The document discusses updates in the diagnosis and treatment of myeloproliferative disorders and chronic myeloid leukemia. It summarizes long-term data from the COMFORT-II trial showing that ruxolitinib provided durable spleen reductions and potential survival benefit compared to best available therapy in myelofibrosis patients. It also reviews investigational agents being studied for myeloproliferative disorders including pacritinib, which showed consistent efficacy across patient subgroups in the PERSIST-1 trial, and PRM-151, a recombinant human pentraxin-2 that aims to reduce bone marrow fibrosis.

1. Updates in Myeloproliferative Disorders,
including Chronic Myeloid Leukemia
Katherine Walsh, MD
No conflicts of interest to disclose
Off-label use: pacritinib, radotinib, PegIFN, ABL001, and combinations with ruxolitinib

2. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
A 72 year old gentlemen is referred to hematology for
treatment recommendations for newly diagnosed JAK2
positive primary myelofibrosis. He reports symptoms of
fatigue and decreased appetite. On exam, he appears pale
and has palpable splenomegaly. The most recent CBC
values were WBC 11K with 2% circulating blasts,
hemoglobin 9, and platelet count of 30K.
What agent has been submitted to the FDA for new drug
application for myelofibrosis with thrombocytopenia
(platelet count <50K)?
A) Azacitidine
B) Imetelstat
C) Momelotinib
D) Pacritinib
E) Pomalidomide

3. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
A 32 year old woman with chronic phase CML has had a
good response to tyrosine kinase inhibitor therapy with
imatinib for the past 3 years comes to clinic for routine
follow-up. While she has met her milestones on time and
overall tolerated therapy well, she doesn’t like the idea of
being on medicine lifelong and is considering having
children in the next year. Her last PCR confirms continued
MMR which she has maintained for 2 years.
What advice can we give her based on current TKI
discontinuation data?
A) Imatinib can be safely stopped now
B) Imatinib can be stopped after 1 more year of MMR
C) Imatinib should not be stopped due to TKI withdrawal syndrome
D) Imatinib should not be stopped outside of a clinical trial
E) Imatinib can’t be stopped due to molecular recurrence resistant to
treatment
3

4. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Objectives
 To discuss clinical updates in diagnosis and
treatment of the myeloproliferative disorders (MPD,
BCR-ABL negative) and chronic myeloid leukemia
(CML).
 To discuss new agents in development and new
combination approaches being investigated for MPD
and CML.

5. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Updates in BCR-ABL Negative
Myeloproliferative Disorders

6. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Mutations in MPNs
Klampfl, T et al. NEJM, December 2013
CALR added to WHO 2015
Abstract 350: 88% “triple negative” MF cases had a non-driver mutation

7. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Abstract 2804:
Continued Treatment
with Ruxolitinib
Provides Additional
Hematocrit Control and
Spleen Volume
Responses in Patients
with PV Treated in the
RESPONSE Study
Jean-Jacques Kiladjian, MD,
Tamas Masszi, MD, PhD, Mark
M. Jones, MD, Brian Gadbaw
MD, Jingjin Li, PhD, Dany
Habr, MD, Alessandro M.
Vannucchi, MD, and, Srdan
Verstovsek, MD, PhD
Vannucchi A, et al, NEJM 2015

8. Long-Term Efficacy and Safety in COMFORT-II,
a Phase 3 Study Comparing Ruxolitinib With
Best Available Therapy for the Treatment of
Myelofibrosis: 5-Year Final Study Results
Claire N. Harrison,1 Alessandro M. Vannucchi,2 Jean-Jacques Kiladjian,3
Haifa Kathrin Al-Ali,4 Heinz Gisslinger,5 Laurent Knoops,6 Francisco Cervantes,7
Mark M Jones,8 Kang Sun,8 Laurence Descamps,9 Viktoriya Stalbovskaya,10
Prashanth Gopalakrishna,10 Tiziano Barbui11
On Behalf of the COMFORT-II Investigators
1Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK; 2University of Florence, Florence, Italy; 3Hôpital Saint-
Louis et Université Paris Diderot, Paris, France; 4University of Leipzig, Leipzig, Germany; 5Medical University of Vienna, Vienna,
Austria; 6Cliniques universitaires Saint-Luc and de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 7Hospital
Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 8Incyte Corporation, Wilmington, DE; 9Novartis
Pharma S.A.S., Rueil-Malmaison, France; 10Novartis Pharma AG, Basel, Switzerland; 11Hospital Papa Giovanni XXIII, Research
Foundation, Bergamo, Italy

