Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Clinical Focus: Options for Treatment-Resistant or Treatment-Intolerant.

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Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC Clinical Focus: Options for Treatment-Resistant or Treatment-Intolerant Chronic Myeloid Leukemia This program is supported by an educational grant from Image: ISM/Copyright©2012 Phototake All Rights Reserved

Expectations on Imatinib: IRIS 8-Yr Update Shows 37% Have Unacceptable Outcome CCyR, complete cytogenetic response. *Unacceptable outcome. 1. Deininger M, et al. ASH 2009. Abstract 1126.

Optimal Dose and Schedule of Dasatinib in CP CML After Imatinib Failure: PFS 1.0 0.8 0.6 0.4 0.2 PFS at 60 mos was similar across treatment arms 70 mg BID 100 mg QD 140 mg QD 50 mg BID Not Progressed (%) PFS Rate, % (95% CI) n 12 Mos 24 Mos 36 Mos 48 Mos 60 Mos 70 mg BID 168 87 76 68 66 61 (52-70) 100 mg QD 167 91 81 72 63 57 (48-67) 140 mg QD 75 61 56 51 (40-62) 50 mg BID 86 73 69 67 (58-75) AP, accelerated phase; BID, twice daily; BP, blast phase; CHR, complete hematologic response; CI, confidence interval; CML, chronic myeloid leukemia; CP, chronic phase; MCyR, major cytogenetic response; PFS, progression-free survival; Ph+, Phildelphia chromosome positive; QD, once daily; WBC, white blood cell. 0 6 12 18 24 30 36 42 48 54 60 66 Mos Progression was defined as increasing WBC count, loss of CHR or MCyR, ≥30% increase in Ph+ metaphases, confirmed AP/BP disease, or death

Nilotinib in CP CML After Imatinib Failure: PFS 100 90 80 70 60 50 PFS (%) 40 Patients 321 114 207 Events 102 26 76 Censored 219 88 131 (1) All patients (2) With baseline CHR (3) Without baseline CHR Censored observations 30 20 CML, chronic myeloid leukemia; CP, chronic phase; PFS, progression-free survival. 10 6 12 18 24 30 36 42 48 Mos Since Start of Treatment Pts at Risk:Events, n (1) (2) (3) 321:0 114:0 207:0 248:21 93:5 155:16 198:45 78:12 120:33 161:70 71:16 90:54 137:88 63:20 74:68 109:95 51:22 58:73 96:101 47:25 49:76 5. Giles FJ, et al. Leukemia. 2012;[Epub ahead of print].

Bosutinib in CP CML After Imatinib Failure: PFS 100 90 80 70 60 Probability of Remaining Progression Free (%) 50 40 30 Total (n = 288) Imatinib intolerant (n = 88) Imatinib resistant (n = 200) 20 10 PFS, progression-free survival. 4 8 12 16 20 24 28 32 36 Mos to Progression Patients at Risk, n Total Imatinib intolerant Imatinib resistant 288 88 200 240 66 174 212 56 156 181 48 133 143 45 98 107 39 68 69 21 48 43 13 30 35 11 24 7. Cortes J E et al. Blood . 2011;118:4567-4576

Response to Bosutinib Third-line Therapy 118 patients who failed imatinib 600 mg and dasatinib or nilotinib Response, % Imatinib + Dasatinib Resistant (n = 37) Intolerant (n = 50) Imatinib + Nilotinib (n = 27) CHR 50 80 77 MCyR 31 30 32 CCyR 14 28 27 PCyR 17 2 8 MMR 3 35 11 2-yr PFS 22 61 2-yr OS 66 85 100 CCyR, complete cytogenetic response; CHR, complete hematologic response; CHR, chronic hematologic response; MCyR, major cytogenetic response; MMR, major molecular response; OS, overall survival; PFS, progression-free survival. 8. Khoury HJ, et al. Blood. 2012;119:3403-3412.

Ponatinib (AP24534): Pan-BCR-ABL Inhibitor Rationally designed inhibitor of BCR-ABL Active against T315I mutant Unique approach to accommodating gatekeeper residue Potent activity against an array of BCR-ABL variants Also targets other therapeutically relevant kinases Inhibits FLT3, FGFR, VEGFR, PDGFR, and c-KIT Once-daily oral activity in murine models N N N Avoids T315I N H N N O CF3 O’Hare T, et al. Cancer Cell. 2009;16:401-412.

