METHOD OF PARTICIPATION CME-certified Oncology Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: Pre-activity Survey Located at the front of your syllabus CME Evaluation with Post-activity Survey Located at the back of your syllabus METHOD OF PARTICIPATION A CME-certified Oncology Exchange Activity

Off-label Discussion Disclosure Disclosures All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers, or their spouses/partners have been listed on page 5 of your program syllabus. Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Identify changes in therapeutic indications and clinical practice guideline for CML Understand practical aspects of monitoring responses in patients with CML Identify the role of BCR-ABL mutations in making treatment decisions in CML Review emerging data from ongoing studies of novel treatment regimens and evaluate ongoing clinical trials of investigational agents

Pre-activity Survey Please remove the Pre-activity Survey from the front of your packet Your answers are vital to our understanding of the effectiveness of this CME program, and will help shape future educational activities and topics Please fill in the most appropriate answer(s) for the questions below: Degree:  MD/DO  Nursing Professional  PharmD  Other: _____________________________ Specialty:  Oncology/Hematology  Transplant specialist  Internal Medicine  Other: ___________

Pre-activity Survey Question 1 Please rate your level of confidence in treating and managing patients with chronic myelogenous leukemia (CML): 1 2 3 4 5 Not confident Expert

Pre-activity Survey Question 2 Please rate your level of competence in individualizing treatment options for patients with CML based on patient and disease characteristics: 1 2 3 4 5 Not competent Expert

Pre-activity Survey Question 3 Six years after starting imatinib, a 53-year-old patient’s BCR-ABL/ABL has increased to 27.3%. After performing a bone marrow biopsy, the patient is still in chronic phase, has 75% Ph+ metaphases and an F317L mutation. The patient receives nilotinib at 400 mg for 12 months after which there is no cytogenetic response. The most suitable option for this patient would be to: Continue therapy unchanged Consider ponatinib, omacetaxine, or SCT Consider bosutinib or dasatinib None of the above, enroll in a clinical trial Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Pre-activity Survey Question 4 A 37-year-old male was diagnosed with CML and treated with imatinib 400 mg for 12 months. He was re-evaluated and found to be in hematologic and partial cytogenetic response. Which of the following options would NOT be appropriate at this point: Repeat mutational analysis Switch therapy Check patient’s compliance with medications Continue treatment None of the above Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Pre-activity Survey Question 5 Cytogenetic analysis at 6 months of a 45-year-old female patient, who received prior imatinib, shows Philadelphia chromosome in 45% of metaphases and a BCR-ABL/ABL of 0.15. According to the 2013 European LeukemiaNet recommendations for the management of CML, how would you characterize this response. Failure Warning Suboptimal response Optimal response Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Pre-activity Survey Question 6 Which of the following treatment options can be considered for a patient who has failed imatinib and dasatinib or nilotinib: Omacetaxine Bosutinib Ponatinib Any of the above Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Evolution of CML Therapy

Signal Transduction Inhibition in CML The Beginning All seven individuals showed a similar minute chromosome. The findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia. Nowell PC & Hungerford DA. Science 1960, 132: 1497

The Evolution of CML Therapy Chemotherapy  SCT  IFN  TKI

History Lesson #1: SCT is Curative (For Some) Overall Survival Leukemia-Free Survival 58% 50% Reprinted with permission. © (2013) American Society of Clinical Oncology. All rights reserved.  Arora, M et al: J Clin Oncol 27(10): 1644-1652.

History Lesson #2: CCyR Correlates with Improved Survival Kantarjian et al. Cancer 2003; 97: 1033

History Lesson #3: SCT is NOT the Only Curative Treatment for CML Kantarjian et al. Cancer 2003; 97: 1033

Survival in Early Chronic Phase CML TKI Interferon Chemotherapy Kantarjian et al. Blood 2012; 119: 1981-7. Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.

Is The Outcome Really That Good? MDACC event: progression to AP/ BP; loss of MCyR; loss of CHR; no response (ELN criteria); intolerance; or death (any cause, any time) Kantarjian et al. ASH 2010; Abstract 672.