9. COMFORT-II Study Design
• Randomized, open-label, multicenter phase 3 study1
• Patients were stratified based on baseline IPSS risk category2
Ruxolitinib
15 or 20 mg oral BID
n = 146
Best available therapy
(BAT)
n = 73
Randomize
Patients with
PMF, PPV-MF,
or PET-MF with
≥ 2 IPSS risk
factors2
N = 219
2:1
1. Harrison C, et al. N Engl J Med. 2012;366(9):787-798; 2. Cervantes F, et al. Blood. 2009;113(13):2895-2901.
• Treatment continued until progressive splenomegaly, unless discontinued
earlier for splenectomy, toxicity, or death
– Progressive splenomegaly was defined as ≥ 25% increase in spleen volume over on-study nadir
(including baseline)
– Patients in the BAT arm were allowed to crossover and receive ruxolitinib following progressive
splenomegaly; some crossed over without progressive splenomegaly following primary analysis
BID, twice daily; IPSS, International Prognostic Scoring System; PET, post–essential thrombocythemia; PMF, primary MF; PPV. post–
polycythemia vera.
Crossover to ruxolitinib

10. Best Percentage Change in Spleen Volume
for Individual Patients
• 97.1% of patients (132/136) experienced some degree of spleen volume
reduction
• 78 patients (53.4%) in the ruxolitinib arm achieved a ≥ 35% reduction in spleen
volume at any time on treatment
a Only patients with baseline and postbaseline spleen volume assessments are included; for crossover patients, the
spleen volume at the time of crossover was used as the new baseline value.
-100
-80
-60
-40
-20
0
20
40
60
35% decrease
BestChangeFromBaseline
inSpleenVolume,%
Ruxolitinib
randomizeda
(n = 136)
After crossovera
(n = 39)

11. Overall Survival
• Median OS was not yet reached in the ruxolitinib arm (ie, > 5 years)
— ITT: HR, 0.67 (95% CI, 0.44-1.02); P = .06
— RPSFT: HR, 0.44 (95% CI, 0.18-1.04) in favor of ruxolitinib vs BAT
1.0
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6
146 130 109 100 88 61 0
73 58 48 35 30 22 0
Ruxolitinib
BAT (ITT)
BAT (RPSFT)
Probability
Time, years
n =
Median Overall Survival
Ruxolitinib (ITT) = not reached
BAT (ITT) = 4.1 years
BAT (RPSFT) = 2.7 years
HR, hazard ratio; ITT, intent-to-treat; RPSFT, Rank-Preserving Structural Failure Time.

12. Conclusions
• These 5-year findings demonstrate that the immediate benefits of ruxolitinib
treatment, such as improvements in spleen size, were maintained with long-
term therapy
• Reductions in JAK2 V617F allele burden were apparent with longer-term
treatment; improvement or stabilization of bone marrow fibrosis was seen in
48% of ruxolitinib-treated patients (18.5% worsening; 34% missing)
• Long-term safety and tolerability were consistent with previous findings
• Patients randomized to ruxolitinib treatment in the study had a relatively lower
risk of death compared with patients on the BAT arm, most of whom switched
to receive ruxolitinib at a later date
— In the ITT analysis, reduction in the risk of death with ruxolitinib was 33%
• This hypothetical benefit with earlier treatment with ruxolitinib is being
evaluated through a phase 3 study in patients with early MF

13. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Investigational Agents and New Combinations for
MPD

14. ANALYSIS OF OUTCOMES BY
PATIENT SUBGROUPS IN
PATIENTS WITH MYELOFIBROSIS
TREATED WITH PACRITINIB VS
BEST AVAILABLE THERAPY (BAT)
IN THE PHASE III PERSIST-1 TRIAL
Alessandro M. Vannucchi1, Ruben A. Mesa2, Francisco Cervantes3, Ritam Prasad4,
Janos Jakucs5, Anna Elinder6, Christian Recher7,
Peter A. te Boekhorst8, Steven Knapper9, Tim Somervaille10, James P. Dean11,
Tanya Granston11, Adam Mead12 and Claire N. Harrison13
1University of Florence, Florence, Italy; 2Mayo Clinic, Scottsdale, AZ; 3Hospital Clinic, IDIBAPS, University of Barcelona,
Barcelona, Spain; 4Royal Hobart Hospital, Hobart, Australia; 5Békés Megyei Pándy Kálmán Kórház, Gyula, Hungary;
6North Shore Hospital, Takapuna, New Zealand; 7Institut Universitaire du Cancer Toulouse, Toulouse, France; 8Erasmus
University Medical Center, Rotterdam, Netherlands; 9Cardiff University, Cardiff, United Kingdom; 10The Christie NHS
Foundation Trust, Manchester, United Kingdom; 11CTI BioPharma Corp., Seattle, WA; 12Oxford University Hospitals,
Oxford, United Kingdom; 13Guy's and St. Thomas' NHS Foundation Trust, Guy’s Hospital, London, United Kingdom

15. PERSIST-1 Study Design
Best Available
Therapy (BAT)a
excluding ruxolitinib
(n=107)
Pacritinib 400 mg qd
(n=220)
aCross-over from BAT allowed after
progression or after Week 24 assessment
Key Eligibility Criteria
PMF, PET-MF, or PPV-MF
Intermediate- or high-risk disease
Palpable spleen ≥5 cm
No exclusion for baseline platelet levels;
stratified by platelet counts ≥100,000/µL,
≥50,000-<100,000/μL, and <50,000/µL
No exclusion for baseline Hgb levels
No prior treatment with JAK2 inhibitors
R
(2:1)
N=327
• Stratification at randomization: platelet count category, risk category, and region
• Study endpoints
– Primary: proportion of patients achieving a ≥35% reduction in spleen volume (by MRI/CT)
from baseline to Week 24
– Secondary: proportion of patients with a ≥50% reduction in Total Symptom Score (TSS) from
baseline to Week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form v 2.0
• Trial conducted in US, Europe, Russia, and Oceania
CT, computed tomography; Hgb, hemoglobin; JAK, Janus kinase; MRI, magnetic resonance imaging; PET-MF, post-essential thrombocythemia myelofibrosis;
PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; R, randomized.
Mesa RA, et al. ASCO 2015. Abstract LBA7006.

16. aBy central laboratory. bBased on linear regression using mixed model.
BAT, best available therapy; BL, baseline; Hgb, hemoglobin; PAC, pacritinib; RBC, red blood cell.
1. Mesa RA, et al. ASCO 2015. Abstract LBA7006. 2. Gale RP, et al. Leuk Res. 2011;35:8-11.
Patients With Baseline Hgb <10 g/dL
Mean Hgb (g/dL) (± SEM)1,a
MeanHgb(g/dL)(±SEM)
Weeks
10
9.5
9
8
8.5
PAC
BL 3 4 8 12 16 20 24
BAT
Patients With Baseline Platelets <50,000/μL
Mean Platelets×109/L (± SEM)1,a
MeanPlatelets×109/L(±SEM)
Weeks
60
50
40
0
30
20
10
p=0.0034b
p=0.1927b
BL 3 4 8 12 16 20 24
PAC
BAT
25.7%
0%
0%
5%
10%
15%
20%
25%
30%
PAC
BAT
p=0.043
Patients
Patients Achieving RBC Transfusion Independence1
• At baseline, 15.9% of PAC and
14.0% of BAT patients were RBC
transfusion dependent, per
Gale criteria (≥6 units/90 days2)
Changes in Platelet Levels, Hemoglobin, and
RBC Transfusion Dependence Over Time

