5(n=27) Poor risk, >2.5(n=29) Milojkovic D et al, Haematolgica 2010

Disease status does matter at time of SCT: Cytogenetic Response 0/38 Abl kinase mutations 12/31 Abl kinase mutations HR=5.31, 95% CI 1.13-25.05, p=0.03 Oehler V et al, Blood 2007

Disease status does matter at time of SCT: mutations Jabbour E et al, Blood 2011

Disease status does matter at time of SCT: CP vs AP Jabbour E et al, Blood 2011

TKI exposure prior to SCT does not appear deleterious Point 2: TKI exposure prior to SCT does not appear deleterious

Effects of pre-transplant imatinib on post-transplant outcome N=91 (70 CML, 21 Ph+ ALL) Compared to EBMT controls No effect on OS, PFS, or NRM Higher relapse mortality Lower chronic GVHD Relapse Mortality FHCRC Analysis, IM versus historical control (survival) Non-relapse Mortality Deininger et al, Haematolgica 2006 Oehler V et al, Blood 2007

Ponatinib is by far the most efficacious salvage regimen Point 3: Ponatinib is by far the most efficacious salvage regimen

Comparative Efficacy Among Chronic –Phase CML Patients After Failure of 2nd generation TKIs Lipton, J. ASH Abstract 4010 2013

PACE Trial (Ponatinib in TKI-Resistant CML): 2-Yr Update Ponatinib: oral BCR-ABL TKI Active against multiple mutations including T315I Heavily pretreated study population CP-CML pts: ≥ 2 TKIs: 93%; ≥ 3 TKIs: 60% Current follow-up: 2 years Patients with CML or Ph-positive ALL resistant or intolerant to dasatinib or nilotinib or with emergent T315I mutation (N = 449) Ponatinib 45 mg/day Cortes JE, et al. ASH 2013. Abstract 650.

Response in Heavily Pretreated Pts with Ph+ Disease PACE: Response in Heavily Pretreated Pts with Ph+ Disease Outcome  CP-CML AP-CML BP-CML Ph+ ALL MCyR* CCyR* MMR* MaHR R/I, % 56 48 31 62 32 50 T315I, % 72 70 58 61 29 36 Total, % 60 54 38 41 Median TTR, mos 2.8 2.9 5.5 0.7 1.0 *At any time after initial ponatinib dose. †14 AP CML pts w/baseline MaHR + 1 AP-CML pt w/no baseline MaHR assessment counted as nonresponders. Estimated 89% of pts with CP-CML to maintain MCyR ≥ 2 yrs Estimated 21% of pts with AP-CML to maintain MaHR ≥ 2 yrs Cortes JE, et al. ASH 2013. Abstract 650.

PACE Trial: Baseline BCR-ABL Mutations and Response to Ponatinib Characterized baseline BCR-ABL mutations in patients with CP-CML (N = 267) Sanger sequencing (sensitivity > 10% to 20% frequency) Next generation sequencing (sensitivity > 1% frequency) Low-level BCR-ABL mutations in 27% of patients (sole mutation in 12%) Compound BCR-ABL mutations in 15% of patients High MCyR (> 40%) by 12 mos for patients regardless of identified mutation status (0, 1, ≥ 2, low-level alone, or compound) Including specific baseline mutations identified in > 10 pts (T315I, F317L, F359V, E255K, G250E) Deininger MW, et al. ASH 2013 Abstract 652.

PACE Trial: BCR-ABL Mutation Analysis After Ponatinib Treatment Sanger sequencing (N = 146) Failed to reach MCyR at 12 months (n =118) Lost MCyR (n = 13) Discontinued in MCyR (n = 27) Few new BCR-ABL mutations developed in patients treated with ponatinib Failed to reach MCyR at 12 months: 4 of 102 evaluable patients Lost MCyR: 2 of 13 evaluable patients Discontinued in MCyR: 2 of 13 evaluable pts No single mutation detected that confers ponatinib resistance Deininger MW, et al. ASH 2013. Abstract 652.

Point 4: Adverse events on ponatinib may warrant limited exposure and risk mitigation

Most Common Treatment-Emergent Adverse Events With Ponatinib Select Any Grade AEs, % CP CML (n = 270) Total Population (N = 449) Any Grade Grade 3/4 Nonhematologic Rash* 44 4 40 Abdominal pain 43 9 Headache 41 3 36 2 Dry skin Hypertension 27 10 24 Elevated lipase 25 12 21 Hematologic Thrombocytopenia 35 Neutropenia 19 16 22 Anemia 15 *Combines the terms erythematous, macular, and papular rash. Cortes JE, et al. ASH 2013. Abstract 650.

Most Common Treatment-Emergent Serious Adverse Events With Ponatinib Serious AE, % CP CML (n = 270) Total Population (N = 449) Pancreatitis 7 6 Atrial fibrillation 4 3 Myocardial infarction Coronary artery disease 2 Cerebrovascular accident Cardiac failure 1 Hypertension Anemia Thrombocytopenia Febrile neutropenia < 1 As of December 2013, ponatinib is approved for patients with CML or Ph+ ALL and the T315I mutation or for whom no other TKI therapy is indicated Cortes JE, et al. ASH 2013. Abstract 650.

Vascular Adverse Events With Ponatinib US Ponatinib Insert (2012-07-23) Median Follow-up: 2 Mos  (340 Patient Yrs) PACE Trial (2013-09-03) Median Follow-up: 24 Mos (578 Patient Yrs) Serious AE AE Cardiovascular 5 6 9 Cerebrovascular 2 3 4 Peripheral vascular Venous thromboembolism Total vascular occlusion By trial criteria 14 20 By FDA criteria 10 18 15 24 Cortes JE, et al. ASH 2013. Abstract 650.

Time to First Vascular Occlusive Event: Ponatinib Proportion of Patients Without Vascular Occlusive Events NIL 400 BID NIL 300 BID IM 400 QD Vascular Events Time Time (Days)

Hypertension observed on Ponatinib

Concluding Points: Multi-drug resistant CML has lower odds of success with subsequent TKI based salvage Amongst TKI options, ponatinib offers margin of superiority albeit with significant toxicity risk Shorter term TKI salvage likely optimal for many to examine response, avoid subsequent relapse and minimize vascular/other toxicity TKI exposure does not impact transplant Disease state does impact SCT Final advice: ponatinib->SCT when possible Younger patient with low risk SCT option Any cases with prior transformation to AP/BC

Thank you! maurom@mskcc.org 212-639-3107