chronic myelogenous leukemia: applying emerging evidence in practice

Chronic Myelogenous LeukemiaApplying Emerging Evidence in Practice

Michael J. Mauro, MDProfessor of Medicine

Leader, Myeloproliferative Neoplasms ProgramMemorial Sloan Kettering Cancer Center

Disclosures

Dr. Mauro discloses the following commercial relationships:– Novartis (consultant)– Bristol-Myers Squibb (consultant)– Pfizer (consultant)– Ariad Pharmaceuticals (consultant)

Nursing Learning Objectives Describe clinical challenges associated with the

contemporary management of CML Evaluate patient- and tumor-related factors that

inform evidence-based treatment planning Recognize the clinical application of novel therapies

in the treatment of newly CML lymphoma Assess side-effect profile of novel therapies for CML

The History of CML Is Long, the Kinase Inhibitor Era Short

1845

First description of CML

1865

Fowler’s solution - 1% arsenic trioxide

2001

Imatinib

1879

Staining methods for blood

1903 1953 19831965

RadiotherapyBusulfan

Hydroxyurea

Interferon

1968

Bone Marrow Transplant

2006

Dasatinib, Nilotinib

2012

Bosutinib Ponatinib

1960:Nowell & Hungerford describe the Philadelphia Chromosome

1973:Janet Rowley describes the9:22 translocation

1999: After seminal preclinical work first clinical trials commence with STI571 (imatinib)

1845:John Hughes Bennett reported a “Case of Hypertrophyof the Spleen and Liver in which Death Took Place from Suppuration of the Blood” in the Edinburgh Medical Journal

2016

Generic Imatinib

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 205020000

40000

60000

80000

100000

120000

140000

160000

180000

200000

Incidence 4,700 per year

Age-matched mortality ratio vs normal popula-tion = 1.50

Accounts for increased US population to 410 million in 2050

CML = chronic myelogenous leukemia.Huang et al, 2012.

Year

Num

ber o

f Cas

es 10x greatersteady state number

of CML patients in USby 2050

As Result of Treatment Success the Prevalence of CML Is Increasing Steadily

CML in 2016

qPCR = quantitative polymerase chain reaction.NCCN, 2016.

CML is now highly treatable and “functional cure” appears to be within our grasp

Initial therapy for many is an “embarrassment of riches”– Five approved tyrosine kinase inhibitors (TKIs) overall, three front-line, in the US

Key diagnostic (qPCR): blood-based and widely available Rapidity of response and passing key thresholds improve odds of

deep remission in the short and long term

Success in CML contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and vigilance for ‘late effects’

CML is a marathon, not a sprint!

Topics to Discuss

1. What should we be looking at upon diagnosis and what is best initial therapy?

2. How to define and manage resistance3. Is stopping therapy going to be appropriate?4. Are we seeing late complications with TKI

therapy?5. What else is new on the horizon for CML?

Making the Diagnosis of CML

History and physical(record spleen size)

Complete blood count/differential Ph+ chromosome determination

(cytogenetics > FISH > PCR) Baseline qPCR for BCR-ABL

(quantitative, International Scale reported)

Required

Bone marrow aspirate/biopsy HLA typing of siblings

Suggested/Implied

Ph = Philadelphia chromosome; FISH = fluorescence in situ hybridization; HLA = human leukocyte antigen. NCCN, 2016.

Risk score calculation– Predicts treatment response

• NCCN guidelines suggest risk-based approach to TKI choice– Predicts “treatment free remission” success

• Independent predictor of relapse with cessation

Baseline Bcr-Abl transcript level– Clarifies determination of “early molecular response”– Patient-specific “kinetics” of transcript reduction

P= 0.0076

Low Sokal risk

High and Intermediate Sokal risk

@ 60 months 73% ( 95 %CI: 61-84)

@ 60 months 47% ( 95 %CI: 34-62)

Mahon et al, 2011.

Why?

What Do NCCN Guidelines Recommend at Diagnosis?

H&P = history and physical exam; CBC = complete blood count; HSCT = hematopoietic stem cell transplant. NCCN, 2016.

Which TKI to Choose?

High dose imatinib (IM) for all?– Randomized trial (TOPS) of 400 mg vs 800 mg did not show difference in major

molecular response (MMR) rates at 12 months; greater toxicity in high-dose arm

High-dose IM for high-risk patients only?– GIMEMA study of 800 mg for high Sokal risk: no difference in cytogenetic response

(CyR)

– Impact of higher dose diluted by inability to deliver (toxicity)

Early dose optimization/600 mg IM (TIDEL, TIDEL II)?– Response very closely approximates second generation TKIs

With all these data, 3 available TKIs for new diagnosis and a generic option coming, how to decide?

NCCN, 2016.

Dasatinib and nilotinib?

– Offer clear advantages but no overall survival (OS) benefit yet; “promise” of treatment-free remission (TFR) not a reality yet

IM + Interferon (IFN)?

– SPIRIT trial showed increase in molecular response (MMR, MR4 and MR4.5) particularly if IFN tolerated for a critical amount of time (>4 mos)

Ponatinib?