17. Conclusions
• Treatment with pacritinib resulted in consistent rates of
SVR ≥35% and TSS reduction ≥50%, irrespective of
baseline characteristics, including baseline platelet
count
• Comparisons of pacritinib vs BAT were favorable for all
patient subgroups examined for both endpoints
• These results support the use of pacritinib across all
intermediate- and high-risk myelofibrosis patient
subgroups analyzed
BAT, best available therapy; SVR, spleen volume reduction; TSS, total symptom score.

18. 18
PRM-151 in Myelofibrosis:
Durable Efficacy and Safety at 72 Weeks
Srdan Verstovsek1, Olga Pozdnyakova2,Robert Hasserjian3,
Mohamed Salama4, Ruben Mesa5, Lynda Foltz6, Vikas Gupta7,
John Mascarenhas8, Ellen Ritchie9, Ronald Hoffman8, Richard
Silver9, Marina Kremyanskaya8, Zeev Estrov1, Elizabeth Trehu10,
Hagop Kantarjian1, Jason Gotlib11
1MD Anderson Cancer Center, Houston, TX, 2Brigham and Women’s Hospital, Boston, MA,
3Massachusetts General Hospital, Boston, MA, 4University of Utah, Salt Lake City, UT, 5Mayo
Clinic, Scottsdale, AZ, 6St. Paul’s Hospital, University of British Columbia, BC, CA, 7Princess
Margaret Hospital, Toronto, ON, CA, 8Mt Sinai Medical Center, New York, NY, 9Weill Cornell
Medical Center, New York, NY, , 10Promedior, Inc., Lexington, MA, 11Stanford Cancer
Institute, Stanford, CA

19. 19
PRM-151: Recombinant Human Pentraxin-2 (PTX-2)
X
X X
Pro-inflammatory
macrophages
Pro-fibrotic
macrophages
Pro-resolutive
macrophages
Hypothesis:
Reduction of bone
marrow fibrosis will
restore hematopoiesis
and improve
cytopenias
• 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

20. 20
Weekly PRM-151
10 mg/kg IV
Monthly PRM-151
10 mg/kg IV
Weekly PRM-151 10
mg/kg IV + ruxolitinib
Monthly PRM-151 10
mg/kg IV + ruxolitinib
27 Patients Enrolled
PRM-151G-101 Stage 1 and Extension
• 24 week treatment period
– Patients with clinical benefit may continue beyond 24 weeks
• PRM-151 + RUX: stable RUX dose ≥3 months with no decrease in splenomegaly for ≥ 4
weeks
• No eligibility restrictions for anemia, thrombocytopenia, leukopenia, or spleen size
7
8
6
6
20 Patients completed
24 weeks
13 patients completed
72 weeks
5 9
5
6 4
4
1 PD
2 deaths
1 PD
1 lack of benefit
1 death
1 splenectomy
2 stopped < 72 weeks
5 switched to
monthly
1 stopped rux
3 stopped < 72 weeks
2 stopped < 72 weeks
5 switched to monthly

21. 21
Bone Marrow Fibrosis Improvement
as Measured by WHO Criteria
• Response assessment by central hematopathologists blinded to patient, treatment
and time point. WHO MF Response = % of patients with ≥1 grade reduction in MF
score at any time point
• Reduction in BM fibrosis was associated with normalization of bone marrow
architecture: Normal erythroid clustering, Normal or decreased myeloid:erythroid
ratio, Fewer paratrabecular megakaryocytes
%Patientswith
BoneMarrowImprovement
Patient n 13 10 6 6 6 5
0
10
20
30
40
50
60
70
80
Wk 12 Wk 24 Wk 36 Wk 48 Wk 60 Wk 72
WHO MF Response

