1. ASH UPDATE 2014 Las Vegas, Nevada
Richard T. Silver, MD, FACP
Professor of Medicine
Weill Cornell Medical College

2. Disclosure
Grants and honoraria from Novartis, Incyte, Gilead

3. Major Categories in CML, ASH 2014
Clinical Trials
New Technologies and Next Generation Sequencing
Stopping Treatment
Registry Data

4. Updates of Clinical Trials
Many clinical trials, none very exciting
- Can Interferon improve molecular response?
To date: All 2nd Generation TKIs compared to imatinib show deeper, quicker molecular response, but no difference in overall survival
Value of 2nd Generation TKIs: Patients not responding to imatinib
However, 94% OS at 10 yrs for imatinib
Toxicity to imatinib

5. Trials Reviewed Toxicity DASISION (Dasatinib) SPIRIT (Dasatinib)
ERNEST – ND (Nilotinib)
Ponatinib
Toxicity
Dasatinib: Cumulative Increase in Pleural effusions
Nilotinib: Vascular events
Note: No substantial increase in toxicity with imatinib

6. Ponatinib Lower doses evaluated
45 mg dose excessive cardiovascular and increased RISK

7. New Drugs ABL001 works against T315I
ABT 199 May eliminate CML stem cells
BCL-2 inhibitor useful in lymphoid malignancies
BMS – – Smoothin inhibitor
Pyrvivium – blast phase CML
P13K inhibitors
Etc.

8. ABL-001 Potent selective inhibition of ABL-1
Inhibits at myristoyl site
In vitro: Combination with nilotinib prevents emergence of resistance

9. Next Generation Sequencing
More than 100 mutations, but T315 remains most important
Mutations in non BCR-AbL genes
- Abnormal DNA methylation patterns
Can ship samples of blood dropped on paper
- Will greatly expand availability of PCR testing

10. Value of PCR-BCR-ABL Early response, even at 1 month may be of value
Standardization of BCR-ABL still not uniform in the USA. Europe and ELN way ahead of us. Be careful with laboratory evaluation!
Major value of MR4.5 or MR5 is for stopping drug trial, which we will discuss.
Should be done in a study

11. STIM Study Design
N=100
Q- RT-PCR from peripheral blood every month in the first year and every 2 months thereafter
STOP
Start Imatinib
CMR
Sustained CMR
for ≥ 2 years
Molecular recurrence: positivity of BCR–ABL transcript in Q-RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point.
Five BCR–ABL analyses by Q- RT-PCR during these 2 years
Sixth datapoint checked in centralized laboratory
Mahon FX et al. The Lancet Oncology, 2010;11(11):

12. Treatment-free survival of the STIM study
At 60 months 40% ( 95% CI: 30-49)
Median follow up: 55 months (range 9-72)
5 extra-hematological deaths were observed: 1 case in DMR after 9 months of imatinib cessation (due to myocardial infarction) and 4 cases in the molecular relapse group due to stroke, mesothelioma, and gastric carcinoma respectively).
Mahon et al., ASH 2013 [abstract 255].

13. Stopping TKI Euro SKI: 648 patients, on TKI 3 years, MR4 for one year
18 month relapse-free survival 55%
IVAD study: 12 patients
Only 15% maintained complete MR
Some patients relapse quite late
Answer not in: Stop only in pregnant women
Should be on clinical trial

14. Molecular relapse-free survival 200 interim patients by TKI duration
Pts treated > 8 y N = 86, loss MMR = 29
Pts treated < 8 y N = 114, loss MMR = 60
At 18 months :
> 8 y : 65 % (95% CI : 53 % - 74%)
< 8 y : 47 % (95% CI : 38 % - 56%)
Overall P =0.007

15. Molecular relapse-free survival 200 interim patients by MR4 duration
MR4 duration > 5 y : N = 92, loss MMR = 32
MR4 duration < 5 y : N = 108, loss MMR = 57
At 18 months :
MR4 duration > 5 y : 65 % (95% CI : 54 % - 74%)
MR4 duration < 5 y: 46 % (95% CI : 38 % - 56%)
Overall P =0.0122

