DISCLOSURES
I am a consultant for Ariad, BMS, Gilead, Incyte and Novartis.Gilead, Incyte and Novartis.
As Result of Treatment Success the As Result of Treatment Success the Prevalence of CML Is Increasing SteadilyPrevalence of CML Is Increasing Steadily
180000
200000
Prevalence of CML Is Increasing SteadilyPrevalence of CML Is Increasing Steadily
140000
160000
ases 10x greater
steady state number
100000
120000
ber o
f Ca steady state number
of CML patients in USby 2050
60000
80000 Incidence 4,700 per year
Age-matched mortality ratio vs normal population = 1.50
Num
b
20000
40000
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
p p
Accounts for increased US population to 410 million in 2050
CML = chronic myelogenous leukemia.Huang et al, 2012.
Year
NCCN Guidelines Version 1.2017 Chronic MyeloidLeukemia
NCCN Guidelines Index Table of Contents
Discussion
LeukemiaWORKUP
Chronic phase CML
Determine risk score (See Risk Calculation Table CML-A)
See Primary Treatment (CML-2)
CLINICAL PRESENTATION ADDITIONAL EVALUATION
• H&P, including spleen size by palpation (cm below costal margin)
• CBC with differential, platelets• Chemistry profile• Bone marrow evaluationa
Aspirate and biopsy for morphologic review
Ph positive or BCR-ABL1positive Accelerated
phasec
Table CML-A) (CML-2)
Additional testing• Flow cytometry to
determine cell lineage See Primarymorphologic review• CytogeneticsFISH (blood, if bone marrow
not available)b• MolecularQuantitative RT-PCR (QPCR)
using International Scale (IS) for Ph negative and BCR- Evaluate for diseases other than CML
(S NCCN G id li f
Advanced phase CML
Blast phased
determine cell lineage• Mutational analysis• HLA testing, if
considering allogeneic HCT (See CML-6)
See Primary Treatment (CML-4)
BCR-ABL1 (blood)• ECG for prolonged QTc• Hepatitis panel
ABL1negative
(See NCCN Guidelines for Myeloproliferative Neoplasms)
aBone marrow evaluation should be done for the initial workup, not only to provide morphologic review, but also to detect chromosomal abnormalities that are not detectable on peripheral blood FISH.
bSee Discussion for further details.cSee Definitions of Accelerated Phase (CML-B)See Definitions of Accelerated Phase (CML-B).dSee Definitions of Blast Phase (CML-C).
Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CML-5Version 1.2017, 11/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
NCCN Guidelines Version 1.2017 Chronic MyeloidLeukemia
NCCN Guidelines Index Table of Contents
Discussion
Leukemia PRIMARY TREATMENT
Accelerated h c
Clinical trial orTKI (CML-G)
CLINICAL PRESENTATION
Advanced phase CML
phasec TKI (CML G)orOmacetaxinek (CML-G)
Clinical trial orALL-type induction chemotherapy + TKI(CML G)
Treatment Considerations• Role of allogeneic HCT should be
discussed based on response.Disease progression to advancedphase CML
Blast phased
Lymphoid (CML-G)(See NCCN Guidelines for Acute Lymphoblastic Leukemia)orTKI (CML-G) + steroids
Clinical trial
• Disease progression to advanced phase while on TKI therapy has worse prognosis than presenting with advanced phase CML.
• Treatment options are based on patient comorbidities and age.
• Selection of TKI is based on
Myeloid
Clinical trial orAML-type induction chemotherapy + TKI (CML-G)(See NCCN Guidelines for Acute Myeloid Leukemia)orTKI (CML G)
prior therapy and/or BCR-ABL mutation profile.
• CNS involvement has been described in blast phase CML. Lumbar puncture and CNS prophylaxis is recommended for lymphoid blast phase
cSee Definitions of Accelerated Phase (CML-B).dSee Definitions of Blast Phase (CML-C).kOmacetaxine is a treatment option for patients with disease progression to accelerated phase CML. Omacetaxine is not a treatment option for patients that present with
TKI (CML-G) lymphoid blast phase.
Omacetaxine is a treatment option for patients with disease progression to accelerated phase CML. Omacetaxine is not a treatment option for patients that present withaccelerated phase CML.
Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CML-6Version 1.2017, 11/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
NCCN Guidelines Version 1.2017 Chronic MyeloidLeukemia
NCCN Guidelines Index Table of Contents
Discussion
Leukemia PRIMARY TREATMENT
Dasatinib 100 mg QD (category 1) or
CLINICAL PRESENTATION
See Response Milestones and Treatment Options (CML-3)f
Low-risk score(See Risk CalculationTable CML-A)
Imatinib 400 mg QD (category 1) orNilotinib 300 mg BID (category 1) orClinical trial
Treatment Considerations:P ti t biditi d d t i iti
Chronic phase CML
• Patient comorbidities and drug toxicities• Monitor responsef
• Evaluate patient compliance and drug interactions
• Early toxicity monitoring
Dasatinib 100 mg QD (preferred)e
Intermediate- or high-risk score(See Risk Calculation Table CML-A)
orNilotinib 300 mg BID (preferred)e
orImatinib 400 mg QD orClinical trial
See Response Milestonesand Treatment Options(CML-3)f
ePreliminary data suggest that patients with an intermediate- or high-risk Sokal or Hasford score may preferentially benefit from dasatinib or nilotinib. See Discussion for additional informationadditional information.
fSee Monitoring Response to TKI Therapy and Mutational Analysis (CML-D).
Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CML-7Version 1.2017, 11/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Why?Why? Risk score calculation
P di t t t t
Why?Why?
– Predicts treatment response• NCCN guidelines suggest risk-based approach to TKI choice
– Predicts “treatment free remission” success
High and Intermediate Sokal risk
@ 60 months 73% ( 95 %CI: 61-84)
• Independent predictor of relapse with cessation
Baseline Bcr-Abl transcript level
Low Sokal risk
@ 60 months 47% ( 95 %CI: 34-62)
– Clarifies determination of “early molecular response”
– Patient-specific “kinetics” of transcript reductionP= 0.0076
Mahon et al, 2011.Mahon et al, 2011.
Value of MMR in Prolonging RemissionValue of MMR in Prolonging Remission
100Response at 12 months n
Loss of CCyR
CCyR without MMR 95 24%
CCyR plus MMR 32 3%CC
yR (
%)
60
80
100
CCyR plus MMR 32 3%Lo
ss o
f C
P=0.0420
40
Months Since Start of Imatinib Therapy
00 6 12 18 24 30 36 42 48 54 60
Hughes et al, 2010; Cortes et al, 2005; Marin et al, 2008.
3-Mo BCR-ABL Predicts MMR, PFS Similarly for Imatinib and Nilotinib Nilotinib (300 mg BID) Imatinib (400 mg QD)
11
100
≤ 1% n = 120n = 41
By 1 Year By 2 Years
3-y PFS
R
100
90
80
70
> 1% – ≤ 10%
> 10% 76%
By 1 Year By 2 Years89%
67%
78%
n = 89n = 133
n = 24n = 88
95.6%
98 5%
95.3%
With
MM 70
60
50
4040%
71%52%
98.5%96.5%
% 40
30
20
10 4%
29%31%
2%
20%
82.9%83.8%
33
Time Since Randomization (Months)
00 3 6 9 12 15 18 21 24 27 30 36
4%
Time Since Randomization (Months)
2%
Hochhaus A, et al. Haematologica. 2012;97(s1). Abstract 584.
Note: greater numbers of early responders with frontline nilotinib
Estimated 5-year (A, B) overall survival (OS) and (C, D) progression-free survival (PFS) by molecular response at 3 months for both treatment arms.