22. 22
Platelets and Platelet Transfusions
Plateletsx109/Land
%ofpatientswithPLTtransfusions
Patients with Baseline Platelets < 100 x 109/L who completed ≥ 72 weeks (n=9)
0
10
20
30
40
50
60
Baseline Week 12 Week 24 Week 36 Week 48 Week 60 Week 72
Median PLT (x 109/L) % pts receiving plt transfusions

23. 23
Conclusions
• 13 patients have completed 72 weeks of PRM-151 treatment
• Reductions in bone marrow fibrosis have been accompanied by
– Median increase in Hgb in patients with baseline Hgb < 100 g/L
– Decreased RBC transfusions
– Median increase in PLT in patients with baseline PLT < 100 x 109/L
– Decreased PLT transfusions
– > 50% reduction in symptoms in 62% of patients
– > 50% reduction in splenomegaly in 2 patients on PRM-151 alone
• PRM-151 was well-tolerated
– 13 related adverse events, 11 Grade 1
– 6 SAEs, none related

24. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Combination Therapy in MPN
Ruxolitinib
plus:
N Descriptors Toxicity Results
Pomalidomide 25 Immunomodulation
for cytopenia (MF)
Anemia (G4)
Neuropathy (G3)
3 CI
AZA 24 MDS/MPN overlap Myelosuppression (G3/4) 12 CI
IFN 30 Better tolerate IFN
for PV or MF
Myelosuppression (G2/3)
Infection (G2/3)
CI for
most
Buparlisib (PI3K)
(HARMONY)
42 Both agents active
in MF (prior
treatment allowed)
Myelosuppression (G3/4) Spleen
reduced
in most
Sonidegib
(Hedgehog)
27 Animal models:
combo reduced
spleen size
Anemia (G3/4)
Muscle spasms (G3/4)
Spleen
reduced
in 25 pts
24
CI = clinical improvement

25. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Updates in Chronic Myeloid Leukemia:

26. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Combination Therapy: TKI plus PegIFN
 Abstract 134 (Roy et al): French Intergroup of CML
 Treatment plan: Dasatinib alone x 3 months; then
combination with PegIFN for 21 months maximum
 Abstract 477 (Hjorth-Hansen et al)
 Treatment plan: Dasatinib alone x 3 month; then
combination with PegIFN for 12 months
 Potential AE benefit = pleural effusions rare
26
N=61 3 months 6 months 9 months 12 months
MMR 16% 51% 70% 70%
N=40 3 months 6 months 9 months 12 months
MMR 8% 53% 66% 82%

27. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Combination Therapy: Nilopeg Study
27
The Lancet Haematology 2015 2, e37-e46DOI: (10.1016/S2352-3026(14)00027-1)
In future, combination of 2nd generation TKI plus PegIFN may have a role for
TKI discontinuation attempts after MMR.

