Practical Guidance for the Management of CML in 2016 · 1.6 0.9 0.8 0.5 0.3 0 2.0 0.4 • KM...

Practical Guidance for the Management of CML in 2016

Neil Shah, MD, PhDEdward S. Ageno Distinguished Professor in Hematology/Oncology

Leader, Hematopoietic Malignancies ProgramHelen Diller Family Comprehensive Cancer Center at UCSF

San Francisco, California

The Importance of CML to Molecular Oncology

• Chronic myeloid leukemia (CML) was the first malignancy

shown to be associated with a particular genetic mutation

• CML was the first disease to be treated with small

molecule tyrosine kinase inhibitors (TKIs)

• Lessons learned from TKI treatment have informed

multiple other oncologic areas

• In 2016, the diagnosis, treatment, and monitoring of

malignancies is increasingly molecular and personalized,

and to a large extent CML has paved the way

1. Patlak M. FASEB J. 2002;16:273. 2. Bolin RW, et al. Cancer. 1982;50(9):1683-1686. 3. Frame D. Am J Health-Syst Pharm.

2006;63(23 Suppl 8):S10-S14. 4. Doti CA, et al. Leuk Lymphoma. 2009;50:27-31. 5. Bonifazi F, et al. Blood. 2001;98(10):3074-3081.

Timeline of Clinical Events in CML

First description of leukemia1

Radiotherapy2

Busulfan2

Nowell and Hungerford identify the Philadelphia (Ph) chromosome1

Hydroxyurea3

Hematopoietic stem cell transplantation (HSCT)4

Interferon5

Imatinib approved for CML

Dasatinib and nilotinib approved

for second-line use in CML

1845

Early

1900s 1953 1960 1972

Late

1970s

Early

1980s 2001

2006-

2007 2010 2012

Bosutinib, ponatinib

approved in USA

Dasatinib and nilotinib approved

for first-line use in CML in USA

Imatinib as Front-Line Therapy for CML

7-8 year update of newly-diagnosed

chronic phase (CP) CML patients treated

with 400 mg daily imatinib

O’Brien S, et al. Blood. 2008;112: Abstract 186.

Annual Event Rates: Imatinib Arm

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8Year

% W

ith

Even

t

EventLoss of complete hematologic response (CHR)

Loss of major cytogenetic response (MCR)

AP/BC, death during treatment

AP/BC

3.3

7.5

4.8

1.71.5

2.8

1.6

0.9 0.8

0.30.5

0

2.0

0.4

• KM estimated event-free survival at 8 years = 81%

• KM estimated rate without accelerated-phase (AP) or blast crisis (BC) at 8 years = 92%

*Total events (n = 3), including two CML-unrelated deaths (n = 2), and one patient with progression to AP/BC

*

Deininger D, et al. Blood. 2009;114: Abstract 1126.

0.4

1.2

Overall Survival (ITT Principle): Imatinib Arm

Estimated overall survival (OS)

at 8 years is 85%

(93% considering only

CML-related deaths)

Survival: Deaths associated with CML

Overall survival

% W

ith

ou

t E

ven

t

0

10

20

30

40

50

60

70

80

90

100

Months Since Randomization

0 12 24 36 48 60 72 84 96


Leitner AA, et al. Internist (Berl). 2011;52:209-217. Hochhaus A. In: Faderl S, Kantarjian H, eds. Leukemias: Principles

and Practice of Therapy. 2010:271-280. Hehlmann R, et al. Haematologica. 2009;94(s2):193 (Abstract 478).

