1. Great Debates and Updates in Hematologic Malignancies 2014
Q: What is the optimal therapeutic choice for CML refractory to first- and second-generation TKIs? A: Stem Cell Transplant
Michael J. Mauro, MD
Leader, Myeloproliferative Disorders Program
Memorial Sloan Kettering Cancer Center, New York, NY

2. Point 1: Prior response may very well predict subsequent response
Both TKI and SCT salvage

3. Hammersmith score: How things went with Imatinib predict success or failure with 2G TGIs ; Might this be true for 3rd line?
Good risk, <1.5 (n=24)
3 factors comprising the score:
best cytogenetic response on imatinib: complete cytogenetic response, 0 points; 1-94% Ph-positive metaphases, 1 point; 95% or more Ph-positive metaphases, 3 points
Sokal risk group: low, 0 points; intermediate or high, 0.5 points
neutropenia: no neutropenia, 0 points; recurrent episodes of grade III-IV neutropenia during imatinib therapy that required dose reduction, 1 point.
Intermediate risk,
≥1.5 and ≤2.5(n=27)
Poor risk,
>2.5(n=29)
Milojkovic D et al, Haematolgica 2010

4. Disease status does matter at time of SCT:
Cytogenetic Response
0/38 Abl kinase mutations
12/31 Abl kinase mutations
HR=5.31, 95% CI , p=0.03
Oehler V et al, Blood 2007

5. Disease status does matter at time of SCT: mutations
Jabbour E et al, Blood 2011

6. Disease status does matter at time of SCT: CP vs AP
Jabbour E et al, Blood 2011

7. TKI exposure prior to SCT does not appear deleterious
Point 2:
TKI exposure prior to SCT does not appear deleterious

8. Effects of pre-transplant imatinib on post-transplant outcome
N=91 (70 CML, 21 Ph+ ALL)
Compared to EBMT controls
No effect on OS, PFS, or NRM
Higher relapse mortality
Lower chronic GVHD
Relapse Mortality
FHCRC Analysis, IM versus
historical control (survival)
Non-relapse Mortality
Deininger et al, Haematolgica 2006
Oehler V et al, Blood 2007

9. Ponatinib is by far the most efficacious salvage regimen
Point 3:
Ponatinib is by far the most efficacious salvage regimen

10. Comparative Efficacy Among Chronic –Phase CML Patients After Failure of 2nd generation TKIs
Lipton, J. ASH Abstract

11. PACE Trial (Ponatinib in TKI-Resistant CML):
2-Yr Update
Ponatinib: oral BCR-ABL TKI
Active against multiple mutations including T315I
Heavily pretreated study population
CP-CML pts: ≥ 2 TKIs: 93%; ≥ 3 TKIs: 60%
Current follow-up: 2 years
Patients with
CML or Ph-positive ALL resistant or intolerant to dasatinib or nilotinib or with emergent T315I mutation
(N = 449)
Ponatinib 45 mg/day
Cortes JE, et al. ASH Abstract 650.

12. Response in Heavily Pretreated Pts with Ph+ Disease
PACE:
Response in Heavily Pretreated Pts with Ph+ Disease
Outcome 
CP-CML
AP-CML
BP-CML
Ph+ ALL
MCyR*
CCyR*
MMR*
MaHR
R/I, % 56 48 31 62 32 50
T315I, % 72 70 58 61 29 36
Total, % 60 54 38 41
Median TTR, mos
2.8
2.9
5.5
0.7
1.0
*At any time after initial ponatinib dose.
†14 AP CML pts w/baseline MaHR + 1 AP-CML pt w/no baseline MaHR assessment counted as nonresponders.
Estimated 89% of pts with CP-CML to maintain MCyR ≥ 2 yrs
Estimated 21% of pts with AP-CML to maintain MaHR ≥ 2 yrs
Cortes JE, et al. ASH Abstract 650.