– Demonstrates no “ceiling effect” response >> imatinib and likely >nilotinib and dasatinib; toxicity questions and time needed to settle this question

Bosutinib?

– BELA trial (bosutinib 500 vs imatinib 400) showed improvement in molecular response but primary end point complete cytogenetic response (CCyR) failed

– “Repeat” bosutinib 400 vs imatinib 400 trial in progress globally

Which TKI to Choose? (cont.)

NCCN, 2016.

Reality CheckCost matters, generics are here!

Sun Pharma (Mumbai, India) began selling generic imatinib in the US on February 1 with exclusive rights (single generic) for 6 months

CML patients with higher copayments were 1.7x more likely to stop and 42% more likely to be nonadherent with TKI therapy in the first 180 days

Dusetzina, 2014; Kantarjian et al, 2013.

Global Generic Experience: Mixed News….

Indian Experience: 2001-07 (n=719)(Courtesy H. Menon, Tata MH, Mumbai) Gleevec Generic

CP n=618; AP n=55; BC n=46 n=372 n=246

CCyR at 1 year 25% 19%

CCyR at 2 years 47% 45%

MCyR at 2 years 88% 94%

What Is the Standard? Comparative Results:Imatinib 400/600,Nilotinib, Dasatinib

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.

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 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%

Second Generation TKIs Have Improved Response But Not Changed Overall Survival Over Imatinib

ResponseLandmarks

ENESTnd DASISION

Imatinib Nilotinib Gain Imatinib Dasatinib Gain

Complete cytogenetic

response at 12 mos65% 80% +15% 73% 85% +12%

Major molecular response at 12 mos 27% 55% +28% 28% 46% +18%

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 at 60 mos 91.7% 93.7% +2% 90% 91% +1%

Saglio et al, 2010; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Larson et al, 2013; Hochhaus et al, 2013.

Green Indicates Statistically Significant DifferenceRed Indicates Nonsignificant DifferenceΔ

The Value of Early Molecular Response on Outcome and Response

Branford, Yeung, Parker, et al, 2014.

Overall Survival Progression-Free Survival Failure-Free Survival

Major Molecular Response Complete Molecular Response

≤ 10%> 10%

≤ 10%> 10%

≤ 10%> 10%

≤ 10%> 10%

≤ 10%> 10%

(BCR-ABL values ≤10% at 3 months)

Pace of Response Matters, Not Just the Milestone

Branford, Yeung, Parker et al, 2014; Branford, Yeung, Ross et al, 2014.

Recent work by the same group:<11 day halving time in first month may be a good judge…

Change in BCR-ABL1 value from the individual patient baseline value according to the halving time at 3 months for patients with >10% BCR-ABL1 (all considered suboptimal by NCCN)

Value of MMR in Prolonging Remission

Response at 12 months n

Loss of CCyR

CCyR without MMR 95 24%

CCyR plus MMR 32 3%

Months Since Start of Imatinib Therapy

Loss

of C

CyR

(%

)

P=0.04

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

Hughes et al, 2010; Cortes et al, 2005; Marin et al, 2008.

Aside From Being a Launching Point for TFR Trials, Does CMR Add Value?

23 11 5 1 0 0 092 81 60 33 10 3 065 63 53 35 15 3 2

CCvR+MMR-CCvR+MMR+CMR-CCvR+MMR+CMR+

Number at risk

23 11 5 1 0 0 092 81 60 33 10 3 065 63 53 35 15 3 2

CCvR+MMR-CCvR+MMR+CMR-CCvR+MMR+CMR+

Number at risk

P=0.00124

P<0.0001

P<0.0001

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120Follow-Up (Months)

Even

t-Fre

e Su

rviv

al

EFS

CCyR+MMR+CMR+

CCyR+MMR+CMR-

CCyR+MMR-

P=0.0335

P<0.0001P<0.0001

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120Follow-Up (Months)

Failu

re-F

ree

Surv

ival

FFS

CCyR+MMR+CMR+

CCyR+MMR+CMR-

CCyR+MMR-

Complete molecular response (CMR) defined as undetectable BCR-ABL with a sensitivity of at least 4.7 logs on 2 consecutive analyses at least 2 months apart.

EFS = event-free survival; FFS = failure-free survival.Etienne et al, 2014.

ASH 2015: Peg-INF + Dasatinib

Roy et al, 2015.

81 Pts(Oct 2013 - Jul 2014)

22 Centers

Key Inclusion/Exclusion

Criteria• Ph+ CP-CML 3 Mo• 18-65 years• No prior TKI nor

IFNα• No CI to Peg-IFNα

nor Dasatinib

M3Eligibility for

Peg-IFN

Yes

At M3ANC ≥1.5 x 109/LPlt ≥ 100 x 109/L

Ly ≤4 x 109/L

Dasatinib 100 mg/d

Dasatinib+ Peg-IFN-2b 30 µg/w

(Max 21 Mo)

D1

DasatinibNo

FU 5 Years

61 pts

18 pts

M12: Primary End Point

M3 M6 M9 M120%

10%20%30%40%50%60%70%80%90%

100%

UNKNo MR3MR3MR4MR4,5

8%

10%31%13%

11%

16%

28%

39%34%

n=3

15%

All pts (N=79), MR 4.5: 25% at M12,

≤ MR3: 73%

Roy et al, 2015.