Years After Diagnosis

Su

rviv

al P

rob

ab

ilit

y

(All

Ph

+ C

ML

Dis

ea

se

Ph

as

es

)

0 2 64 8 10 16 18 20 2212 14

0

0.2

0.1

0.5

0.6

0.7

0.8

0.9

1.0

0.3

0.4 1995-2008, IFN- or SCT‡

1986-2003, IFN-

1983-1994, busulfan

1983-1994, hydroxyurea

1997-2008, interferon-a (IFN-) or

stem cell transplantation (SCT)

plus second-line imatinib†

2002-2008, imatinib*

Best available therapy 5-year OS, %

Imatinib* 93

IFN- or SCT plus

2nd-line imatinib† 71

IFN- or SCT‡ 63

IFN- 53

Hydroxyurea 46

Busulfan 38

1970

2000

1990

1980

1960

2010

Imatinib Has Revolutionized the Therapeutic Landscape for

Patients With CML

*CML IV †CML IIIA ‡CML III

Imatinib: Conclusions

• Imatinib (400 mg daily) remains a front-line option for chronic phase

CML patients

• 85% overall survival with imatinib exceeds that of all previous CML

therapies, with 7% of patients dying from CML after 8 years

• 82% of patients treated with imatinib achieved a complete cytogenetic

response (CCyR)

– 55% of all imatinib randomized patients are still on study treatment,

and nearly all of these are in CCyR

• Responses are typically durable, and the annual risk of progression

appears to decrease after 2-3 years

• No major new safety findings seen with long-term follow-up

– Many patients experience chronic lower grade toxicities

Monitoring Disease in Patients

With CML

Definition

Normal complete blood count and differential, no extramedullary disease

Complete hematologic response

Level of response

Negativity by qPCRComplete molecular response

BCR-ABL1 transcripts 0.1% by qPCR or ≥3-log reduction

Major molecular response (MMR)

0% Ph-positive metaphases*Complete cytogenetic response†

1%-35% Ph-positive metaphases*Partial cytogenetic response (PCyR)†

>35% Ph-positive metaphases*Minor cytogenetic response

Treatment Response

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous

Leukemia. V.1.2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed May 18,

2016. Adapted from: Deininger MW. Hematology Am Soc Hematol Educ Program. 2005;174-182.

*Cytogenetic response is based on analysis of at least 20 metaphases †PCyR + CCyR = major cytogenetic response (MCyR)

Monitoring Disease Burden in CML

Time

Dx

CytogeneticsFISH

RT-PCR

Treatment

CM

L (

log

10) 1-2 log reduction

~ 5-6 log reduction

MMR = 3 log

Radich JP. Blood. 2009;114:3376-3381.

Imatinib-Resistant Disease

How is it defined?

Imatinib Resistance in Chronic Phase CML Definitions

• Primary resistance: Lack of an acceptable initial response

– Primary hematologic resistance: Rare

– Primary cytogenetic resistance: ~35% of patients

• Lack of PCyR (≤35% Ph) by 3 months

• Lack of CCyR (0% Ph) by 12-18 months

– Primary molecular resistance: ~35% of patients

• Lack of BCR-ABL/ABL (IS) ≤10% by 3 months

• Lack of BCR-ABL/ABL (IS) ≤0.1%-1% by 12 months

Imatinib Resistance in Chronic Phase CML Definitions

• Primary resistance: Lack of an acceptable initial response

– Primary hematologic resistance: Rare

– Primary cytogenetic resistance: ~35% of patients

• Lack of PCyR (≤35% Ph) by 3 months

• Lack of CCyR (0% Ph) by 12-18 months

– Primary molecular resistance: ~35% of patients

• Lack of BCR-ABL/ABL (IS) ≤10% by 3 months

• Lack of BCR-ABL/ABL (IS) ≤0.1%-1% by 12 months

• Secondary resistance: Loss of an established initial response (relapse despite treatment)

– Hematologic relapse: White cell blood count >normal and increasing or new immature forms/basophilia/accelerated or blast phase transformation

– Cytogenetic relapse: ≥30% increase in Ph+ metaphases

– Molecular relapse: Confirmed 1-log increase in BCR-ABL transcript level with lack/loss of MMR

Primary resistance is a risk factor for the development of secondary resistance

Importance of Achieving CCyR: IRIS Study

Druker B et al. N Engl J Med. 2006;355:2408-2417.