Or Is It Really That Bad? 281 pts Rx with imatinib as initial therapy (73 SD, 208 HD) CCyR 88%  75 stopped IM 41 events  23 received subsequent TKI  14 (67%) CCyR CEFS at 7 yrs = 88% EFS at 7 yrs = 81% Probability (%) 0.2 0.4 0.6 0.8 1.0 0.0 12 24 36 48 60 72 84 Al-Kali et al. Cancer 2011; 117: 327-35 CEFS = Current event free survival; EFS = Event free survival

Good Outcome: Just in Clinical Trials? 65 pts treated off protocol & 71 on protocols Imatinib 400 mg; Median f/u 51 mo Median [range], or Percentage On protocol Off protocol US Population Age, y 49 [15-79] 49 [15-84] High-risk Sokal 6 5 3-mo MCyR 71 69 12- mo CCyR 84 83 12-mo MMR 30 24 5-yr EFS 86 5-yr TFS 96 94 5-yr OS 90 Median income, $ 45,735 44,606 42,148 Education HS or less 42 43 48 Uninsured 10 8 14 Yilmaz et al. ASH 2012; Abstract #1693

Clinical Case Discussions Case 1: Frontline Therapy in Newly Diagnosed Setting

Case 1: History & Presentation 37 year old male, manufacturing employee at a mechanical shop. Married with two children. Presented with noted weight loss of 22 pounds in the last 12 months, with simultaneous onset of night sweats and fullness in the left side of his abdomen. This patient did not have a PCP and had not been seen by a physician since his childhood days for routine checkups.

Case 1: Work-up The major clinical finding was splenomegaly at 14 cm below the costal margin. Laboratory tests revealed: WBC of 317,000/ml with 47% immature myeloid cells (meta myelocytes, myelocytes, promyelocytes) 3% blast cells and 7% basophils in the peripherial blood Blood chemistries were abnormal with elevated lactated dehydrogenase of 842 u/L Platelet count was 916,000 Hemoglobin was 9.3 Other blood chemistries were WNL.

Case 1 (continued) CML is suspected and a test for bcr-abl revealed that the disease was bcr-abl positive leukemia with b3 a2 transcript consistent with CML. A bone marrow test followed and revealed bone marrow with high cellularity of 100% with predominant but well matured myeloid series. The bone marrow had 4% myeloblasts Bone marrow cytogenetic test revealed 20/20 cells with Ph+ and no evidence of additional chromosomal abnormalities was noted. With the diagnosis of CML in the chronic phase the patient was placed on imatinib 400 mg daily.

Case 1: Question 1 Is this the correct treatment decision? Imatinib is approved as first line treatment for CML and it is the correct choice The patient has high risk CML and he would have benefited from starting nilotinib or dasatinib With high-risk disease the patient should have been placed on ponatinib All are correct Only 1 & 2 are correct Only 2 & 3 are correct

Case 1: Answer Is this the correct treatment decision? Imatinib is approved as first line treatment for CML and it is the correct choice The patient has high risk CML and he would have benefited from starting nilotinib or dasatinib With high-risk disease the patient should have been placed on ponatinib All are correct Only 1 & 2 are correct Only 2 & 3 are correct Choices 1 and 2 are correct. Although imatinib, nilotinib, and dasatinib are all approved treatment options, the patient has a high risk CML by SOKAL criteria and responses to nilotinib 300 mgs x2 daily are superior to treatment with imatinib 400 mgs daily.

IRIS 8-Year Update At least 37% Unacceptable Outcome EFS = 81%; Freedom from progression to AP/BC = 92%; OS = 85% Deininger M, et al. Blood . 2009;114(22): 1126.

Imatinib Toxicities Imatinib: Common or Frequent Complaints Neutropenia Musculoskeletal complaints Thrombocytopenia – mainly during yr 1 Hypophosphatemia GI disturbances / Diarrhea Rash Edema and fluid retention Pediatrics: growth retardation Occasional bone mineral metabolism problem Long Term Toxicities of Imatinib Liver, kidney, cardiac toxicity and immunosuppression. CHF: 1276 patients at MDACC were studied with median follow up at 47 mos 22 patients, or 1.7% have CHF, however 13/22 had received cardio toxic drugs in the past. Management of Acute Toxicities Management of anemia and neutropenia includes use of erythropoietin and filgrastim Atallah et al, Blood 2007; 110: 1233–1237; Gleevec prescribing information, 2013.; NCCN Guidelines v4.2013.

ENESTnd 3-year update: OS and PFS Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 3-yr OS, % 95.1 97.0 94.0 HR (95% CI) vs imatinib 0.75 (0.37-1.55) 0.46 (0.20-1.07) -- P value vs imatinib .4413 .0639 PFS Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 3-yr PFS, % 96.9 98.3 94.7 HR (95% CI) vs imatinib 0.44 (0.17–1.15) 0.30 (0.10–0.92) -- P value vs imatinib . 0.0842 0.0260 BID, twice daily; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; QD, once daily. BID, twice daily; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; QD, once daily. Larson RA, et al. Leukemia 2012; 26: 2197-2203.; Kantarjian et al , ASH 2012 Abstract 1676.

