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

3. 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.
Mos
Progression was defined as increasing WBC count, loss of CHR or MCyR, ≥30% increase in Ph+ metaphases, confirmed AP/BP disease, or death

4. Nilotinib in CP CML After Imatinib Failure: PFS
100 90 80 70 60 50
PFS (%) 40
Patients
Events
Censored
(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].

5. 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
7. Cortes J E et al. Blood ;118:

6. 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:

7. 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:

8. 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 Abstract 6503.

9. 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 Abstract 6503.

10. 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 Abstract 6503.

11. 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 Abstract 6503.

12. 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 Abstract 6503.

13. 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 Abstract 6503.

14. 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 Abstract 601.

15. Omacetaxine for CML With T315I: OSCP
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 Abstract 644.

16. 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 Abstract 6513.

17. 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.

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

19. 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.