28. ASH 2015 RERISE 12 Months Follow-upASH 2015 RERISE 12 Months Follow-up
Abstract 476
Efficacy and Safety of
Radotinib versus Imatinib
for Newly Diagnosed CML-CP Patients
Jae-Yong Kwak1, Hawk Kim2, Jeong-A Kim3, Young Rok Do4, Hyeoung Joon Kim5,
Joon Seong Park6, Joo Seop Chung7, Ho Jin Shin7, Sung-Hyun Kim8, Dae-Young Kim9,
Udomsak Bunworasate10, Chul Won Choi11, Narcisa Sonia Comia12, Dae Young Zang13,
Suk Joong Oh14, Saengsuree Jootar15, Ary Harryanto Reksodiputro16, Won Sik Lee17,
Yeung-Chul Mun18, Jee Hyun Kong19, Priscilla B. Caguioa20, Jinny Park21, Chol Won
Jung22, Dong-Wook Kim23
1Chonbuk National University Medical School & Hospital, Jeonju, South Korea, 2Ulsan University Hospital, Ulsan, South Korea, 3St. Vincent
Hospital, The Catholic University of Korea, Suwon, South Korea, 4Dongsan Medical Center, Keimyung University, Daegu, South Korea,
5Chonnam National University, Hwasun Hospital, Hwasun, South Korea, 6Ajou University Hospital, Suwon, South Korea, 7Pusan National
University Hospital, Pusan, South Korea, 8Dong-A University Medical Center, Busan, South Korea, 9Asan Medical Center, University of Ulsan
College of Medicine, Seoul, South Korea, 10King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand, 11Korea
University, Guro Hospital, Seoul, South Korea, 12Mary Mediatrix Medical Center, Batangas, Philippine, 13Hallym University Sacred Heart Hospital,
Anyang, South Korea, 14Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea, 15Faculty of Medicine,
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 16Rumah Sakit Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia, 17Inje
University Busan Paik Hospital, Busan, South Korea, 18Ewha Womans University Mokdong Hospital, Seoul, South Korea, 19Wonju Severance
Christian Hospital, Wonju, South Korea, 20St.Luke’s Medical Center, Manila, Philippine, 21Gachon University Gil Medical Center, Seoul, South
Korea, 22Samsung Medical Center, Seoul, South Korea, 23Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea

29. ASH 2015 RERISE 12 Months Follow-upASH 2015 RERISE 12 Months Follow-up
Study Design
Radotinib 300 mg BID
(n = 79)
Radotinib 400 mg BID
(n = 81)
Imatinib 400 mg QD
(n = 81)
Extension follow-up 3 years after 1 year treatment
*Stratified by Sokal risk score.
Randomized*
 ≤3 months after
diagnosis of chronic-
phase Ph+ CML (n=241)
 24 sites
 4 Asian countries (KR,
TH, PH & IDN)
 Enrollment
: 2011.08 – 2014.02
 Primary endpoint: MMR by 12 months
 Secondary endpoints: CCyR & CMR by 12 months, MMR at 12 months
Disease Progression
 Other endpoints: OS, PFS

30. ASH 2015 RERISE 12 Months Follow-upASH 2015 RERISE 12 Months Follow-up
Major Molecular Response at Each Time
PatientswithMMR,%
MMR: Major Molecular Response, BCR-ABL1 transcript level ≤ 0.1% (MR3.0)
(N=79) (N=81) (N=81)
Data cut-off: 17Mar2015
MMR At 12 monthsMMR By 12 months
p=0.0342
p=0.0044
p=0.0667
p=0.0065

31. ASH 2015 RERISE 12 Months Follow-upASH 2015 RERISE 12 Months Follow-up
Conclusion
 Radotinib demonstrated significantly higher molecular response rate
at both 300mg BID and 400mg BID group compared with imatinib
- Radotinib 300mg BID, 400mg BID vs Imatinib 400mg QD:
52%, 46% vs 30%
 Treatment failure and suboptimal response in all radotinib groups
were fewer than imatinib group and no progression in all groups was
occurred
 The safety profiles of the radotinib and imatinib were different, and
most AEs were manageable and well-controlled by dose reduction.
 However, laboratory AEs were high in radotinib 400mg BID group
 These phase 3 data suggest that radotinib can become a new
promising 1st line therapy for patients with newly diagnosed chronic
phase CML