ENESTnd 3-yr Update Nilotinib 300 mg BID (n = 282) (Larson et al 2012, Leukemia 2197-2203.) Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Response by 3 yrs, % MMR 73; P < .0001 70; P < .0001 53 MR4 50; P < .0001 44; P < .0001 26 MR4.5 32; P < .0001 28; P = .0003 15 3-mo landmark analysis: BCR-ABL transcript levels*, % MMR by 1 yr/2 yrs, % ≤ 1% (n = 120, 123, 41) 76/89 72/91 71/78 > 1 to ≤ 10% (n = 89, 95, 133) 40/67 38/54 31/52 > 10% (n = 24, 28, 88) 4/29 14/29 2/20 Freedom from progression to AP/BC, % Estimated 3-yr rate on core treatment 99.3; P = .0059 98.7; P = .0185 95.2 Including events after discontinuation 96.7; P = .0496 98.1; P = .0076 93.5 OS, % Estimated 3-yr OS rate 95.1; P = .4413 97.0; P = .0639 94.0 Only CML-related deaths 98.1; P = .0356 98.5; P = .0159 Patients with BCR-ABL mutation, n Any mutation 11 21 T315I 3 2 * Patients with unevaluable/missing PCR assessments at 3 mo, atypical transcripts, or MMR by 3 mo were excluded.

ENESTnd 3-Yr Update Hematologic AEs and Biochemical Abnormalities Grade 3/4 AEs, % Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Neutropenia 11.8 10.8 21.4 Thrombocytopenia 10.4 12.3 8.9 Anemia 3.9 4.7 5.7 Lipase increase 7.5 7.9 ALT increase 4.3 9.4 2.5 Total bilirubin increase 0.4 Hyperglycemia 6.1 5.4 AEs, adverse events; ALT, alanine aminotransferase; BID, twice daily; QD, once daily. Nilotinib Toxicities Prolongation of QTC and vascular adverse events Coronary events Peripheral Arterial Occlusive Disease – PAOD Larson RA, et al. Leukemia 2012;26; Tasigna prescribing information, 2013; NCCN Guidelines v4.2013. 32

DASISION 3-Yr Update Cumulative Molecular Responses Outcome, % Dasatinib 100 mg QD (n = 259) Imatinib 400 mg QD (n = 260) Cumulative MMR 1 yr 46* 23 2 yrs 64* 46 3 yrs 68* 55 Cumulative MR4 35† 22 Cumulative MR4.5 22‡ 12 *P < .0001 vs imatinib. †P = .00635 vs imatinib. ‡P = .00069 vs imatinib. OS and PFS 3-Yr Survival Outcome Dasatinib (n = 259) Imatinib (n = 260) HR (95% CI) PFS, % 91.0 90.9 1.00 (0.55-1.80) OS, % 93.7 93.2 0.86 (0.45-1.65) Deaths, n 17 20 - Hochhaus A, et al. ASCO 2012. Abstract 6504.

DASISION 3-Yr Update Hematologic AEs and Biochemical Abnormalities Toxicities Grade 3/4 AEs, % Dasatinib 100 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Neutropenia 24.0 20.9 Thrombocytopenia 19.4 11.2 Anemia 11.6 8.5 Decreased phosphorus 7.0 28.3 Decreased calcium 3.1 1.9 Elevated creatinine 1.2 0.8 Elevated total bilirubin Elevated ALT 0.4 1.6 Elevated AST Decreased potassium 2.3 Impaired platelet aggregation and bleeding Pleural effusion (up to 29% of pts) Reversible pulmonary arterial HTN Dose interruption in 83% of pts Dose reduction in 71% of pts AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; QD, once daily. Hochhaus A, et al. ASCO 2012. Abstract 6504; Sprycel Prescribing information 2013; NCCN Guidelines v4.2013. 34

Case 1 (continued) The patient responded rapidly to imatinib with resolution of his symptoms: weight gain and splenomegaly. The WBC returned to normal as did the platelet count, and the anemia resolved. Repeat quantitative bcr-abl test after 3 months of treatment revealed bcr-abl/abl ratio by international scale of 11%. A FISH test for bcr-abl was 22% positive. With these improved results the physician elected to continue imatinib at 400 mg daily. NCCN Guidelines v4.2013