13. PACE Trial: Baseline BCR-ABL Mutations and Response to Ponatinib
Characterized baseline BCR-ABL mutations in patients with CP-CML (N = 267)
Sanger sequencing (sensitivity > 10% to 20% frequency)
Next generation sequencing (sensitivity > 1% frequency)
Low-level BCR-ABL mutations in 27% of patients (sole mutation in 12%)
Compound BCR-ABL mutations in 15% of patients
High MCyR (> 40%) by 12 mos for patients regardless of identified mutation status (0, 1, ≥ 2, low-level alone, or compound)
Including specific baseline mutations identified in > 10 pts (T315I, F317L, F359V, E255K, G250E)
Deininger MW, et al. ASH 2013 Abstract 652.

14. PACE Trial: BCR-ABL Mutation Analysis After Ponatinib Treatment
Sanger sequencing (N = 146)
Failed to reach MCyR at 12 months (n =118)
Lost MCyR (n = 13)
Discontinued in MCyR (n = 27)
Few new BCR-ABL mutations developed in patients treated with ponatinib
Failed to reach MCyR at 12 months: 4 of 102 evaluable patients
Lost MCyR: 2 of 13 evaluable patients
Discontinued in MCyR: 2 of 13 evaluable pts
No single mutation detected that confers ponatinib resistance
Deininger MW, et al. ASH Abstract 652.

15. Point 4:
Adverse events on ponatinib may warrant limited exposure and risk mitigation

16. Most Common Treatment-Emergent Adverse Events With Ponatinib
Select Any Grade AEs, %
CP CML (n = 270)
Total Population (N = 449)
Any Grade
Grade 3/4
Nonhematologic
Rash* 44 4 40
Abdominal pain 43 9
Headache 41 3 36 2
Dry skin
Hypertension 27 10 24
Elevated lipase 25 12 21
Hematologic
Thrombocytopenia 35
Neutropenia 19 16 22
Anemia 15
*Combines the terms erythematous, macular, and papular rash.
Cortes JE, et al. ASH Abstract 650.

17. Most Common Treatment-Emergent Serious Adverse Events With Ponatinib
Serious AE, %
CP CML (n = 270)
Total Population (N = 449)
Pancreatitis 7 6
Atrial fibrillation 4 3
Myocardial infarction
Coronary artery disease 2
Cerebrovascular accident
Cardiac failure 1
Hypertension
Anemia
Thrombocytopenia
Febrile neutropenia
< 1
As of December 2013, ponatinib is approved for patients with CML or Ph+ ALL and the T315I mutation or for whom no other TKI therapy is indicated
Cortes JE, et al. ASH Abstract 650.

18. Vascular Adverse Events With Ponatinib
US Ponatinib Insert ( )
Median Follow-up: 2 Mos  (340 Patient Yrs)
PACE Trial ( )
Median Follow-up: 24 Mos (578 Patient Yrs)
Serious AE AE
Cardiovascular 5 6 9
Cerebrovascular 2 3 4
Peripheral vascular
Venous thromboembolism
Total vascular occlusion
By trial criteria 14 20
By FDA criteria 10 18 15 24
Cortes JE, et al. ASH Abstract 650.

19. Time to First Vascular Occlusive Event: Ponatinib
Proportion of Patients Without
Vascular Occlusive Events
NIL 400 BID
NIL 300 BID
IM 400 QD
Vascular Events
Time
Time (Days)

20. Hypertension observed on Ponatinib

21. Concluding Points:
Multi-drug resistant CML has lower odds of success with subsequent TKI based salvage
Amongst TKI options, ponatinib offers margin of superiority albeit with significant toxicity risk
Shorter term TKI salvage likely optimal for many to examine response, avoid subsequent relapse and minimize vascular/other toxicity
TKI exposure does not impact transplant
Disease state does impact SCT
Final advice: ponatinib->SCT when possible
Younger patient with low risk SCT option
Any cases with prior transformation to AP/BC

22. Thank you! maurom@mskcc.org 212-639-3107