Jorge E. Cortes et al. JCO 2016;34:2333-2340
©2016 by American Society of Clinical Oncology
SummarySummary>10% at 3 months is a poor risk category>10% at 3 months is a poor risk category
Not all patients with a BCRNot all patients with a BCR--ABL1 value >10% at 3 ABL1 value >10% at 3 months have a high ongoing risk of treatment failure months have a high ongoing risk of treatment failure
any reduction below 10% by 6 months may any reduction below 10% by 6 months may improve outcomeimprove outcomeimprove outcomeimprove outcome
the rate of reduction over the first 3 months is the rate of reduction over the first 3 months is an important factor for outcome and could be an important factor for outcome and could be considered in therapeutic decisionsconsidered in therapeutic decisions
NCCN Guidelines Version 1.2017 Chronic MyeloidLeukemia
NCCN Guidelines Index Table of Contents
Discussion
fLeukemiaBCR-ABL1 (IS) 3 months 6 months 12 months >12 months
>10%h YELLOW RED
1% 10% GREEN YELLOW RED
RESPONSE MILESTONESf,g
1%–10% GREEN YELLOW RED
0.1%–<1% GREEN YELLOW
<0.1% GREEN
RED • Evaluate patient compliance and drug interations• Mutational analysis
Switch to alternate TKI(CML-5) and Evaluate for HCT (CML-6)
CLINICAL CONSIDERATIONS SECOND-LINE AND SUBSEQUENT TREATMENT OPTIONS
( )YELLOW • Evaluate patient compliance and drug interactions
• Mutational analysisSwitch to alternate TKI(CML-5) or Continue same TKI (CML-G)ior Dose escalation of imatinib (to a max of 800 mg) and Evaluate for HCT (CML-6)
GREEN • Monitor response (CML-D) and side effects Continue same TKI (CML-G)j
fSee Monitoring Response to TKI Therapy and Mutational Analysis (CML-D).gSee Criteria for Hematologic, Cytogenetic, and Molecular Response and Relapse(CML-E).hPatients with BCR-ABL1 only slightly >10% at 3 months and/or with a steep decline from baseline, may achieve <10% at 6 months and have generally favorable
outcomes. Therefore, it is important to interpret the value at 3 months in this context, before making drastic changes to the treatment strategy.iAchievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the
10% cutoff can continue the same dose of dasatinib or nilotinib for another 3 months10% cutoff can continue the same dose of dasatinib or nilotinib for another 3 months.jDiscontinuation of TKI with careful monitoring is feasible in selected patients. See Discontinuation of TKI Therapy (CML-F).
Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CML-14
Version 1.2017, 11/15/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
What Is the Standard? Comparative Results:What Is the Standard? Comparative Results:I ti ib 400/600 Nil ti ib D ti ibI ti ib 400/600 Nil ti ib D ti ibImatinib 400/600,Nilotinib, DasatinibImatinib 400/600,Nilotinib, Dasatinib
IRIS(IM400)
IM400ENEST/DASISION
TIDEL I(IM600)
TIDEL II(IM600)
SPIRIT FRANCE(IM600)
ENESTnd(NIL)
DASISION(DAS)
>10% at 3 mos --- 33%/36% 24% 12% --- 9% 16%
CCyR at 12mos 69% 65%/73% 88% 87%a 65% 80% 85%
MMR at 12mos 40% 27%/28% 47% 64% 49% 55% 46%MMR at 12mos 40% 27%/28% 47% 64% 49% 55% 46%
MMR at 24 mos 55% 44%/46% 73% 73% 53% 71% 64%
MR4.5 at 12mos --- 4%/--- 18%b 19% 22%b 11% 5%
MR4.5 at 24mos --- 9%/8% --- 34% 26%b 25% 17%
OS at 3 yrs 92% 94%/93% --- 96% --- 95% 94%
aInferred from MR2.0; bMR4.0 rather than MR4.5.Druker et al, 2006; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Hughes et al, 2008; Yeung et al, 2015; Preudhomme et al, 2010.
Second Generation TKIs Have Improved Response But Second Generation TKIs Have Improved Response But Not Changed Overall Survival Over ImatinibNot Changed Overall Survival Over ImatinibNot Changed Overall Survival Over ImatinibNot Changed Overall Survival Over Imatinib
ResponseLandmarks
ENESTnd DASISION
I ti ib Nil ti ib G i I ti ib D ti ib G iLandmarks Imatinib Nilotinib Gain Imatinib Dasatinib Gain
Completecytogenetic
response at 12 mos65% 80% +15% 73% 85% +12%
response at 12 mosMajor molecular
response at 12 mos 27% 55% +28% 28% 46% +18%
Major molecular 60% 77% 17% 64% 76% 12%Major molecular response at 60 mos 60% 77% +17% 64% 76% +12%
Complete molecular response at 60 mos 31% 54% +23% 33% 42% +9%
Overall survival at60 mos 91.7% 93.7% +2% 90% 91% +1%
Green Indicates Statistically Significant Differencef ff∆
Saglio et al, 2010; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Larson et al, 2013; Hochhaus et al, 2013.