32. ABL001, a Potent, Allosteric Inhibitor of
BCR-ABL1, Exhibits Safety and Promising Single-
Agent Activity in a Phase 1 Study of Patients With
CML and Failure of Prior TKI Therapy
Oliver Ottmann, Giuliana Alimena, Daniel J. DeAngelo, Yeow-Tee Goh,
Michael Heinrich, Andreas Hochhaus, Timothy P. Hughes,
Francois-Xavier Mahon, Michael Mauro, Hironobu Minami, Marie Huong
Nguyen, Delphine Rea, Juan-Luis Steegmann, Arkendu Chatterjee,
Varsha Iyer, Noelia Martinez, Gary J. Vanasse, Dong-Wook Kim
American Society of Hematology
Annual Meeting 2015
Abstract 138

33. • Developed to gain
greater BCR-ABL1
inhibition, with activity
against BCR-ABL1
mutations conferring
resistance to TKIs
• Potential to combine
with TKIs for greater
pharmacological
control of BCR-ABL1
BCR-ABL1
Protein
Nilotinib
(ATP Site)
ABL001
(Myristoyl Site)
ABL001 Is a Potent, Specific Inhibitor of BCR-ABL1
With a Distinct Allosteric Mechanism of Action

34. SH2
SH3
BCR
ACTIVE
ABL001 Allosterically Inhibits BCR-ABL1 Kinase
Activity
Kinase
ABL001
t(9;22)BCR
SH3
Kinase
INACTIVE
ABL001
SH2

35. ABL001X2101: Study Design
A multicenter, phase 1, first-in-human study
Dose Escalation Dose Expansion
MTD/RDE
CML, Resistant/Intolerant to
Prior TKI
ABL001 BID, Oral
Combo Dose Escalation – CML
ABL001 40 mg BID +
Nilotinib 300 mg BID, Oral
Dose Expansion – CML
ABL001 40 mg BID +
Nilotinib 300 mg BID, Oral
CML, Resistant/Intolerant
ABL001 QD, Oral
MTD/RDE
MTD/RDE
CML, Resistant/Intolerant
ABL001 QD, Oral
CML, Resistant/Intolerant
to Prior TKI
ABL001 BID, Oral
•
•
Primary outcome: estimation of MTD/RDE
Secondary outcomes: safety, tolerability, preliminary anti-CML activity,
pharmacodynamics, pharmacokinetic profile
Ph+ ALL, Resistant/Intolerant
to Prior TKI
ABL001 BID, Oral

36. Responses in Patients With ≥ 3 Months of Follow-up on
Study (n = 29)
100
90
80
70
60
50
40
30
20
10
0
Hematologic relapse
(n = 12)
Cytogenetic relapse
(> 50% Ph+; n = 12)
Molecular relapse
(no MMR; n = 29)
PatientsWithResponse,%
CHR within 2
months:
100% (12/12)
CCyR:
66.7% (8/12)
MMR:
34.5% (10/29)
≥ 1-log
reduction:
24.1% (7/29)
< 1-log
reduction:
31.0% (9/29)
None:
33.3% (4/12)
None:
10.3% (3/29)
Hematologic Response
Within 2 Months
Cytogenetic Response
Within 3-6 Months
Molecular Response
Within 6 Monthsa
Status at Baseline
a BCR-ABL1IS reduction achieved.

37. Conclusions
• ABL001 was generally well tolerated in heavily treated
CML patients resistant to or intolerant of prior TKIs
• Preliminary pharmacokinetic exposures appear linear
in the dose range tested
• Early evidence of single-agent efficacy at ≥ 10 mg BID
– Clinical activity across TKI-resistant mutations (eg, V299L, F317L,
Y253H)
– Myristoyl binding pocket mutations (V468H, I502L) may lead to clinical
resistance
• Allosteric inhibition of BCR-ABL1 is a promising
therapeutic approach in patients with CML
• Enrollment ongoing to determine a recommended dose
and to assess safety and tolerability