ASH 2015: Peg-INF + Dasatinib

Putting CML Response Into Perspective

Mauro, 2014.

International Standard (IS) qPCR

10%

1%

0.1%

0.01%0.0032%

Early Molecular Response: <10% or 1-log (10x) drop from

starting levelComplete Cytogenetic Response:

<1% or 2-log (100x) drop

Major Molecular Response:<0.1% or 3-log (1000x) drop

4-log drop (<0.01%)

4.5 log drop, MR4.5,Complete Molecular Remission:

<0.0032%; below the level ofdetection for standard labs

Early Molecular Response

Complete Cytogenetic Response

Major Molecular Response

MR4

MR5-6?

MR4.5CMR

The

Future ?

Early Molecular Response

Complete Cytogenetic Response

Major Molecular Response

MR4MR4.5CMR

“Inverted iceberg” schematic of CML response over time

Reality of US/EU Risk Stratification and Monitoring Patient baseline risk and ECOG PS scores Only 32.6% of patients had either Hasford or Sokal scores recorded 68.4% of EU patients had available Hasford or Sokal scores, compared with 14.3% of US patients (P<0.001)

50% or more, no Cy testing 15-20%, no Molecular testing

Cortes et al, 2013.

Topics to Discuss




What Do the Guidelines Tell Us at 3 and 6 Months?

NCCN, 2016.

What Do the Guidelines Tell Us at 12 and 18 Months?At 12 months and 18 months

NCCN, 2016.

Practical Approach to a Patient With Resistance (or Intolerance ± Resistance)

First, determine what the disease state requires– Disease phase– Prior TKI exposure– Mutational status

• T315I unique• Select mutations may

support role of specific 2nd generation TKIs

• Predictive potential imprecise• “Iceberg” phenomenon• More detailed assays

forthcoming (like ultra deep sequencing)

Next, balance therapy risk and toxicity potential with known comorbidities– Are there true

contraindications?– Does risk outweigh benefit

expected from therapy?– Can risk be mitigated or

anticipated?– Enlist the patient’s insight,

trust, and awareness

NCCN, 2016.

Mutations Mirror the Degree of Genetic Instability of the Ph+ Clone

gene

tic in

stab

ility

Mutations are not induced by TKI therapy TKI therapy simply results in selection of

mutations independently arisen as a consequence of the genetic instability of the Ph+ clone

Genetic instability is most probably fostered by BCR-ABL itself

The longer BCR-ABL remains active, or the less efficiently it is inhibited, the higher the mutation rate

BCR-ABL is still the key target for therapeutic improvement

mut

atio

n fre

quen

cy

BCR-ABLNCCN, 2016.

P-loop SH2 contact A-loop SH3 contact

M244V

G250E/RQ252R/H

E255K/VY253F/H

V280A

L273M

D276G

E292V/Q

F311L/IT315I

F317L/V/I/C

M343T

L364I

H396P/R/A

M351T

S417F/YF359V/I/C/L

F486S

E459K/V/G/QE453G/K/V/Q

E355D/G/A

L248V E279KT277A

V379IA380T

F382LL384ML387M/F/V

E450K/G/A/V

M237V

I242T

E258D

V299L

Y342H

D363Y

A365VA366G

M388LY393C

A397P

I418S/V

S438C

M472I

P480L

K247R

E275K/Q

L298V

A433T

Y320CV371A

E373KL324Q

W261L

V289A/I

I293VA344V

A350V

L370P

E507G

10 most frequent mutations, accounting for ~70% of resistance, highlighted in redMutations: Many Besides T315I

Soverini et al, 2011.

DASISION ENESTndDasatinib100 mg

QDn=258

Imatinib 400 mg

QDn=258

Nilotinib 300 mg

BIDn=282

Nilotinib400 mg

BIDn=281

Imatinib 400 mg

QDn=283

Patients with any newly detectable mutations on treatment, n

10 11 10 8 20

Mutation category:

T315I, n 7 0 3 2 3Less sensitive to dasatinib (DASISION) or nilotinib (ENESTnd), n 1 0 5 6 4Sensitive to dasatinib (DASISION) or nilotinib (ENESTnd), n 3 11 2 0 13

Mutations clinically less sensitive to dasatinib included V299; less sensitive to nilotinib E255K/V, F359C/V,and Y253H

Mutations sensitive to nilotinib or dasatinib included all mutations other than less-sensitive mutations and T315I

Mutations Identified During Treatment in Frontline Trials

Kantarjian, Shah, et al, 2012; Kantarjian et al, 2011.

Mutations: When to Look

Soverini et al, 2011; NCCN, 2016.