Red Indicates Nonsignificant Difference∆
DASISION 4-Year FolBCR-ABL Mutations: 3-Year Exploratory Analysis
Dasatinib100 mg QD
(n=259)
Imatinib400 mg QD
(n=260)Patients with mutations detected 17 18
Clinically relevant on-treatment events, na
No MMR within 12 months 12 16
No cCCyR within 12 months 8 12y
Loss of CCyR 6 4
5-fold BCR-ABL increase with loss of MMR 2 1
Tested at discontinuation ≤12 months 3 2Tested at discontinuation ≤12 months 3 2
Mutations detected (n) F317I/L (3) V299L (3)G250E (1)T315I (11)
M244V (1)G250E (3) D276G (1) E355G (2)
L248V (1) E255K/V (4) M351T (3)
F359C/I/V (5)E355G (2) L387M (1) E450G (1)
F359C/I/V (5) H396P (1) Y253H (1)
Three additional patients in the imatinib arm (and no additional patients in the dasatinib arm) had mutations in the 4-year per-protocol analysis: G250E, M244V, and F317L/H396R
aPatients may have had multiple events.
y p p y , , Includes 7 patients with 2 mutations: 1 dasatinib patient (V299L/F317I) and 6 imatinib patients (M351T/F359V,
E255V/E450G, L248V/E355G, E255K/M351T, E255V/Y253H, D276G/F359C)
Second Generation TKIs, CML Chronic Phase, Second Generation TKIs, CML Chronic Phase, Aft I ti ib Si il B fitAft I ti ib Si il B fitAfter Imatinib: Similar BenefitsAfter Imatinib: Similar Benefits
D ti ib B ti ib Nil ti ibDasatinib Bosutinib Nilotinib
Months follow-up >24 Median of 24 >24
Complete Hematologic Response 89% 86% 77%
Major Cytogenetic Response 59% 54% 56%
Complete Cytogenetic Response 44% 41% 41%
2 year Progression Free Survival 80% 79% 64%2-year Progression Free Survival 80% 79% 64%
2-year Overall Survival 91% 92% 87%
Shah et al, 2010; Kantarjian, Giles et al, 2011; Cortes et al, 2011.
Mutations: When to LookMutations: When to LookMutations: When to LookMutations: When to Look Both the European LeukemiaNet (ELN) and National Comprehensive Cancer Network
d ABL ki d i t ti l l i d t i i t
Recommendations on When to Perform Mutational AnalysisELN NCCN
recommend ABL kinase domain mutational analysis under certain circumstances:
ELN NCCN At diagnosis
- Only in advanced phase or blast crisis patients
During first line imatinib therapy
BCR-ABL transcript levels >10% by qPCR IS or less than partial cytogenetic response at 3 months
During first-line imatinib therapy- In case of failure- In case of an increase in BCR-ABL
transcript levels leading to loss of major molecular response
Less than complete cytogenetic response at 12 or 18 months
Any sign of loss of response - Defined as hematologic ormajor molecular response
- In any other case of suboptimal response
During second-line dasatinib or nilotinib therapy
Defined as hematologic or cytogenetic relapse or 1 log increase in BCR-ABL transcript levels and loss of major molecular response
Disease progression to advanced phase
Soverini et al, 2011; NCCN, 2016.
- In case of hematologic or cytogenetic failure
Disease progression to advanced phase
Iceberg Analogy #2:Iceberg Analogy #2:R i t M B M C l Th W Thi kR i t M B M C l Th W Thi kResistance May Be More Complex Than We ThinkResistance May Be More Complex Than We Think
Y253HOld sequencing (Sanger sequencing): lower detection
limit 20% F359Vlimit, 20%
T315I +
L248RNew sequencing techniques, like ultra deep sequencing:
T315I + Y253H
T315Ilike ultra deep sequencing:
lower detection limit, 1%
Soverini et al 2013.
BCR‐ABL1 Kinase Domain (KD) Mutations
T i ki i hibit (TKI ) th i t f thChoice of TKI
• Tyrosine‐kinase inhibitors (TKIs) are the mainstay of the treatment of CMLAfter Resistance
• BCR‐ABL1 KD mutations are the most frequently identified mechanism of acquired TKI resistance1
• BCR‐ABL1 mutation testing by conventional Sanger sequencing is recommended for patients with progressionsequencing is recommended for patients with progression, failure and warning2
1 ( ) 2 ( )
155th American Society of Hematology Annual Meeting December 7‐10, 2013 New Orleans, LA
1Clin Cancer Res. 2006; 12(24):7374‐9. 2Blood. 2013;121(3):489‐498.