PACE Phase II Ponatinib Trial: Study Design Study enrolled patients with CML or Ph+ ALL resistant/ intolerant to dasatinib or nilotinib, or with T315I 449 patients entered into 1 of 6 cohorts between Sept 2010 and Sept 2011; enrollment complete Primary endpoints MCyR for CP CML; MaHR for AP CML, BP CML, Ph+ ALL Patients, n CP CML AP CML BP CML Ph+ ALL R/I to dasatinib or nilotinib 203 65 48 T315I 64 18 46 Total* 270 85 94 ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; MaHR, major hematologic response; MCyR, major cytogenetic response; Ph+, Philadelphia chromosome positive; R/I, resistant/intolerant. *Includes 5 additional patients (3 CP, 2 AP) unassigned (post imatinib, non-T315I) but treated. 11. Cortes JE, et al. ASCO 2012. Abstract 6503.

PACE Interim Results: Primary Endpoint Response Response by Subgroup, n/N* (%) CP CML MCyR AP CML MaHR† BP CML Ph+ ALL MaHR R/I to dasatinib or nilotinib 99/203 (49) 39/65 (60) 17/48 (35) T315I 45/64 (70) 9/18 (50) 15/46 (33) Total‡ 144/267 (54) 48/83 (58) 32/94 (34) *N = evaluable patients. †Excludes 15 patients with baseline MaHR or no baseline assessment. ‡Excludes 5 patients ineligible (post imatinib, non-T315I) but treated; all 5 achieved MCyR. ALL, acute lymphoblastic leukemia; AP, accelerated phase; CML, chronic myeloid leukemia; CP, chronic phase; MaHR, major hematologic response; MCyR, major cytogenetic response; Ph+, Philadelphia chromosome positive; R/I, resistant/intolerant. 12. Cortes JE, et al. ASCO 2012. Abstract 6503.

PACE Interim Results: Response in CP CML Cohorts Response, n (%) Overall* (n = 267) R/I Cohort (n = 203) T315I Cohort (n = 64) CHR† 249 (93) 191 (94) 58 (91) MCyR‡ CCyR 144 (54) 118 (44) 99 (49) 76 (37) 45 (70) 42 (66) MMR§ 79 (30) 47 (23) 32 (50) *Excludes 3 patients unassigned (post imatinib, non-T315I) but treated. †CHR maintained or achieved during study; 103 patients had CHR at baseline. ‡MCyR is primary endpoint. §Patients with baseline MMR or no baseline assessment counted as nonresponders. CCyR, complete cytogenetic response; CHR, chronic hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; MCyR, major cytogenetic response; MMR, major molecular response; R/I, resistant/intolerant. 13. Cortes JE, et al. ASCO 2012. Abstract 6503.

PACE Interim Results: Response in Advanced Phase Cohorts Response, n (%) AP CML BP/Ph+ ALL R/I (n = 65) T315I (n = 18) (n = 48) (n = 46) MaHR* 39 (60) 9 (50) 17 (35) 15 (33) MCyR CCyR 22 (34) 13 (20) 10 (56) 6 (33) 13 (27) 11 (23) 16 (35) 12 (26) MMR† 6 (9) 3 (17) 9 (19) 2 (4) *MaHR is primary endpoint (15 patients with baseline MaHR or no baseline assessment counted as nonresponders). †Patients with baseline MMR or no baseline assessment counted as nonresponders. ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; MaHR, major hematologic response; MCyR, major cytogenetic response; MMR, major molecular response; Ph+, Philadelphia chromosome positive; R/I, resistant/intolerant. 14. Cortes JE, et al. ASCO 2012. Abstract 6503.

PACE Interim Results: Nonhematologic Treatment-Related Adverse Events Adverse Events (≥ 10% Any Grade), n (%) CP CML (n = 270) Entire Study (N = 449) Any Grade Grade ≥ 3 Rash* 100 (37) 10 (4) 143 (32) 16 (4) Dry skin 97 (36) 5 (2) 134 (30) 7 (2) Abdominal pain 71 (26) 18 (7) 97 (22) 25 (6) Headache 60 (22) 81 (18) 6 (1) Lipase increased 53 (20) 27 (10) 74 (17) 45 (10) Fatigue 51 (19) 4 (2) 73 (16) Constipation 50 (19) 3 (1) 67 (15) 5 (1) Myalgia 45 (17) 68 (15) Arthralgia 6 (2) 70 (16) Nausea 37 (14) 1 (0.4) 57 (13) 1 (0.2) Elevated ALT 29 (11) 9 (3) 41 (9) 14 (3) Asthenia 2 (1) 35 (8) 4 (1) Pancreatitis 19 (7) 17 (6) 27 (6) 22 (5) ALT, alanine aminotransferase; CML, chronic myeloid leukemia; CP, chronic phase. *Combines the terms erythematous, macular, and papular rash. 15. Cortes JE, et al. ASCO 2012. Abstract 6503.