Recommendations on When to Perform Mutational AnalysisELN NCCN

At diagnosis- Only in advanced phase or blast

crisis patients 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

- In any other case of suboptimal response

During second-line dasatinib or nilotinib therapy

- In case of hematologic or cytogenetic failure

BCR-ABL transcript levels >10% by qPCR IS or less than partial cytogenetic response at 3 months

Less than complete cytogenetic response at 12 or 18 months

Any sign of loss of response - 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

Both the European LeukemiaNet (ELN) and National Comprehensive Cancer Network recommend ABL kinase domain mutational analysis under certain circumstances:

Likelihood Mutation Testing Will Influence TKI Choice

LBC = lymphoid blast crisis; MBC = myeloid blast crisis; AP = acute phase; CP = chronic phase; ALL = acute lymphoblastic leukemia.Branford et al, 2009.

Mutation Spectrum at Time of Switch Is More Complicated When Assessed by Ultra Deep Sequencing

SS = simple sequencing; UDS = ultra deep sequencing.Soverini et al, 2013.

02468

1012141618202224

No Mutations 1 Mutation 2 Mutations ≥3 Mutations

Num

ber o

f Pat

ient

s

SSUDS

What Do the Guidelines Tell Us About Switching Treatment?

Primary Treatment Second-line Therapy and Subsequent Therapy

Imatinib

BosutiniborDasatiniborNilotinib

Dasatinib or Nilotinib or Ponatinib

Bosutinib or Nilotinib or Ponatinib

Bosutinib or Dasatinib or Ponatinib

Clinical trialor

HSCTor

Omacetaxine

Dasatinib

BosutiniborNilotinib

Nilotinib or Ponatinib

Bosutinib or Ponatinib Clinical trialor

HSCTor

Omacetaxine

Nilotinib

BosutiniborDasatinib

Dasatinib or Ponatinib

Bosutinib or Ponatinib

Management of Cytogenetic or Hematologic Resistance to TKIs

NCCN, 2016.

ELN Treatment Recommendations for Switch: Chronic Phase CML

SCT = stem cell transplantation.Baccarani et al, 2013

1st line

2nd line

3rd line

Any line, T315I

mutation

Imatinib, nilotinib, dasatnib

Intolerance to 1st TKI

Failure of 1st line imatinib

Failure of 1st line nilotinib or dasatinib

Nilotinib, dasatinib, bosutinib, ponatinib

Ponatinib

Failure of, and/or intolerance to 2 TKIs

Any of the remaining TKIs

Imatinib, nilotinib, dasatinib

Nilotinib/dasatinib, bosutinib, ponatinib SCT

considerationin many cases

SCT investigation

warranted

Second Generation TKIs, CML Chronic Phase, After Imatinib: Similar Benefits

Shah et al, 2010; Kantarjian, Giles et al, 2011; Cortes et al, 2011.

Dasatinib 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 Overall Survival 91% 92% 87%

Third-Line Therapy: Response to Bosutinib

Response (n)

Imatinib and Dasatinib Resistant

(n=38)

Imatinib Resistant, Dasatinib Intolerant

(n=50)

Imatinib and Nilotinib

Resistant(n=26)

Complete hematologic response 68 76 76Major cytogenetic response 39 42 36

Complete cytogenetic response 22 40 28

Partial cytogenetic response 17 2 8Major molecular response 3 25 11Transformation (3 yr) 8 0 4

Cortes, Khoury et al, 2013.

Pfizer Study 200 118 patients who failed imatinib and either dasatinib or nilotinib

Switching to Other Second Generation TKI(s) After Imatinib Failure

Study Garg, et al Rossi, et al

Ibrahim, et al

Giles, et al

Khoury, et al

Third-line treatment

Dasatinib or nilotinib

Dasatinib or nilotinib

Dasatinib or nilotinib Nilotinib Bosutinib

N 25 (CP) 66 (91% CP) 26 (CP) 37 (CP) 118 (CP)

Complete cytogenetic response (%)

24 15 35 24 24

Garg et al, 2009; Rossi et al, 2010; Ibrahim et al, 2010; Giles et al, 2010; Khoury et al, 2012.

If a second generation TKI is not successful after imatinib, how successful is switching to other second generation TKI(s)?

Omacetaxine for CML After Failure of ≥2 TKIs

Response, % CPN=81

APN=41

Primary end point(s)

Major cytogenetic response: 20%

Major hematologic response: 27%

Complete cytogenetic response: 10%

Complete hematologic response: 24%

Median duration, months 17.7 9

Median progression-free survival, months 9.6 4.7

Median overall survival, months 33.9 16

11 patients (9 chronic phase, 2 accelerated phase) ongoing response Median 35 cycles over median 39 months Median response duration: 14 months for chronic phase, 24 months for accelerated phase

Cortes et al, 2013.

Ponatinib After Second Generation TKI Failure

Lipton et al, 2013.

In a cross-study comparison, ponatinib consistently achieved higher complete cytogenetic response rates after 2nd generation TKI failure

Ponatinib Response Rates in3rd- and 4th-Line CP-CML

I-N I-D

n=33 n=52

MCyR, % Patients MMR, % Patients CCyR, % Patients

73 58

25%

100%

0%

50%

75%

25%

100%

0%

50%

75%

25%

100%

0%

50%

75%

I-N I-D

n=33 n=52

67

44

I-N I-D

n=33 n=52

4637

Imatinib-nilotinib Imatinib-dasatinib

35

I-D-N

n=68

Imatinib-dasatinib-nilotinib Imatinib-nilotinib-dasatinib

46 44 4033

28

I-D-N I-N-D

n=68 n=46

I-D-N I-N-D

n=68 n=46

I-N-D

n=46

Hochhaus et al, 2013; Kantarjian et al, 2013.