Case 1: Question 2 Is continuation of imatinib an appropriate option? No, the patient failed to achieve a bcr-abl/abl ratio of <10% and should be a candidate for allogeneic bone marrow transplant. It is the correct treatment. The patient has achieved a hematologic response and a partial cytogenetic response The response is inadequate and the patient should have been switched to a 2nd generation TKI inhibitor, either nilotinib or dasatinib A mutation analysis should have been performed first and if there was no bcr-abl mutation, then the decision to continue with the same treatment could have been made NCCN Guidelines v4.2013

Case 1: Answer Is continuation of imatinib an appropriate option? No, the patient failed to achieve a bcr-abl/abl ratio of <10% and should be a candidate for allogeneic bone marrow transplant. It is the correct treatment. The patient has achieved a hematologic response and a partial cytogenetic response The response is inadequate and the patient should have been switched to a 2nd generation TKI inhibitor, either nilotinib or dasatinib A mutation analysis should have been performed first and if there was no bcr-abl mutation, then the decision to continue with the same treatment could have been made Patients with more than 10% bcr-abl/abl ratio are at a higher risk of progression and have a lower chance to achieve MMR at 12 months. NCCN Guidelines suggest treatment switch which involves 2nd generation TKI’s or dose escalation of imatinib. Bcr-abl mutation analysis can be performed at that stage and if mutations are detected this can served as a guide for treatment choices. NCCN Guidelines v4.2013

Case 1 (continued) After six months of therapy the patient started to complain of worsening diarrhea – up to 6x daily, poorly controlled with Imodium. The patient states that it has been embarrassing at times because of an inability to control it and that it is interfering with his work and social activities. At this juncture the hematologist lowered the imatinib to 200 mg daily

Adverse Event Management: Diarrhea Imatinib’s most frequently reported drug-related adverse events were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash Important to listen to patients and acknowledge that diarrhea can be debilitating and may seriously affect their daily activities. Physicians should discuss diet and explain to patients that certain foods, like spicy ones, can worsen diarrhea. Patients should be prescribed anti-diarrheal medications as needed. TKI dosage should be adjusted accordingly. Gleevec prescribing information 2013; DeAngelo, 2012; Kurtin, 2010.

NCCN Guidelines for CML Treatment Continuation or Change Time Response Recommendation 3 mo. Bcr/abl: ≤ 10 % Continue treatment Bcr/abl: > 10% Evaluate compliance ; Mutation Analysis; Change Therapy 12 mo. CCYR Continue Treatment ≤ PCYR Evaluate compliance ; Mutation Analysis; Change Therapy /Evaluate for HSCT 18 mo. NCCN Guidelines v4.2013

Case 1: Outcome The patient continued on imatinib 200 mg daily for an additional 9 months. At 12 months was found to be in hematologic response and partial cytogenetic response. Overall, he tolerated this change in treatment reasonably well and his diarrhea was moderately well controlled.

Clinical Case Discussions Case 2: Relapsed/Refractory Setting

Case Study 2 A 54-year old man has been receiving therapy with imatinib 400 mg daily for 6 months. Cytogenetic analysis shows Philadelphia chromosome in 25% of metaphases. Question 1 How would you label this response: Failure Secondary resistance Suboptimal response Optimal response Warning None of the above

Case Study 2: Answer How would you label this response: Failure Secondary resistance Suboptimal response Optimal response [ELN 2009 criteria] Warning [ELN 2013 criteria] None of the above Answer = 4; Optimal Response [per ELN 2009 criteria for failure and suboptimal response] Answer = 5; Warning [per ELN 2013 criteria for failure and suboptimal response]

Criteria for Failure and Suboptimal Response to Imatinib – ELN 2009 Time (mo) Response Failure Suboptimal Optimal 3 No CHR No CgR >95% Ph+ ≤65% Ph+ 6 >35% Ph+ ≤35% Ph+ 12 1-35% Ph+ CCgR 0% Ph+ 18 ≥5% Ph+ No MMR MMR Any Loss of CHR; Loss of CCgR; Mutation; CCA/Ph+ Loss of MMR; Mutation Stable or improving MMR Acronyms: Ph = Philadelphia chromosome; CHR = complete hematologic response; CgR = cytogenetic response; MMR = major molecular response; CCgR = complete cytogenetic response; CCA = clonal chromosome abnormalities. Baccarani et al. JCO 2009; 27: 6041-51

Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013 Time (mo) Response Failure Warning Optimal 3 No CHR, and/or Ph+ >95% BCR-ABL1 >10%, Ph+ 36-95% BCR-ABL ≤10%, Ph+ ≤35% 6 BCR-ABL1 >10% Ph+ >35% BCR-ABL1 1-10%, Ph+ 1-35% BCR-ABL <1%, Ph+ 0% 12 BCR-ABL1 >1% Ph+ >0% BCR-ABL1 >0.1-1% ≤0.1% Any Loss of CHR Loss of CCgR Confirmed loss of MMR Mutations CCA/Ph+ CCA/Ph- (-7, or 7q-) BCR-ABL1 ≤0.1% Acronyms: Ph = Philadelphia chromosome; CHR = complete hematologic response; CgR = cytogenetic response; MMR = major molecular response; CCgR = complete cytogenetic response; CCA = clonal chromosome abnormalities. Baccarani et al. Blood 2013; 122: 872-84. Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.

Case Study 2: Question 2 The patient has occasional muscle cramps, and no other toxicity. Your treatment recommendation: Continue therapy unchanged Increase the dose of imatinib to 400mg BID Change therapy to nilotinib 400mg BID Change therapy to dasatinib 100mg QD SCT

Case Study 2: Answer The patient has occasional muscle cramps, and no other toxicity. Your treatment recommendation: Continue therapy unchanged Increase the dose of imatinib to 400mg BID Change therapy to nilotinib 400mg BID Change therapy to dasatinib 100mg QD SCT Answer = 1; Continue therapy unchanged

Treatment Discontinuation for Frontline TKIs in CML Percentage F/U (mo) IM400 IM800 Nilotinib Dasatinib Bosutinib ENESTnd*¥ >36 38 29 DASISION 31 30 BELA >24 37 MDACC 24 18 8 We also compared the incidence of treatment discontinuation among the different therapies. In the large randomized studies, 20-25% of patients have been reported to have discontinued therapy by approximately 2 years. We analyzed the incidence of and reasons for treatment discontinuation for each arm within the first THREE years. We included treatment discontinuation due to any cause including: insurance issues, non-compliance, toxicity, or loss to follow up. Twenty-nine percent of patients had discontinued standard dose imatinib by 3 years, with failure being a prominent reason. Twenty-four percent had discontinued imatinib800 by 3 years; but there was no difference in the rate of discontinuation for toxicity in comparison to the lower standard dose of imatinib 400. Fewer of our patients discontinued dasatinib and nilotinib, even when considering the significant percentage that discontinued because of insurance and personal reasons. Personal reasons included the fear that these options were too experimental back in 2005. * Nilotinib 300mg BID shown. ¥ Includes patients who discontinued into extension study; rates are 26% imatinib and 22% nilotinib if all excluded Alattar et al. ASH 2011; Abstract #745; Saglio et al. ASH 2011; Abstract #452; Kantarjian et al. ASCO 2011; Abstract #6510; Cortes et al. ASH 2011; Abstract #455

Factors Influencing Early Discontinuation of 2nd Generation TKI Adverse events Lack of efficacy Availability of alternative options Decrease tolerance to adverse events Unreasonable expectations regarding toxicity Suboptimal management of AEs Lack of familiarity Baccarani et al. Blood 2013; 122: 872-84

Case Study 2: Question 3 Question 3 The patient has been on imatinib therapy now for 48 months. He had achieved an MMR (BCR-ABL/ABL <0.1% IS) that had been sustained for the last 18 months, most recently at 0.05 at 36 months and 0.03 at 42 months. A routine follow up assessment shows a normal CBS with a BCR-ABL/ABL of 0.09. Question 3 What additional tests would you request: Obtain FISH Repeat PCR in 3 months Assess for mutations Repeat cytogenetic analysis Perform a bone marrow aspiration All of the above 1 & 3 3 & 5

Case Study 2: Answer What additional tests would you request: Obtain FISH Repeat PCR in 3 months Assess for mutations Repeat cytogenetic analysis Perform a bone marrow aspiration All of the above 1 & 3 3 & 5

Significance of KD Mutations in Patients Responding to Imatinib PFS by Mutation at 2 Yrs 10 of 214 (5%) pts who achieved CCyR had mutation 4 before CCyR Median time from mutation to loss CCyR 20.7 months Median time from detection of mutation to 2-fold  PCR 12 mo KD mutation predictive of loss of CCyR Reprinted with permission. © (2013) American Society of Clinical Oncology.  All rights reserved.  Khorashad, JS et al: J Clin Oncol 26(29): 4806-4813.

