1. Great Debates-CML Omacetaxine succinate
What is the optimal therapeutic
choice for CML-refractory
to first and and second generation TKIs?
Omacetaxine succinate
John F. DiPersio, MD, PhD
Division of Oncology
Siteman Cancer Center
Washington University School of Medicine

2. Disclosures
No Disclosures

3. Can TKI Eliminate all the Leukemic Population?
Stem cell population (partially Go)
Proliferating
population
Sensitivity to IM
Inhibited by imatinib?
Inhibited by imatinib
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4. Background
Pts with advanced Ph+ leukemia and failure on current TKIs have limited Rx options
Sequential use of TKIs has minimal value1-4
NCCN recommends SCT or clinical trials for pts who fail 2nd and 3rd line TKIs5
Prognosis poor for pts with advanced disease
Post-imatinib
OS (mos)
Failure of 2 TKIs
FFS (mos)
T315I*
AP-CML
166 51
287
BP-CML 56 31 47
OS, overall survival; FFS, failure free survival. *Post first or second generation TKI
1. Garg RJ et al. Blood. 2009;114: Ibrahim AR et al. Blood. 2010;116: Giles FJ et al. Leukemia. 2010;24: Quintás-Cardama A et al. Blood. 2007;109: NCCN Guidelines for CML v Kantarjian et al. Cancer 2007;109: Nicolini FE et al. Blood 2009;114:

5. Clonal Evolution in CML

6. PACE. Study Design Primary Objective
Efficacy of ponatinib in CML or Ph+ ALL:
resistance or intolerance (R/I) to dasatinib or nilotinib, or
T315I mutation (confirmed by a central lab at entry)
Cohort Assignment
CP-CML*
AP-CML
BP-CML/
Ph+ ALL
R/I to dasatinib or nilotinib
203 65 48
T315I mutation 64 18 46
Total**
270 85 94
*Cortes et al, ASH 2012, Abstract 163
**Includes 5 additional patients (3 CP‑CML; 2 AP‑CML) who were non-cohort assigned (post-imatinib, T315I not detected), but treated

7. PACE. Primary Endpoint n (%) AP-CML N=83 BP-CML/Ph+ ALL N=94 R/I N=65
T315I
N=18
N=48
N=46
MaHR*
39 (60)
9 (50)
17 (35)
15 (33)
Any CyR**
34 (52)
12 (67)
19 (40)
20 (43)
MCyR
22 (34)
10 (56)
13 (27)
16 (35)
CCyR
13 (20)
6 (33)
11 (23)
12 (26)
MMR#
6 (9)
3 (17)
N/A
*MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders
**CCyR + PCyR + minor CyR + minimal CyR
#MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR assessment , or who meet the criteria for MMR at baseline, counted as non-responders

8. PACE. Response by Number of Prior TKIs
n/N (%)
AP-CML
N=85
BP-CML/Ph+ ALL
N=94
No. Prior TKIs*
MaHR
MCyR 1
5/6 (83)**
6/6 (100)**
3/9 (33)
5/9 (56) 2
20/33 (61)
13/33 (39)
15/37 (41) ≥3
24/46 (52)
15/46 (33)
14/48 (29)
9/48 (19)
*TKIs = imatinib, dasatinib, nilotinib
**Includes 2 AP-CML patients who were non-cohort assigned (post-imatinib, non-T315I), but treated

9. PACE. PFS AP-CML BP-CML/Ph+ ALL PFS at 12 mos: 55% (median 18 mos)
Criteria for progression: AP – death, development of BP, loss of HR over 2 wks, or no reduction in %blasts on all assessments over 4 wks; BP or Ph+ ALL – death or increasing blasts in PB or BM over 4 wks

10. PACE. Survival AP-CML BP-CML/Ph+ ALL
OS at 12 mos: 83% (median not reached)
OS at 12 mos: 33% (median 6.9 mos)

11. Updated AEs and SAEs Thrombotic events
Med F/U: % AEs and 7.4% SAEs
Additional 13 mo F/U: % AEs and 11.8% SAEs

12. Structure: Omacetaxine

14. Omacetaxine in CP CML

29. Conclusion Accepting this debate position is akin to being a Kamikaze
Definition: (during World War II) a member of a special corps in the Japanese airforce charged with the suicidal mission of crashing an aircraft laden with explosives into an enemy target, especially a warship.
Or.. a person or thing that behaves in a wildly reckless or destructive manner: We were nearly run down by a kamikaze on a motorcycle.