What Is the Role of Allografting in CML?

QOL = quality of life.NCCN, 2016.

Status TKIs TransplantAccelerated or blast transformation has occurred

Interim treatment to best response/minimal residual disease

ASAP

Imatinib failure in chronic phase, T315I (+)

Ponatinib If no response to ponatinib

Imatinib failure in chronic phase without clonal evolution, mutations, good response

Long-term second line TKIs

Third line post second TKI failure or beyond

IM failure in chronic phase with clonal evolution, mutations, poor response

Interim treatment to best response

Second line, taken case by case

Older age (≥65 – 70) post imatinib failure

Long-term second line TKIs

May forgo allo SCT for many yrs of QOL

In CP and AP CML, No Early Gain in OS With SCT vs Ponatinib

*P-value <0.05. OS = overall survival; IQR = interquartile range; NR = not reached.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 12 24 36 48

Surv

ival

Rat

e (%

)

Months from Treatment Initiation

Adjusted OS, CP-CML

PonatinibSCT

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 12 24 36 48

Surv

ival

Rat

e (%

)


Adjusted OS, AP-CML

PonatinibSCT

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 12 24 36 48

Surv

ival

Rat

e (%

)


Adjusted OS, BP-CML

SCTPonatinib

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 12 24 36 48

Surv

ival

Rat

e (%

)


Adjusted OS, Ph+ ALL

SCTPonatinib

Treatment N Median (IQR)Ponatinib 64 NR (45.9 - NR)SCT 26 103.3 (6.6 - 103.3)Log-rank p-value = 0.013*

Treatment N Median (IQR)Ponatinib 18 NR (24.6 - NR)SCT 8 55.6 (11.4 - NR)Log-rank p-value = 0.889

Treatment N Median (IQR)Ponatinib 24 7.0 (3.5 - 11.0)SCT 17 10.5 (5.8 - 49.0)Log-rank p-value = 0.026*

Treatment N Median (IQR)Ponatinib 22 6.7 (4.0 - 15.3)SCT 5 32.4 (7.8 - NR)Log-rank p-value = 0.119

Nicolini et al, 2015.

Topics to Discuss




The Promise of 2nd Generation TKIs Regarding TFR: Frontline Imatinib, Dasatinib, or Nilotinib (Postulated)

Hughes & White, 2013.

0102030405060708090

100

Cum

ulat

ive

Inci

denc

e %

0 4 5 6 7Years After Commencing 2nd Gen TKI

1 2 3

60-80%

24-32%

16%

40%

Deep molecularremission (CMR)

TFR

36 mo: 61%

0

20

40

60

80

100

0 6 12 18 24 30 36 42

Sur

viva

l with

out M

MR

loss

%

Months since 2G-TKI discontinuation

12 mo: 61.1%(95% CI: 45.6-76.6)

Survival Without Loss of MMR: Approximately 60% Success

Rousselot et al, 2014; Rea et al, 2012; Ross et al, 2013.

AUSTRALASIAN CML8

STOP 2G TKIA-STIM study

Stable confirmed CMR before stopUnstable cCMR before stop

Mol

ecul

ar

Rel

apse

-Fre

e Su

rviv

al (%

)

100

80

60

40

20

012 24 36 48 60 72 84

Time (months)

A-STIM study

ASH 2015: STIM Trial Long-Term Follow-Up/Molecular recurrence

N=61; median follow-up = 63 mo 4 patients died after molecular recurrence (MR) of CML-unrelated causes MR: 80% within M 1-3, 15% within M 4-7 and 5% (n=3) within M 18 to 22

a(Pleural mesothelioma, metastatic gastric adenocarcinoma, acute renal failure, cerebral hemorrhage; one case of each)Etienne et al, 2015.

Number at risk: 100 44 41 38 38 38 38 37 29 25 19 11 5 1 0

Cum

ulat

ive

Inci

denc

e o

f MR

Months Since Stop of Imatinib

• Median time to MR : 2.5 mo (range,0.8 to 22.2)

• 57 out of the 61 pts restarted TKI (imatinib, n=56; dasatinib , n=1) and 55 achieved 2nd CMR at a median of 4.2 months

• Median follow-up of 63 mo : - None of the MR patients have CML progression

event

Paradise Lost, Regained?

Months

Perc

ent C

MR

4.5

0 12 24 360

20

40

60

80

100

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

MMR after restarting imatinib

Rousselot et al, 2014.

Perc

ent M

R4.