When to Look For Mutations? Mutation analysis in 1301 pts receiving imatinib or 2nd generation TKI (GIMEMA) Clinical condition % Positive Failure 27 No CHR @ 3 mo 19 No CyR @ 6 mo 11 No PCyR @ 12 mo 17 No CCyR @ 18 mo Loss CCyR 31 Loss CHR 50 Suboptimal 5 No CyR @ 3 mo 7 No PCyR @ 6 mo No CCyR @ 12 mo 8 No MMR @ 18 mo Loss MMR 4 Soverini et al. ASH 2011; Abstract #112

Molecular Response in CML TFS and OS by MR at 24 months Survival (%) Response Total AP/BP P-value (vs. UND) 66 1 n/a 113 .25 37 .38 72 .33 25 .56 Response Total Died P-value (vs. UND) 66 3 n/a 113 4 .89 37 2 .94 72 .70 25 .22 Time (months) Falchi et al. Am J Hematol 2013: (In press)

Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013 Time (mo) Response Failure Warning Optimal 3 No CHR, and/or Ph+ >95% BCR-ABL1 >10%, Ph+ 36-95% BCR-ABL ≤10%, Ph+ ≤35% 6 BCR-ABL1 >10% Ph+ >35% BCR-ABL1 1-10%, Ph+ 1-35% BCR-ABL <1%, Ph+ 0% 12 BCR-ABL1 >1% Ph+ >0% BCR-ABL1 >0.1-1% ≤0.1% Any Loss of CHR Loss of CCgR Confirmed loss of MMR Mutations CCA/Ph+ CCA/Ph- (-7, or 7q-) BCR-ABL1 ≤0.1% Baccarani et al. Blood 2013; 122: 872-84

Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013 Time (mo) Response Failure Warning Optimal 3 No CHR, and/or Ph+ >95% BCR-ABL1 >10%, Ph+ 36-95% BCR-ABL ≤10%, Ph+ ≤35% 6 BCR-ABL1 >10% Ph+ >35% BCR-ABL1 1-10%, Ph+ 1-35% BCR-ABL <1%, Ph+ 0% 12 BCR-ABL1 >1% Ph+ >0% BCR-ABL1 >0.1-1% ≤0.1% Any Loss of CHR Loss of CCgR Confirmed loss of MMR Mutations CCA/Ph+ CCA/Ph- (-7, or 7q-) BCR-ABL1 ≤0.1% Lack of MMR is not a criterion for failure; confirmed loss of MMR is Baccarani et al. Blood 2013; 122: 872-84

Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013 Time (mo) Response Failure Warning Optimal 3 No CHR, and/or Ph+ >95% BCR-ABL1 >10%, Ph+ 36-95% BCR-ABL ≤10%, Ph+ ≤35% 6 BCR-ABL1 >10% Ph+ >35% BCR-ABL1 1-10%, Ph+ 1-35% BCR-ABL <1%, Ph+ 0% 12 BCR-ABL1 >1% Ph+ >0% BCR-ABL1 >0.1-1% ≤0.1% Any Loss of CHR Loss of CCgR Confirmed loss of MMR Mutations CCA/Ph+ CCA/Ph- (-7, or 7q-) BCR-ABL1 ≤0.1% Lack of MMR represents warning; lack of CMR is neither loss nor warning Baccarani et al. Blood 2013; 122: 872-84

Case Study 2: Question 4 Six years after the start of therapy, on a routine follow-up assessment you find the BCR-ABL/ABL has increased to 27.3% (IS). You perform a bone marrow and confirm that the patient is still in chronic phase but has 75% Ph+ metaphases. A mutation analysis shows a mutation F317L. Question 4 Your choice now is: Increase the dose of imatinib to 400mg BID Change therapy to nilotinib 400mg BID Change therapy to dasatinib 100mg QD Change to bosutinib 500 mg BID Change to ponatinib 45 mg daily Proceed to SCT

Case Study 2: Answer Your choice now is: Increase the dose of imatinib to 400mg BID Change therapy to nilotinib 400mg BID Change therapy to dasatinib 100mg QD Change to bosutinib 500 mg BID Change to ponatinib 45 mg daily Proceed to SCT

2nd Generation TKI in CML Parameter Dasatinib Nilotinib Bosutinib Potency (fold vs IM) 325 30 20-50 Target Src & Abl Abl Src & ABL BCR-ABL binding Active + Inactive Inactive Intermediate Resistant mutations T315I Mutations with intermediate sensitivity E255K/V, V299L, F317L E255K/V, Y253F/H, Q252H, F359V E255V/K, V299L, F317L Standard dose (CP) 100mg QD 400mg BID 500mg QD Grade 3-4 neutropenia & thrombocytopenia 33% / 22% 31% / 33% 12% / 21% Other notable toxicities Pleural effusion, bleeding Bilirubin, lipase elevation Diarrhea, rash C-kit inhibition (vs imatinib) Increased Similar None PDGFR inhibition (vs imatinib) Clinical activity Highly active Sprycel®, Tasigna®, Bosulif® prescribing information (2013).