38. Long-term Follow-up of the French
Stop Imatinib Study (STIM1) in
Chronic Myeloid Leukemia Patients*
Gabriel Etienne, Delphine Réa, Joëlle Guilhot, François Guilhot,
Françoise Huguet, Laurence Legros, Franck Nicolini Aude Charbonnier,
Agnès Guerci, Bruno Varet, Philippe Rousselot, François-Xavier Mahon
on behalf of the Intergroupe Français des Leucémies Myéloïdes
Chroniques (FILMC) on behalf of the STIM Investigators
*This study is registered with ClinicalTrials.gov, number NCT00478985
Orlando, ASH 2015, abstract 85121

39. STIM study design*
N=100
STOP
Molecular recurrence: positivity of BCR–ABL transcript confirmed by a
second consecutive analysis point indicating a increase of one log or loss of
MMR at one point.
Molecular recurrence Imatinib rechallenge
Sustained CMR
for ≥ 2 years on imatinib
(5 assessments)
Q- RT-PCR every month in the first year and every 2 months in
the second year and every 3-4 months thereafter
* Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.
Year 1 Year 2 Year 3 and after

40. Molecular Recurrence-free Survival (MRFS)
MRFS after imatinib discontinuation – Median Follow-up = 65 mo.
accounting for competing events (death in complete molecular remission without any relapse, n=1)
43% (95% CI 33-52) at 6 months
38% (95% CI 32-51) at 24 months
38% (95% CI 28-47) at 84 months.
MRFS
0 6
Number at risk 100 44
12 18 24 30 36 42 48
41 38 38 38 38 37 29 25 19 11 5 1 0
54 60 66 72 78 84 90
Months since Imatinib Discontinuation

41. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
 TKI Withdrawal Syndrome
 Upper extremity and shoulder pain lasting median of 7
months
 Patient Preference
 Data emerging about predictors of which patients will
maintain MMR versus recur after stopping TKI
therapy
Additional TKI Discontinuation
Considerations

42. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
A 72 year old gentlemen is referred to hematology for treatment
recommendations for newly diagnosed JAK2 positive primary
myelofibrosis. He reports symptoms of fatigue and decreased appetite.
On exam, he appears pale and has palpable splenomegaly. The most
recent CBC values were WBC 11K with 2% circulating blasts,
hemoglobin 9, and platelet count of 30K.
What agent has been submitted to the FDA for new drug application for
myelofibrosis with thrombocytopenia (platelet count <50K)?
A. Azacitidine
B. Imetelstat
C. Momelotini
b
D. Pacritinib
E. Pomalidom
ide
42
Azacitidine
Im
etelstat
M
om
elotinib
Pacritinib
Pom
alidom
ide
50% 50%
0%0%0%

43. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
A 32 year old woman with chronic phase CML has had a good
response to tyrosine kinase inhibitor therapy with imatinib for the past 3
years. While she has met her milestones on time and overall tolerated
therapy well, she doesn’t like the idea of being on medicine lifelong and
is considering having children in the next year. Her last PCR confirms
continued MMR which she has maintained for 2 years.
What advice can we give her based on current TKI discontinuation
data?
A. Imatinib can be safely stopped
now
B. Imatinib can be stopped after 1
more year of MMR
C. Imatinib should not be stopped
due to TKI withdrawal syndrome
D. Imatinib should not be stopped
outside of a clinical trial
E. Imatinib should not be stopped
due to the risk of molecular
relapse that would most likely
be resistant to imatinib re-
challenge
43
Im
atinib
can
besafelyst...
Im
atinib
can
bestopped
...
Im
atinib
should
notbes...
Im
atinib
should
notbes...
Im
atinib
should
notbes...
50% 50%
0%0%0%

44. The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
MPD Summary
 Current therapy updates:
 Continued responses to ruxolitinib in the front line
myelofibrosis setting and second line polycythemia
vera treatment
 Application under review for approval of pacritinib for
MF with thrombocytopenia, plt <50K (PERSIST)
 TKI discontinuation still needs to be done in clinical
trial setting for close PCR monitoring
 Areas of ongoing and future investigation:
 MPD: ruxolitinib combinations, PRM-151
 CML: TKI plus PegIFN, radotinib, ABL001
44