16. Melo, Ross, 2011

17. Conceptual Approach for Path to Cure Studies
START
Deep MR
STOP
1+ years?
Deep MR Induction
MR Consolidation
Sustained Deep MR off-therapy
PCR monitoring
Reintroduce TKI at relapse
PCR monitoring
PCR monitoring

18. TFR Trials: Path to Cure Strategy
Induction
Consolidation Phase
Treatment-Free Remission
ENESTFreedom
> 3 years on Nilotinib
BCR-ABL Monitoring
De Novo Patients
MR4.5 with > 2 years Nilotinib
Nilotinib 1 year sustain MR4.5
Treatment-free
Maintain ≤ MR3.0
Study period
ENESTop
> 3 years on Nilotinib
BCR-ABL Monitoring
Imatinib > 4 weeks not achieved MR4.5
MR4.5 with > 2 years Nilotinib
Nilotinib 1 year sustain MR4.5
Treatment-free
Maintain ≤ MR4.0
SWITCH
Study period
2 or 3 years on Nilotinib
BCR-ABL Monitoring
Nilotinib 1 or 2 years sustain MR4.0
1 year Nilotinib induction
Treatment-free
Maintain at least MMR
for 2 or 3 years
Imatinib > 2 yr not achieved MR4.0
ENESTPath
Study period
SWITCH

19. Role of IFN for TFR

21. Medical need: Clinical trial to address the WARNING category
Milestones
Resistance
Warning
Optimal response
Diagnosis
High risk
Major Route ACA
3 Mo.
No CHR Ph >95%
Ph >35%
BCR-ABL >10%
Ph <35%
BCR-ABL <10%
6 Mo.
Ph 1-65% BCR-ABL 1-10%
Ph 0% BCR-ABL <1%
12 Mo.
Ph >1%
BCR-ABL >1%
BCR-ABL 0,1-1%
BCR-ABL <0,1%
18-24 Mo.
BCR-ABL >0,1%
BCR-ABL 0,01-0,1%
BCR-ABL <0,01%
Any time
Relapse,
Loss of MMR
Baccarani M, et al. BLOOD 2013 .

22. MPN Topics Molecular and Cytogenic Abnormalities Scoring Systems
Clinical Findings

23. Molecular Abnormalities in MPNs
JAK2V617F - 98% of PV - 50%, ET and PM Others: JAK2 Exon 12, MPL, TP53, TET2 ASXL1, IDH1/2 and EZH2 Also Play a Role in Pathogenesis CALR Mutation: Improved Survival in ET, PV Triple Negative: Worse in PM

25. Background - I
In primary myelofibrosis (PMF), survival from time of diagnosis is predicted by the International Prognostic Scoring System (IPSS).
Variables included are age, leukocytosis, blasts, anemia, constitutional symptoms.
The dynamic IPSS (DIPSS) or DIPSS-plus provide survival estimates from time of patient referral.
Cervantes F et al. Blood 2009;113: Passamonti F et al. Blood 2010;115: Tefferi A. et al, Mayo Clin Proc 2012; 87:25-33

26. The objective of this study (Vannucchi) was to devise a new score by including clinical and mutation-relevant prognostic information.
The prognostic model (MIPSS) was developed through a stepwise selection process, based on a z-test of the regression coefficients, and its relative quality was measured by means of the Akaike information criterion.
We used a "learning cohort" (European; n= 588 PMF patients at diagnosis) and a "validation cohort" (Mayo Clinic, Rochester; n= 398 PMF patients at the time of referral)
Mutations were analyzed by deep target resequencing (Ion PGM platform), RTQ-PCR, bidiretional Sanger sequencing, as appropriate