2nd Generation TKI in CML CP Post-Imatinib Resistance Response Percentage Dasatinib Nilotinib Bosutinib FU (mo) >24 24* CHR 89 77 86 MCyR 59 56 54 CCyR 44 41 24 mo PFS** 80% 64% 79% 24 mo OS** 91% 87% 92% * Median ** All patients Shah et al. Haematologica 2010; 95: 232-40; Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76

2nd Generation TKI in CML CP Post-Imatinib Intolerance Response Percentage Dasatinib Nilotinib Bosutinib CHR 100 NR 85 MCyR 77 66 49 CCyR 67 51 41 Shah et al. Haematologica 2010; 95: 232-40; Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76

2nd-Generation TKI in CML CP Post- Imatinib Failure Toxicity Dasatinib Nilotinib Bosutinib Pleural effusion ++ - Liver + Transaminases Bilirubin Rash Diarrhea Lipase - (+) Glucose Hypophosphatemia Bleeding QTc

2nd-Generation TKI in CML CP Post- Imatinib Failure Toxicity Dasatinib Nilotinib Bosutinib Anemia 13 11 Neutropenia 35 31 18 Thrombocytopenia 23 30 24 Shah et al. Haematologica 2010; 95: 232-40; Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76

Sensitivity of Mutations to TKI IC50-fold increase (WT=1) Imatinib Bosutinib Dasatinib Nilotinib WT 1 L248V 3.54 2.97 5.11 2.80 G250E 6.86 4.31 4.45 4.56 Q252H 1.39 0.31 3.05 2.64 Y253F 3.58 0.96 1.58 3.23 E255K 6.02 9.47 5.61 6.69 E255V 16.99 5.53 3.44 10.31 D276G 2.18 0.60 1.44 2.00 E279K 3.55 0.95 1.64 2.05 V299L 1.54 26.10 8.65 1.34 T315I 17.50 45.42 75.03 39.41 F317L 2.60 2.42 4.46 2.22 M351T 1.76 0.70 0.88 0.44 F359V 2.86 0.93 1.49 5.16 L384M 1.28 0.47 2.21 2.33 H396P 2.43 0.43 1.07 2.41 H396R 3.91 0.81 1.63 3.10 G398R 0.35 1.16 0.69 0.49 F486S 8.10 2.31 3.04 1.85 Highly Resistant / Resistant / Sensitive Redaelli et al. JCO 2009; 27: 469-71

CCyR by Mutations in CML Treated with 2nd Generation TKI after IM Failure 86/169 (51%) pts treated had mutation CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%) IC50 for mutation with dasatinib, nilotinib predictive for response in CP and AP Chronic Phase Accelerated Phase Jabbour et al, Blood 2009; 114: 2037-43. . Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.

Case Study 2: Question 5 The patient has received nilotinib for 12 months with no cytogenetic response. You elect now to: Continue therapy unchanged Change therapy to dasatinib 100mg QD Change therapy to bosutinib 500 mg QD Change therapy to ponatinib 45 mg QD Change to omacetaxine SCT

Case Study 2: Answer The patient has received nilotinib for 12 months with no cytogenetic response. You elect now to: Continue therapy unchanged Change therapy to dasatinib 100mg QD Change therapy to bosutinib 500 mg QD Change therapy to ponatinib 45 mg QD Change to omacetaxine SCT Answer = 4, 5, 6

Survival free from transformation Are Responses Less Than CCyR Clinically Meaningful in 2nd Line Therapy for CML? 165 pts treated with ≥2nd line TKI after imatinib failure Best response: CCyR 52%, PCyR 7%, mCyR 14%, CHR 14%, no response 17% Overall responses Survival Survival free from transformation % 95% C.I. CCyR 98 94-100 95 90-100 PCyR 89 71-100 73 47-100 MinCyR 85 84 69-100 CHR only 72 52-100 88 67-100 No response 67 45-100 NA Responses inferior to CCyR still confer a long-term clinical benefit to patients treated with ≥2nd line TKI in CML CP compared to no response Cortes et al. Clin Lymphoma Myeloma Leuk 2011; 11: 421-6

