Great Debates-CML Omacetaxine succinate

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Presentation transcript:

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

Disclosures No Disclosures

Can TKI Eliminate all the Leukemic Population? Stem cell population (partially Go) Proliferating population Sensitivity to IM Inhibited by imatinib? Inhibited by imatinib Menu

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;114:4361-4368 2. Ibrahim AR et al. Blood. 2010;116:5497-5500 3. Giles FJ et al. Leukemia. 2010;24:1299-1301 4. Quintás-Cardama A et al. Blood. 2007;109:497-499 5. NCCN Guidelines for CML v.2.2013 6. Kantarjian et al. Cancer 2007;109: 1556-60 7. Nicolini FE et al. Blood 2009;114:5271-5278.

Clonal Evolution in CML

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

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

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

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

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)

Updated AEs and SAEs Thrombotic events Med F/U: 11.4% AEs and 7.4% SAEs Additional 13 mo F/U: 17.1% AEs and 11.8% SAEs

Structure: Omacetaxine

Omacetaxine in CP CML

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.