27. MIPSS: Molecular International Prognostic Score System
MULTIVARIATE ANALYSIS
Variables
HR (95% CI) P
Age >60yrs
3.8 ( )
<0.0001
Hb <100g/L
1.4 ( )
0.04
Constitutional Symptoms
1.5 .( )
0.007
PLT <200x109/L
2.5 ( )
Triple Negativity
3.9 ( )
JAK2/MPL mutation
1.8 ( )
0.016
ASXL1 mutation
1.4 ( )
0.02
SRSF2 mutation
1.7 ( )

28. Background - II
The mutational status of JAK2, MPL and CALR and the presence and number of other prognostically-relevant mutations (ASXL1, SRSF2, EZH2, IDH1/2) provide IPSS/DIPSS-plus independent prognostic information.
HR= 2.29 (P< .0001)
CALR mutant
JAK2 mutant
MPL mutant
Triple negative
CALR mutant (median OS 17.7 yr)
JAK2 mutant (median OS 9.2 yr)
MPL mutant (median OS 9.1 yr)
Triple negative (median OS 3.2 yr
High risk: any mutation in ASXL1, EZH2, SRSF2, IDH1/2
HR: 2.3 for JAK2V617F (P<.001)
2.6 for MPL (P=.009)
6.2 for TN (P<.001)
Rumi E et al, Blood 2014; 124:1062-9; Vannucchi AM et al, Leukemia 2013; 27:1861-9

29. MIPSS: Molecular International Prognostic Score System
MULTIVARIATE ANALYSIS
Variables
HR (95% CI) P
Age >60yrs
3.8 ( )
<0.0001
Hb <100g/L
1.4 ( )
0.04
Constitutional Symptoms
1.5 .( )
0.007
PLT <200x109/L
2.5 ( )
Triple Negativity
3.9 ( )
JAK2/MPL mutation
1.8 ( )
0.016
ASXL1 mutation
1.4 ( )
0.02
SRSF2 mutation
1.7 ( )
Weighted
value
1.5
0.5
1.0

30. Conclusions
MIPSS, a novel clinico-molecular score for patients with PMF, incorporates 4 clinical variables (age, HB, platelet count, constitutional symptoms) and 4 molecular variables (Triple negativity, JAK2/MPL mutation, ASXL1 and SRSF2 mutations)
MIPSS allows to identify subgroups of patients with less favorable prognosis within the conventional IPSS categories

31. Update on JAK1,2 Inhibitors
Results about the same with slight differences in
toxicities

32. Phase 2 trial of PRM-151, an anti-fibrotic agent, in patients with myelofibrosis: Stage 1 results
1MD Anderson Cancer Center, Houston, TX, 2Mayo Clinic, Scottsdale, AZ, 3St. Paul’s Hospital, University of British Columbia, BC, CA, 4Princess Margaret Hospital, Toronto, ON, CA, 5Mt Sinai Medical Center, New York, NY, 6Weill Cornell Medical Center, New York, NY, 7Brigham and Women’s Hospital, Boston, MA, 8Massachusetts General Hospital, Boston, MA , 9Promedior, Inc., Lexington, MA, 10Stanford Cancer Institute, Stanford, CA

33. PRM-151: Recombinant Human Pentraxin-2 (PTX-2)
PTX-2 ( ) is an endogenous regulator of tissue repair
PTX-2 binds to damaged tissue ( ) and monocytes/macrophages
PTX-2 prevents and reverses fibrosis
in pre-clinical models
PTX-2 levels are low in MF patients
Also low in patients with renal, pulmonary
and liver fibrosis X
Pro-inflammatory
macrophages
Pro-fibrotic
Pro-resolutive
Hypothesis:
Reduction of bone marrow fibrosis will restore hematopoiesis and improve cytopenias

34. Patient 101-004: PRM-151 QW Hemoglobin Platelets Screening: MF-3
12 weeks: MF-2
24 weeks: MF-3
36 weeks: MF-1
Hemoglobin
Platelets
Last prior therapy: NS018 experimental JAK inhibitor discontinued 3 weeks pre C1D1

35. Results with Imetelstat

36. Concluding Remarks: ASH 2014
Most exciting aspect of CML is “stopping drug.”
Most exciting aspect of MPN is “molecular risk categorization and evaluation.”