What is the optimal management strategy for younger CP-CML patients with matched, related donors who fail to achieve CCyR

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Amberly Morrison
5 years ago
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imatinib? Second generation TKIs as a bridge to allogeneic SCT Charles A.

Karmanos Cancer Institute Wayne State University School of Medicine

Science 132, 1960, 1497. P.C. Nowell, D.A.

1 What is the optimal management strategy for younger CP-CML patients with matched, related donors who fail to achieve CCyR after 18 months of imatinib? Second generation TKIs as a bridge to allogeneic SCT Charles A. Schiffer, M.D. Karmanos Cancer Institute Wayne State University School of Medicine Detroit, MI 1960 A minute chromosome oso in human granulocytic leukemia. Science 132, 1960, P.C. Nowell, D.A. Hungerford, University of Pennsylvania in Philadelphia the findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia 1

2 Italian Cooperative Study Group % Survival IFN CHT Years IFN CHT Blood. 1998; 92:

3 Which h patients t are at risk of being considered for transplantation? IMATINIB IS WONDERFUL, BUT NOT PERFECT ~ 60% of chronic phase patients remain in CyCR on imatinib at 5 years 3

% without AP/BC Survival Without AP/BC by Level of

60 50 40 30 20 10 0 ~ 2/3 of patients Response at 12

4 % without AP/BC Survival Without AP/BC by Level of CyR at 12 months on First-line Imatinib ~ 2/3 of patients Response at 12 months CCyR PCyR No MCyR Estimated rate at 60 months n= % n= 86 93% p<0.001 p=0.20 n= 73 81% Months since randomization 4

5 MECHANISMS OF IMATINIB RESISTANCE reactivation of Bcr-Abl? ASSUMING THAT THE yes no PATIENT IS TAKING THE DRUG! Bcr-Abl over-expression Src (10-30%) activation Bcr-Abl kinase mutations Others? (40-50%) Expression of ABC transporters? SUMMARY OF THE DASISION and ENEST STUDIES I D* N** I CyCR 80% 85% 87% 77% MMR ON THERAPY AP/BC *DASISION 18 months F/U; **ENESTnd 24 months, 300 mg ARM 5

6 LATE COMPLICATIONS OF TKIs IMATINIB none identified DASATINIB late pleural effusions, pulmonary hypertension NILOTINIB peripheral arterial occlusive disease (PAOD)?? WE NEED DRUGS FOR THE ROW Results with TKIs are worse in chronic phase patients t presenting with higher h Sokol scores and unsatisfactory in patients with accelerated or blast phases 6

7 What can we expect from second line treatment with nilotinib or dasatinib? Ph II Nilotinib in CML-CP: Response Patients % % N evaluable % 55% 63% 41% CHR Major CG Imatinib ib Imatinib ib CCyR Resistant Intolerant Median time to CHR= 1 mo, to MCyR= 2.8 mo Kantarjian H et al, Blood 2007,110;11:#735. ASH 2007 Oral Presentation 14 7

8 WHAT TO EXPECT FROM DASATINIB AS SECOND LINE TREATMENT: 5 YEAR FOLLOW-UP Shah, et al. Proc ASCO, 2011 DASITINIB SECOND LINE - PFS 8

9 9

10 MMR PCyCR CYCR MMR, CyCR,, y, PCyCR 10

$bond to triple bond accommodate T315I ponatinib Phase 1 trial Recommended dose: 45 mg/day Well-tolerated Early and durable responses in refractory patients This is the initial report of the pivotal$

11 Ponatinib Oral pan-bcr ABL TKI with potent activity against native and mutated BCR-ABL and other kinases Rationally designed with extensive network of optimized molecular contacts I315 and triple bond to triple bond accommodate T315I ponatinib Phase 1 trial Recommended dose: 45 mg/day Well-tolerated Early and durable responses in refractory patients This is the initial report of the pivotal phase 2 PACE trial Prior TKIs PACE Initial Results Prior Treatments R/I N=207 CP-CML N (%) T315I N=64 Overall N=444 Imatinib only* 0 (0) 10 (16) 16 (4) Imatinib + (dasatinib OR nilotinib)* 76 (37) 31 (48) 172 (39) Imatinib + dasatinib + nilotinib* 124 (60) 21 (33) 237 (53) 2 prior TKIs ** 98% 83% 94% 3 prior TKIs ** 66% 41% 59% Data as of 02 Dec

12 PACE Initial Results Response CP-CML Cohorts Response n Response / N Evaluable (%) Overall R/I Cohort T315I Cohort CHR 248/271 (92) 193/207 (93) 55/64 (86) MCyR* 116/248 (47) 79/191 (41) 37/57 (65) 96/248 63/191 33/57 CCyR (39%) (33%) (58%) MMR 51/265 (19) 31/205 (15) 20/60 (33) *MCyR is the primary endpoint Data as of 02 Dec 2011 PACE Initial Results Response Advanced Phase Cohorts n Response / N Evaluable (%) Response AP-CML BP-CML/Ph+ALL MaHR* MCyR R/I T315I R/I T315I 31/42 (74) 17/54 (32) CCyR 6/54 (11%) 6/13 (46) 17/46 (37) 16/43 (37) 9/17 (53) 14/41 (34) 15/41 (37) 4/17 (24%) 11/41 (27%) 11/41 (27%) MMR 4/59 (7) 1/15 (7) 9/41 (22) 2/29 (7) *MaHR is the primary endpoint (excludes 15 patients with baseline MaHR) Data as of 02 Dec

THE YIN AND YANG OF TRANSPLANTATION CAN BE CURATIVE

with more advanced disease GVHD acute and chronic -

13 THE YIN AND YANG OF TRANSPLANTATION CAN BE CURATIVE But. Early mortality (20+%) - affected by age, donor compatibility, comorbidities, etc. - can therefore shorten survival Relapse higher with more advanced disease GVHD acute and chronic - mortality + appreciable morbidity The cost of cure: Chronic GVHD 13

14 14

15 ADDITIONAL CONSIDERATIONS Effectiveness may decrease with delay - more advanced stage increased relapse - new comorbidities - limited number of donors for some patients THEREFORE Initiate donor search after failure of first TKI unless treatment was stopped or switched because of side effects ects or poor compliance Early transplant if second generation TKIs are not effective, if there is evidence of clonal evolution or accelerated phase, T315I mutation Continue TKI for patients in continued hematologic response if transplant cannot be done or if the patient refuses (??) There is still an art to some medical decisions 15

CML: Living with a Chronic Disease

CML: Living with a Chronic Disease Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia M. D. Anderson Cancer Center Houston, Texas Survival in Early Chronic Phase CML TKI Interferon Chemotherapy