PACE Interim Results: Hematologic Treatment-Related Adverse Events Adverse Events (≥ 10% Any Grade), n (%) CP-CML (n = 270) Entire Study (N = 449) Any Grade Grade ≥ 3 Thrombocytopenia 109 (40) 84 (31) 158 (35) 126 (28) Neutropenia 43 (16) 38 (14) 82 (18) 74 (17) Anemia 25 (9) 15 (6) 58 (13) 40 (9) CML, chronic myeloid leukemia; CP, chronic phase. 16. Cortes JE, et al. ASCO 2012. Abstract 6503.

Phase I Study of DCC-2036 in CML Switch pocket inhibitor active against T315I and other mutations 30 patients with CML: 19 CP, 9 AP, 2 BP MTD 150 mg BID (formulated tablets) DLT at 200 mg BID (muscle weakness, peripheral neuropathy) No myelosuppression Response: 4/19 (21%) in CP (1 MMR, 1 CCyR, 1 PCyR, 1 CHR) 1 AP with MaHR Correlation of efficacy with biomarker response Expansion cohort ongoing AP, accelerated phase; BID, twice daily; BP, blast phase; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; DLT, dose-limiting toxicities; MaHR, major hematologic response; MMR, major molecular response; MTD, maximum tolerated dose; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome positive. 17. Cortes JE, et al. ASH 2011. Abstract 601.

Omacetaxine for CML With T315I: OS CP 1.0 AP 0.9 BP 0.8 0.7 n = 49 Median: NA 0.6 Proportion Surviving 0.5 n = 17 Median: 18.8 mos 0.4 n = 15 Median: 2.4 mos CML, chronic myeloid leukemia; NA, not available; OS, overall survival. 0.3 0.2 0.1 5 10 15 20 25 30 35 40 Mos 18. Cortes-Franco J, et al. ASH 2009. Abstract 644.

Omacetaxine for CP CML Following Failure of ≥ 2 TKIs 122 patients with CP (n = 81) or AP (n = 41) CML with intolerance/resistance to ≥ 2 previous TKIs Omacetaxine 1.25 mg/m2 BID x 14 days of 28-day cycle (induction), then x 7 days of 28-day cycles (maintenance) Outcome CP (n = 81) AP (n = 41) 2 TKIs (n = 45) 3 TKIs (n = 36) 2 TKIs (n = 17) 3 TKIs (n = 24) Primary endpoints MCyR, % Median duration, mos CCyR, % MHR, % CHR, % 27.0 17.7 13.0 -- 11.0 NR 6.0 35.0 13.4 21.0 6.4 17.0 Median PFS, mos 10.5 6.5 3.6 4.8 Median OS, mos 30.1 12.0 24.6 AP, accelerated phase; BID, twice daily; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; MHR, major hematologic response; NR, not reported; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. 20. Nicolini FE, et al. ASCO 2012. Abstract 6513.

CML: Role and Timing of Allo SCT Status TKIs Allo SCT AP-BP Interim Rx to MRD ASAP IM failure in CP, T315I Ponatinib interim Rx to MRD IM failure in CP: no CE, no mutations, good initial response Long-term second-line TKIs Third line, post second TKI failure IM failure in CP: CE, bad mutations, no CG response Second line Older (65 yrs or older): 70 post-IM failure Long term May forgo allo SCT for many yrs of QoL Allo SCT, allogeneic stem cell transplantation; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; IM, imatinib; QoL, quality of life; TKI, tyrosine kinase inhibitor.

CML: Eradication of MRD Older agents Peginterferon Decitabine Omacetaxine Novel agents Hedgehog inhibitors JAK2 inhibitors IL3-DT toxins CML, chronic myeloid leukemia.

Summary Second-line/salvage Rx: new standards? Mutation analysis when clinical failure Sequential therapy? What is the role of bosutinib? Ponatinib: new TKI with promising activity in heavily pretreated patients or those with T315I Other agents in clinical development TKI, tyrosine kinase inhibitor.