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CML UPDATE 2017

DAVID S. SNYDER, M.D.

MARCH 16, 2017

Click to edit Master Presentation Date

DISCLOSURES

I am a consultant for Ariad, BMS, Gilead, Incyte and Novartis.Gilead, Incyte and Novartis.

2001 20162001 2016

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®.



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.





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).



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



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).


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®.

FIRST LINE THERAPY


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)

RESISTANCE AND 2ND /3RD LINE THERAPY


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

EARLY AND LATE COMPLICATIONS


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

TKI DISCONTINUATION


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


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

FUTURE AND CURRENT STATE


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

cml update 2017 - cme syllabuscmesyllabus.com/.../uploads/2017/02/chronic-myeloid-leukemia.pdf ·...

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