ohio state's 2016 ash review - updates in myeloproliferative disorders, including chronic...
TRANSCRIPT
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
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
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
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.
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
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
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
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
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
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
Bes
t Cha
nge
From
Bas
elin
e
in S
plee
n Vo
lum
e, %
Ruxolitinib randomizeda
(n = 136)
After crossovera
(n = 39)
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) P
roba
bilit
y
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.
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
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
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
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.
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
Mea
n H
gb (g
/dL)
(± S
EM)
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
Mea
n Pl
atel
ets×
109 /L
(± S
EM)
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%
PACBAT
p=0.043
Patie
nts
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
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
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
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
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
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
% P
atie
nts w
ith
Bo
ne M
arro
w Im
prov
emen
t
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
Platelets and Platelet Transfusions Pl
atel
ets x
109 /
L an
d
% o
f pat
ient
s with
PLT
tran
sfus
ions
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
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
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
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Updates in Chronic Myeloid Leukemia:
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%
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.
ASH 2015 RERISE 12 Months Follow-up ASH 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
ASH 2015 RERISE 12 Months Follow-up ASH 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
ASH 2015 RERISE 12 Months Follow-up ASH 2015 RERISE 12 Months Follow-up
Major Molecular Response at Each Time P
atie
nts
with
MM
R, %
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 months MMR By 12 months
p=0.0342
p=0.0044
p=0.0667
p=0.0065
ASH 2015 RERISE 12 Months Follow-up ASH 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
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
• 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
SH2
SH3
BCR
ACTIVE
ABL001 Allosterically Inhibits BCR-ABL1 Kinase Activity
Kinase
ABL001
t(9;22) BCR
SH3
Kinase
INACTIVE
ABL001
SH2
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
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)
Patie
nts
With
Res
pons
e, %
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.
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
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
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
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
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
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
Imetelst
at
Momelotinib
Pacritin
ib
Pomalidomide
50% 50%
0%0%0%
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
Imatin
ib can be sa
fely st.
..
Imatin
ib can be st
opped ...
Imatin
ib should not b
e s...
Imatin
ib should not b
e s...
Imatin
ib should not b
e s...
50% 50%
0%0%0%
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