5

Cumulative incidence of regained MR4.5 in A-STIM retreated patients after loss of MMR

With >500 patients reported and very large numbers under investigation, single case of transformation resulting from TFR trial

Relapse defined as BCR-ABL >0.1%(loss of MMR) at one time point

TKI Discontinuation From Detectable Levels of MR (MR4): EURO-SKI Study Design

Inclusion violation n=2,- Restart of TKI without relapse n=4,

Not eligible for interim analysis n=48

n=200Evaluable at 6 mos

n=254

Mahon et al, 2014.

100

80

60

40

20

0

Rel

apse

-Fre

e Su

rviv

al

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Months From Discontinuation of TKI

EURO-SKI: Survival Without Loss of MMR(Molecular Relapse-Free Survival)

9 patients with relapse after 6 months (month 7-16) 4 patients also had loss of CCyR, no loss of complete hematologic response Of 26 patients with relapse, 13 regained MR4

n=200Relapses, n=86Relapses within 6 months , n=77

Molecular relapse-free survival at 6 months: 61% (54-68)

Mahon et al, 2014.

Do Adverse Events Occur With TKI Withdrawal?

PatientsAll Grade

(n)

PatientsGrade 3

(n)

AEsAll Grade

(n)

AEsGrade 3

(n)

Musculoskeletal pain, joint pain, arthralgia23 3 39 6

Other(sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, weight loss)

8 0 18 3

Musculoskeletal pain in CML patients after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?Richter J et al (2014). J Clin Oncol, 32(25):2821-2823.

Tyrosine kinase inhibitor withdrawal syndrome: a matter of c-kit?Response to Richter et al. Rousselot et al.

N=200; 222 AEs in 98 patients were reported 57 AEs in 31 patients were related to treatment stop, no grade 4

Mahon et al, 2014.

What Is Really Happening With TFR?Patients who maintain MR4.5 off imatinib commonly have evidence of BCR-ABL when assessed with a more sensitive genomic DNA (gDNA) based test

Ross et al, 2010.

Ten patients with loss of CMR had rising gDNA PCR levels, whereas a generally stable gDNA level was detectable in 7/8 patients with sustained CMR (follow-up 12-41 months).

Topics to Discuss




The Spectrum of CML TKI Toxicities

Myelosupression

Transaminase

Electrolyte ΔQT

prolongation

ImatinibEdema/fluid

retentionMyalgias

Hypophosphatemia

GI effects (diarrhea, nausea)

?Renal changes Bosutinib

Diarrhea/nauseaTransaminitis?Renal effects

DasatinibPleural/pericardial

effusionPulmonary arterial

hypertensionBleeding risk

PonatinibVascular adverse

eventsHypertension

Pancreatic enzyme elevation

Rash

NilotinibVascular adverse

eventsHyperglycemia,

LipidsPancreatic enzyme

elevationIndirect

hyperbilirubinemia

NCCN, 2016.

Kantarjian, O’Brien et al, 2012.

BCR-ABL1 TKI-Associated Cardiovascular Adverse Events

Cerebrovascular Disease

Coronary Heart DiseaseMyocardial Infarction

Pulmonary Arterial Hypertension

Venous ThrombosisPeripheral Arterial Disease

CardiomyopathyCongestive Heart Failure

Morbidity and mortality; effect on OS observations in frontline studies Delay/deferral of advantageous therapy both in frontline and salvage

Cardiomyocyte injury?

Endothelial dysfunction?Atherosclerosis?



Endothelial dysfunction?

Platelet dysfunction?Prothrombotic state?

Fatigue Musculoskeletal symptoms/

cramping Exercise-induced symptoms

Other:

ENESTnd: Select Cardiovascular Events by 5 Years

Patients had longer exposure to nilotinib than imatinib due to treatment discontinuation Approximately 85% of patients with a cardiovascular event had at least 1 risk factor and

were not optimally managed for hyperglycemia and hypercholesterolemia

Patients With an Event, n

Imatinib400 mg QD

n=280

Nilotinib300 mg BID

n=279

Nilotinib400 mg BID

n=277

Total, n

Y1-4, n

Y5, n

Total, n

Y1-4, n

Y5, n

Total, n

Y1-4, n

Y5, n

Ischemic heart disease

5 3 2 11 11 0 21 14 7

Ischemic cerebrovascular disease

1 1 0 4 3 1 8 5 3

Peripheral arterial disease

0 0 0 7 4 0 6 5 1

Larson et al, 2014.

All Cause (Treatment Related or Not), All Grades

Dasatinib (n=259) Imatinib (n=260)

Adverse event (AEs) Grade1/2

Grade 3/4

Grade 5

Totaln (%)

Grade 1/2

Grade 3/4

Grade 5

Totaln (%)

Cardiac ischemia 10(3.9%)

3(1.2%)

Myocardial infarction 1 2 2 5 (1.9%) 0 1 1 2

(0.8%)

Angina 2 1 0 3 (1.2%) 1 0 0 1

(0.4%)Coronary artery disease, myocardial ischemia

2 0 0 2 (0.8%) 1 0 0 1

(0.4%)

Peripheral arterial occlusive disease 0 0 0 0 0 0 0 0

DASISION: Arterial Occlusive Events of Interest (Any Cause)

Patients with a history of cardiac disease were included in DASISION, except those who had angina within 3 months, myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation

9 of 10 dasatinib and 2 of 3 imatinib patients with cardiac ischemia had at least 1 baseline risk factor for cardiovascular disease (eg, diabetes, hypertension, hyperlipidemia, left ventricular dysfunction, coronary artery disease)

Cortes, Hochhaus, et al 2013.