Response to Bosutinib 3rd Line Therapy 114 pts who failed imatinib (600mg) & dasatinib or nilotinib Minimum 24 mo F/U Response, % IM + D resistant (n = 37) intolerant (n = 49) IM + NI (n = 27) CHR 62 80 76 MCyR 33 48 39 CCyR 19 43 27 PCyR 14 5 12 MMR 3 25 11 2-yr progression or death 21 49 IM, imatinib; D, dasatinib; NI, nilotinib. Khoury et al. ASH 2012; Abstract #3785

Ponatinib Phase 2 Study - PACE Response Characteristics CP-CML 93% failed ≥2 TKI, 58% failed ≥3 TKI Response Rate, n (%) N=267 Any Cytogenetic Response 180 (67) MCyR 149 (56) CCyR 124 (46) MMR 91 (34) MR4.5 39 (15) BCR-ABL ≤10% at 3 months, n/N(%) 142/240 (59) 1 prior approved TKI 14/16 (88) Median Time to Response*, months [range] 2.8 [1.6 – 11.3] 5.5 [1.8 – 19.2] 91% MCyR sustained at 12 months (K-M) Cortes et al. ASH 2012; Abstract #163

Omacetaxine for CML CP After Failure to ≥2 TKI 122 pts with CML CP (n=81) or AP (n=41) with ≥2 prior TKI Omacetaxine 1.25 mg/m2 BID x14d, then x7d Response, % CP N=81 AP N=41 Primary endpoint MCyR 20% MaHR 27% CCyR 10% CHR 24% Median duration, mo 17.7 9 Median PFS, mo 9.6 4.7 Median OS, mo 33.9 16 11 pts (9 CP, 2 AP) ongoing response Median 35 cycles over median 39 months Median response duration: 14 mo CP, 24 mo AP Cortes et al. Clin Lymphoma Myeloma Leuk 2013 [Epub ahead of print] 73

Management of Failure After TKI Close monitoring per standard recommendations (ELN) required Indication to change therapy when failure (not warning/suboptimal) Mutation analysis when failure; informative in some patients Avoid rapid succession of TKI Manage adverse events effectively Consider all your options

Participant Post-activity Survey Please remove the Participant Post-survey & CME Evaluation from the end of your packet By completing both the Pre- and Post-survey forms, you will help provide benchmarks and feedback that are vital to our understanding of the effectiveness of this CME program, and will help shape future educational activities and topics

Post-activity Survey Please fill in the most appropriate answer(s) for the questions below: Degree:  MD/DO  Nursing Professional  PharmD  Other: _____________________________ Specialty:  Oncology/Hematology  Transplant specialist  Internal Medicine  Other: ___________ Approximately, how many patients with CML do you treat/diagnose every month? _________

Post-activity Survey Question 1 As a result of attending the educational activity, please rate your level of confidence in treating and managing patients with CML: 1 2 3 4 5 Not confident Expert

Post-activity Survey Question 2 As a result of attending the educational activity, please rate your level of competence in individualizing treatment options for patients with CML based on patient and disease characteristics: 1 2 3 4 5 Not competent Expert

Post-activity Survey Question 3 Six years after starting imatinib, a 53-year-old patient’s BCR-ABL/ABL has increased to 27.3%. After performing a bone marrow biopsy, the patient is still in chronic phase, has 75% Ph+ metaphases and an F317L mutation. The patient receives nilotinib at 400mg for 12 months after which there is no cytogenetic response. The most suitable option for this patient would be to: Continue therapy unchanged Consider ponatinib, omacetaxine, or SCT Consider bosutinib or dasatinib None of the above, enroll in a clinical trial Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Post-activity Survey Question 4 A 37-year-old male was diagnosed with CML and treated with imatinib 400 mg for 12 months. He was re-evaluated and found to be in hematologic and partial cytogenetic response. Which of the following options would NOT be appropriate at this point: Repeat mutational analysis Switch therapy Check patient’s compliance with medications Continue treatment None of the above Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Post-activity Survey Question 5 Cytogenetic analysis at 6 months of a 45-year-old female patient, who received prior imatinib, shows Philadelphia chromosome in 45% of metaphases and a BCR-ABL/ABL of 0.15. According to the 2013 European LeukemiaNet recommendations for the management of CML, how would you characterize this response. Failure Warning Suboptimal response Optimal response Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Post-activity Survey Question 6 Which of the following treatment options can be considered for a patient who has failed imatinib and dasatinib or nilotinib: Omacetaxine Bosutinib Ponatinib Any of the above Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

Thank you for joining us today! Please remember to turn in your evaluation form. Your participation will help shape future CME activities.