Resistance to TKIs and Compound MutationsResistance to TKIs and Compound MutationsResistance to TKIs and Compound MutationsResistance to TKIs and Compound Mutations
Hard to differentiate polyclonal t ti (2 diff t l )mutations (2 different clones)
From compound mutations(>1 mutation in the same clone)
Zabriskie et al, 2014.That may be challenging to treat…
Characterization of the Genomic Landscape of BCR-ABL1 Kinase-Independent Mechanisms of Resistance to ABL1Kinase Independent Mechanisms of Resistance to ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
Christopher Eide
Knight Cancer Instituteg Ca ce s u eOregon Health & Science
University
Frequency of mutations in cancer-associated genes varies by resistance type
Among CML-CP patients, frequency of variants in cancer associated genes varies by resistance type
Variants in TET2, TP53, ASXL1, EZH2 demonstrate an increased frequency among BCR ABL1 kinase independentamong BCR-ABL1 kinase-independent resistant patients
Conclusions
Most patients with BCR-ABL1 kinase-independent resistance harbor mutations in common, cancer-associated genes
Many of these variants map to reactivation of pathways involved in CML pathogenesis
S l t i l d i NF kB WNT SRC d JAK/STAT i li l t d i CML ti t ith BCR ABL1Select genes involved in NF-kB, WNT, SRC, and JAK/STAT signaling are upregulated in CML patients with BCR-ABL1 kinase-independent resistance
Importance of these pathways is supported by drug screening ex vivo; further mechanistic validation will be required
Rationally designed, mutationally guided combination therapies involving an ABL1 TKI and a second pathway inhibitor may offer improved options for disease management in patients with this type of resistance
Presence of mutation in genes associated with epigenetic regulation confer poor long-term TKI response.
TaeHyung Kim et al. Blood 2017;129:38-47
©2017 by American Society of Hematology
Ponatinib After Second Generation TKI FailurePonatinib After Second Generation TKI Failure In a cross-study comparison, ponatinib consistently achieved higher complete
cytogenetic response rates after 2nd generation TKI failure
Lipton et al, 2013.
Ponatinib Response Rates inPonatinib Response Rates in3 d3 d d 4thd 4th Li CPLi CP CMLCML3rd3rd-- and 4thand 4th--Line CPLine CP--CMLCML
Imatinib-nilotinib Imatinib-dasatinib Imatinib-dasatinib-nilotinib Imatinib-nilotinib-dasatinib
I-N I-D
MCyR, % Patients MMR, % Patients CCyR, % Patients
100% 100% 100%
I-N I-D I-N I-D I-D-NI-D-N I-N-D I-D-N I-N-D I-N-D
73 58
100%
75%
100%
75%
100%
75%67
4446
25%
50%
25%
50%
25%
50%44 4637 35
46 44 4033
28
n=33 n=52
0% 0% 0%
n=33 n=52 n=33 n=52 n=68n=68 n=46 n=68 n=46 n=46
Hochhaus et al, 2013; Kantarjian et al, 2013.
Omacetaxine ConclusionsOmacetaxine Conclusions•• Omacetaxine is a firstOmacetaxine is a first--inin--class protein synthesis inhibitor withclass protein synthesis inhibitor with
modest activity in highly pretreated CPmodest activity in highly pretreated CP--CML and acceleratedCML and acceleratedy g y py g y pphase patients, including those with the BCRphase patients, including those with the BCR--ABL T315I ABL T315I mutationmutation
•• Response duration appears to be modestResponse duration appears to be modest
•• Grade 3/4 myelosuppression is commonGrade 3/4 myelosuppression is common
•• NonNon--hematologic grade 3/4 toxicities are uncommonhematologic grade 3/4 toxicities are uncommon
•• Omacetaxine was approved by the US FDA in October 2012 Omacetaxine was approved by the US FDA in October 2012 for the treatment of imatinibfor the treatment of imatinib--resistant resistant chronic and acceleratedchronic and acceleratedphase CMLphase CML
The Spectrum of CML TKI ToxicitiesThe Spectrum of CML TKI ToxicitiesThe Spectrum of CML TKI ToxicitiesThe Spectrum of CML TKI ToxicitiesImatinib
Edema/fluid retentionMyalgias
HypophosphatemiaGI effects (diarrhea, nausea)
?Renal changes Ponatinib
MyelosupressionTransaminase
BosutinibDiarrhea/nauseaTransaminitis?Renal effects
PonatinibVascular adverse events
HypertensionPancreatic enzyme
elevation Transaminase
Electrolyte ∆QT prolongation
?Renal effects
Dasatinib
Rash
Nilotinib
Pleural/pericardial effusionPulmonary arterial
hypertensionBleeding risk
Vascular adverse eventsHyperglycemia, Lipids
Pancreatic enzyme elevationIndirect hyperbilirubinemia
NCCN, 2016.