Pulmonary Hypertension With Dasatinib: Characterization

PH = pulmonary hypertension. Montani et al, 2012.

Pulmonary Hypertension With Dasatinib: Clinical and Functional Evaluation

Montani et al, 2012.

Ponatinib: Arterial and Venous Thrombotic Events (PACE Trial)

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.

Total YearsAE SAE 0-<1 1-<2 2-<3 ≥3a

12 10 14.5 14.1 10.5 7.2

Total YearsAE SAE 0-<1 1-<2 2-<3 ≥3a

2 2 3.5 1.8 1.7 0.9

Exposure-adjusted incidence over time (per 100 patient years):

Vascular occlusive eventsa

Venous thromboembolic events: 5%

Peripheral vascular

Cerebro- vascular

Cardio- vascular

AE 14%

SAE 11%

AE 11%

SAE 9%

AE 11%

SAE 8%

AE 5%

SAE4%

Arterial occlusive events: 28%

Ponatinib Phase II Study (PACE) Multivariate Analysis: Arterial Thrombotic AEs

Factors significantly associated with arterial thrombotic AEs: Older age (P<0.0001) History of diabetes

(P=0.0003) History of ischemia

(P=0.0087) Higher dose intensity to

time of first event (P=0.0009)

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)

Estim

ated

Pro

babi

lity

15 30 450.0

0.1

0.2

0.3

fit & 95% CI

Cortes, Kim et al, 2013.

CML IV Study and Comorbidity:No Effect on CML TKI Response or Transformation

Saussele et al, 2015.

CML IV Study and Comorbidity:Significant Effect on Survival, Irrespective of Age

Saussele et al, 2015.

Charlson Comorbidity Index (CCI)calculated including age

Charlson Comorbidity Indexcalculated without age

Charlson Comorbidity Index Scoring System

Charlson et al, 1987.

Prevalence of Comorbidities: EUTOS Data

Hoffman et al, 2015.

56% with comorbidities42% Cardiovascular

Topics to Discuss




Y253H

T315I

L248R

F359V

New sequencing techniques, like ultra deep sequencing:

lower detection limit, 1%

Old sequencing (Sanger sequencing): lower detection

limit, 20%

Iceberg Analogy #2:Resistance May Be More Complex Than We Think

T315I + Y253H

Soverini et al 2013.

Resistance to TKIs and Compound Mutations

Hard to differentiate polyclonal mutations (2 different clones)

From compound mutations(>1 mutation in the same clone)

Zabriskie et al, 2014.That may be challenging to treat…

Multiple Mutations Often Hide Complex Mixtures of Single and Compound Mutants

Soverini et al, 2013.

quadrupletripledoublesingle

compound49.6% 38.3%

10.6%1.5%

Frequency of single and compound mutants in 33 patients (CML or Ph+ ALL) who had experienced sequential relapses with selection of one or more TKI-resistant mutations:

SH2

SH3

BCR

ACTIVE

4th Generation TKI ABL001 Allosterically Inhibits BCR-ABL1 Kinase Activity

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

Kinase

ABL001

t(9;22)BCR

SH2SH2

SH3

Kinase

INACTIVE

ABL001

Ottman et al, 2015.

Combination of ABL001 and Nilotinib Prevents Emergence of Resistance

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

days post-implant

Tum

or V

olum

e (m

m3 )

0 20 40 60 800

200

400

600

800

1000

180 180

Nilotinib (75 mg/kg) BID

ABL001 (30 mg/kg) BID

Nilotinib (75 mg/kg) BID + ABL001 (30mg/kg) BID

Dosing stopped on day 77, all mice remain disease free >176 days

T315I detected

A337V detected

*Each line represents individual animals.Wylie et al, 2014.

* *

KCL-22 CML Xenograft

ASH 2015: ABL001 Phase I Trial All patients had >1 postbaseline

safety assessment

There were 5 dose-limiting toxicities:

Grade 3 lipase increase (n = 2, 40mg BID, 200 mg QD)

Grade 2 myalgia/arthralgia (80 mg BID)

Grade 3 acute coronary event (150 mg BID)

Grade 3 bronchospasm(200 mg BID)

No deaths occurred on study

Dose escalation is ongoing

Ottman et al, 2015.

0

10

20

30

40

50

60

70

80

90

100

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 ResponseWithin 2 Months

Cytogenetic ResponseWithin 3-6 Months

Molecular ResponseWithin 6 Months

Status at Baseline

Patients With ≥ 3 Months of Follow-Up on Study (n=29)

How I Follow a Recently Diagnosed CML Patient

Cardiovascular evaluation– Overall approach: at least age- and comorbidity-appropriate studies– If nilotinib to be used, inclusive of peripheral/cerebral/cardiovascular– If dasatinib to be used, echocardiogram to estimate pulmonary pressure– Monitoring of blood pressure, lipids, and glycemic control

Initial studies to include bone marrow and baseline qPCR (IS) Lab studies every 1-2 weeks for at least 6 weeks, then less often/as indicated;

frequency increased again for change in therapy 3-mo assessment: qPCR (IS) If response surpasses CCyR equivalent and blood count “new normal” is

acceptable/stable no imperative for repeat BM Sequential molecular analyses every 3 mo Repeat CV eval if/when indicated (eg, for signs/symptoms)

IS = in situ.