Ponatinib: Arterial and Venous Ponatinib: Arterial and Venous Thrombotic Events (PACE Trial)Thrombotic Events (PACE Trial)Thrombotic Events (PACE Trial)Thrombotic Events (PACE Trial)
Vascular occlusive eventsa
Venous thromboembolic events: 5%
Arterial occlusive events: 28%
Peripheral vascular
Cerebro-vascular
Cardio-vascular
AE SAE AE SAE AE SAE
AE 5%
SAE4%
Total Years Total Years
Exposure-adjusted incidence over time (per 100 patient years):
14% 11% 11% 9% 11% 8%
Total Years
AE SAE 0‐<1 1‐<2 2‐<3 ≥3a
12 10 14.5 14.1 10.5 7.2
Total Years
AE SAE 0‐<1 1‐<2 2‐<3 ≥3a
2 2 3.5 1.8 1.7 0.9
aEvents occurring in patients with CP-CML; bMedian follow-up 35.3 months, analysis for ≥3 years does not cover a fourth full year for all patients.Cortes et al, 2015.
Ponatinib Phase II Study (PACE) Multivariate Analysis:Ponatinib Phase II Study (PACE) Multivariate Analysis:Arterial Thrombotic AEsArterial Thrombotic AEs
Factors significantly i t d ith t i l
0.3associated with arterial thrombotic AEs: Older age (P<0.0001) Hi t f di b tob
abili
ty
0.2 History of diabetes
(P=0.0003) History of ischemia
(P=0 0087)stim
ated
Pro
0.1(P=0.0087)
Higher dose intensity to time of first event (P=0.0009)
Es
15 30 450.0
fit & 95% CI
( )
Each 15 mg/d reduction in dose intensity results in a predicted reduction of ~40% in the risk of an arterial thrombotic event
Dose Intensity (mg/day)
40% in the risk of an arterial thrombotic event
Cortes, Kim et al, 2013.
Risk Mitigation Strategies
1. ASA 81 mg a day1. ASA 81 mg a day
2. Dose reduction: at start? After MMR?
3. Control traditional risk factors
ATE with TKI in CMLATE with TKI in CML--CPCPM lti i t A l iM lti i t A l iMultivariate AnalysisMultivariate Analysis
Variables IR 95% CI For IR P valueVariables IR 95% CI For IR P valueAge 1.04 1.00 1.07 0.023TKI
I ti ibImatinibNilotinib 2.77 1.20 6.42 0.017Ponatinib 6.57 1.81 23.78 0.004Dasatinib 3.58 1.40 9.16 0.008
Male 1.35 0.63 2.90 0.445Race (white) 1.19 0.43 3.29 0.744Diabetes 3.03 1.36 6.74 0.007Coronary artery disease 2.09 0.88 5.09 0.104Hypertension 1 19 0 54 2 62 0 658Hypertension 1.19 0.54 2.62 0.658Dyslipidemia 1.39 0.63 3.08 0.416
ATE with TKI in CMLATE with TKI in CML--CPCPConclusionConclusionConclusionConclusion
•• ATE occur relatively frequently during therapy with TKIATE occur relatively frequently during therapy with TKI
•• Incidence increases with time of exposureIncidence increases with time of exposure•• Incidence increases with time of exposureIncidence increases with time of exposure
•• Higher incidence with 2Higher incidence with 2ndnd and 3and 3rdrd generation TKI generation TKI compared tocompared to imatinibimatinib ((ponatinibponatinib >> nilotinibnilotinib//dasatinibdasatinib >>compared to compared to imatinibimatinib ((ponatinibponatinib nilotinibnilotinib//dasatinibdasatinib imatinibimatinib))
•• Older age and history of diabetes increase riskOlder age and history of diabetes increase risk
•• Close monitoring and management of coClose monitoring and management of co--morbidities morbidities required during treatmentrequired during treatment
•• Occurrence with all TKI suggests possible association Occurrence with all TKI suggests possible association with with ablabl inhibitioninhibition
REASONS TO DISCONTINUE:REASONS TO DISCONTINUE:
1. ONGOING TOXICITY- FATIGUE, ARTHRALGIAS, GI UPSET, ETC.
2. FINANCIAL TOXICITY
3 FEMALE PATIENT AND PREGNANCY3. FEMALE PATIENT AND PREGNANCY
Click to edit Master Presentation Date
EURO-SKI: Adverse events – musculoskeletal symptoms
A TKI withdrawal syndrome consisting of new, mostly transient, musculoskeletal pain or discomfort has been described in EUROSKI patients and other cessation trials (Richter et al JCO 2014 Mori etEUROSKI patients and other cessation trials (Richter et al JCO 2014 Mori et al 2015, Am J Hematology 2015; Lee et al, Haematologica 2016).
Grade 1‐2 % Grade 3 % TOTAL %
Musculoskeletal 226 29.7 9 1.2 235 30.9
** l k l l i b d/ j i i h l i l i l i
symptoms**
** musculoskeletal pain, bone and/or joint pain, arthralgia, muscle pain, myalgia, joint stiffness, lumbalgia, articular pain, muscular pain, neck pain, arthromyalgia, pain both arms, pain legs.
Paradise Lost, Regained?Paradise Lost, Regained?
100
Cumulative incidence of regained MR4.5 in A-STIM retreated patients after loss of MMR
MR
4.5
60
80R
4.5
With >500 patients
erce
nt C
M
40
60
erce
nt M
R preported and very large numbers under investigation, single case of transformation resulting from TFR trialPe
0 12 24 360
20Pe resulting from TFR trial
Months
Median time to regain deep molecular remission: 7.3 mo One patient with CML >15 yr experienced lymphoid blast crisis 8 5 mo from regained One patient with CML >15 yr experienced lymphoid blast crisis 8.5 mo from regained
MMR after restarting imatinib
Rousselot et al, 2014.
Cumulative incidence of molecular relapses
At 60 months 61% ( 95% CI: 52-70)
Cumulative incidence function, accounting for competing events (death i CMR ith t l 1*)in CMR without any relapse n = 1*)
*1 case in CMR after 9 months of imatinib cessation (due to myocardial infarction)
NK-cell counts at the time of TKI discontinuation (5A)
2nd year1st year 3rd yearStudy start 2 year1 year 3 yearStudy start
0 1 6 120 1 6 12Non-relapsing: patients who do not relapse within 6 months Relapsing: patients who relapse after imatinib discontinuation
NK-cell count
1.0
L
0.0084p=
NK-cell proportion
40
50
cells
0.5
X109
cells
/L
10
20
30
% o
f CD
45+
c 0.0010p=
Non-relapsing Relapsing0.0
Non-relapsing Relapsing0
10
%
Patients who relapsed after the TKI discontinuation had decreased amount of at e ts o e apsed a te t e d sco t uat o ad dec eased a ou t oNK-cells already at the study start when still treated with TKI therapy
Criteria to guide selection of patients suitable for a TFR attempt.
Timothy P. Hughes, and David M. Ross Blood 2016;128:17-23
©2016 by American Society of Hematology
4th Generation TKI ABL001 4th Generation TKI ABL001 AllostericallyAllostericallyInhibits BCRInhibits BCR--ABL1 Kinase ActivityABL1 Kinase Activity
SH3t(9;22)BCR
SH3
SH2
BCRKinase
SH2SH2 Kinase
ABL001
ACTIVEINACTIVE
ABL001
Developed to gain greater BCR-ABL1 inhibition, with activity against BCR-ABL1 mutations conferring resistance u a o s co e g es s a ceto TKIs
Potential to combine with TKIs for greater pharmacological control of BCR ABL1
ABL001
control of BCR-ABL1
Ottman et al, 2015.
CML Therapy in 2017CML Therapy in 2017CML Therapy in 2017CML Therapy in 2017•• ImatinibImatinib for lowfor low--risk risk SokalSokal and older pts (≥ and older pts (≥
6060 yrsyrs))60 60 yrsyrs))
•• Second TKIs for higherSecond TKIs for higher--risk risk SokalSokal
•• Until CGCR, then back to Until CGCR, then back to imatinibimatinib
indefinitelyindefinitely•• indefinitelyindefinitely
•• Second TKIs for younger pts (< 50 Second TKIs for younger pts (< 50 yrsyrs) in ) in whom Rx DC importantwhom Rx DC important