How I Decide/Navigate With My CML Patients

3-mo response: An opportunity to critically appraise therapy choice and response trajectory; change possible, EMR

6-mo, 12-mo response: Change warranted for missed milestone (EMR, CCyR)

18-mo response: Focus on molecular response

Subsequent: Stability of response and progression towards optimization of MRD– CMR > MR4 > MMR– Plateau, fluctuation common

Treatment-free remission: Still the realm of clinical trials– Approximately 3 yrs of therapy in general with approximately 2 yrs of optimal

MRD reduction prior to consideration

MRD = minimal residual disease; EMR = early molecular response.

Key Takeaways

CML is a highly treatable condition Generic imatinib is here; combinations still hold

promise Early response increasingly predictive of long

term success Resistance based in mutations can drive

treatment choice but is likely quite complex; Novel agents in study (ABL001)

Key Takeaways (cont.)

Second-line therapy can be highly effective; third-line therapy needs to be carefully chosen (risk/benefit of ponatinib vs other alternatives)

SCT still needed option

Many TKIsResponseRemission

Cure?

= Long, Happy,

Healthy Life!

Case Discussion 1

45-year-old man New diagnosis of CML No comorbid conditions

Question 1: Which of the following regimens would you select for this patient?

1. Imatinib2. Dasatinib3. Nilotinib4. Bosutinib5. Ponatinib

Question 1: Responses

Imatinib Dasatinib Nilotinib Bosutinib Ponatinib0%

20%

40%

60%

80%

100%

0% 0% 0% 0% 0%

Case Discussion 2

34-year-old manNew diagnosis of CMLNo comorbid conditionsArrives late for appointmentsMissed three appointmentsWorks irregular shifts



10%20%30%40%50%60%70%80%90%

100%

0% 0% 0% 0% 0%

Case Discussion 3

55-year-old womanNo known comorbid conditionsGlucose consistently 150 rangeHeight 65 inchesWeight 190 poundsBMI 31.6



10%20%30%40%50%60%70%80%90%

100%

0% 0% 0% 0% 0%

Case Discussion 4

57-year-old man42-pack-year smoking historyNo diagnosed comorbid conditions



10%20%30%40%50%60%70%80%90%

100%

0% 0% 0% 0% 0%

Thank you to i3 Health and USF Health for the kind invitation to join you, and you for your attention!

[email protected]

212-639-3107

ReferencesBaccarani M, Deininger MW, Rosti G, et al (2013). European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood, 122(6):872-884. Branford S, Melo JV, Hughes TP (2009). Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood, 114(27):5426-5435. Branford S, Yeung DT, Parker WT, et al (2014). Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood, 124(4):511-518. Branford S, Yeung DT, Ross DM, et al (2014). The adverse effect of high sokal risk for first line imatinib treated patients is overcome by a rapid rate of BCR-ABL decline measured as early as 1 month of treatment. Blood (ASH Annual Meeting Abstracts), 124. Abstract 816. Charlson ME, Pompei P, Ales KL & MacKenzie CR (1987). A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis, 40(5):373-383.Cortes J, Hehlmann R, Gambacorti-Passerini C, et al (2013). Baseline characteristics of patients with chronic myeloid leukemia in a prospective observational study (SIMPLICITY). 55th ASH Annual Meeting and Exposition. Abstract 4026.Cortes J, Hochhaus A, Kim D-W, et al (2013). Four-year (yr) follow-up of patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib or imatinib: efficacy based on erarly response. 56th ASH Annual Meeting and Exposition. Abstract 653.Cortes J, Khoury HJ, Kantarjian HM, et al (2013). Bosutinib as therapy for chronic phase chronic myeloid leukemia following failure with imatinib plus dasatinib and/or nilotinib: 36-month update. Blood (ASH Annual Meeting Abstracts), 122. Abstract 4025. Cortes J, Kim DW, Pinilla-Ibarz J, et al (2013). Ponatinib in patients (pts) with chronic myeloid leukemia (CML) and philadelphia chromosome-positive acute lymphoblastic leukemia (ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 2-year follow-up of the PACE trial. Blood (ASH Annual Meeting Abstracts), 122. Abstract 650. Cortes J, Kim D-K, Pinilla-Ibarz J, et al (2015). Ponatinib efficacy and safety in heavily pretreated leukemia patients: 3-year results of the PACE trial. EHA 20th Congress. Abstract P234.Cortes J, Nicolini FE, Wexler M, et al (2013). Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk, 13(5):584-591. DOI:10.1016/j.clml.2013.03.020

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chronic myelogenous leukemia: applying emerging evidence in practice

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