Time (Months Since Randomization)

n = 54 98%

Estimated rate at 60 months

P<.001

P = .11

Response at 18 months

CCyR with ≥3 log reduction

CCyR with <3 log reduction

No CCyR

Pati

en

ts W

ith

ou

t A

P/B

C (

%)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 54 60 66

n = 88 87%

n = 139 100%

Sustained CCyR on study: 53%

No CCyR: 17%*

Lost CCyR: 15%*

Safety: 5%*

Lost regained CCyR: 3%

CCyR + other: 7%

Imatinib: IRIS 8-Year Update Shows 37% Have Unacceptable Outcome

*Unacceptable outcome


Pro

bab

ilit

y o

f S

urv

ival

Time From Onset of Imatinib Therapy (Years)

BCR-ABL/ABL<9.84% 8-yr OS: 93.3%

BCR-ABL/ABL >9.84% 8-yr OS: 56.9%

Marin D, et al. J Clin Oncol. 2012;30:232-238.

P < .001

BCR-ABL/ABL After 3 Months of Imatinib Predicts OS Outcomes

1.0

0.8

0.6

0.4

0.2

0

0 1 3 4 5 8762

NCCN: 3-Month Milestones

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V.1.2016.

Available at: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed Accessed May 22, 2016.

CML: Monitoring Simplified

• Quantitative BCR-ABL PCR at diagnosis and every

3 months thereafter

• Achievement of ≤10% BCR-ABL (IS) or PCyR after

3 months of imatinib is associated with superior survival

in multiple studies

• Bone marrow cytogenetics should be performed at

diagnosis in all patients and at 3 and/or 12 months in

select cases thereafter

• Achievement of a complete cytogenetic response remains

the minimum acceptable level of response on TKI therapy

– Ideally achieved within 12-18 months of TKI initiation

Imatinib-Resistant Disease

What are its causes?

Acquired Clinical Resistance to Imatinib Is Most Often Associated

With Restoration of BCR-ABL Kinase Activity

Wild type T315I mutant (model)

Structural data provided by B Nagar and J Kuriyan UC Berkeley

Gorre ME, et al. Science. 2001;293(5531):876-880.

ATP-Binding Pocket of T315I Mutant BCR-ABL Cannot Accommodate Imatinib

L298V

E292V

(Incomplete) Map of BCR-ABL Kinase Domain Mutations Associated With

Clinical Resistance to Imatinib

Gorre ME, et al. Science. 2001;293(5531):876-880. von Bubnoff N, et al. Lancet. 2002;359(9305):487-491. Branford S,

et al. Br J Haematol. 2002;117(4):875-877. Hofmann WK, et al. Blood. 2003;102(2):659-661. Roche-Lestienne C, et al.

Blood. 2002;100(3):1014-1018. Shah NP, et al. Cancer Cell. 2002;2(2):117-125. Hochhaus A, et al. Leukemia.

2002;16(11):2190-2196. Al-Ali HK, et al. Hematol J. 2004;5(1):55-60.

P C A

Courtesy Tim Hughes

MB13

Imatinib

MB14

Imatinib

Chemotherapy

Gorre ME, et al. Science. 2001;293(5531):876-880.

BCR-ABL Gene Amplification Associated With Clinical Imatinib Resistance

Molecular Mechanisms of Resistance to Imatinib: Implications

BCR-ABL kinase inhibitors that are:

(1) More potent than imatinib and

(2) Have activity against imatinib-resistant kinase

domain mutations

May be of significant therapeutic benefit to imatinib-

resistant and imatinib-intolerant patients

Dasatinib 70 mg BID in CP-CML: 24 Month ResultsCCyR Achieved for the First Time in Many Patients

0

25

50

75

100

% P

ati

en

ts A

ch

ievin

g C

CyR

19

Total

Stone R, et al. Blood. 2007;110: Abstract 734.

53

Prior CCyR on imatinib

(median duration treatments >3 years)

CCyR on dasatinib

Nilotinib Has a Better Fit to the Binding Pocket

• Rationally designed highly specific inhibitor of BCR-ABL

• 30 X more potent than imatinib; maintains target specificity

• No significant effect on other kinases

• (Src, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR, etc)

Imatinib IC50 669 nM Nilotinib IC50 25nM

Swords R, et al. Drug Des Devel Ther. 2009;3:89-101.

Nilotinib in CP-CML: Response Rates

With 24 Months of Follow-Up1

Median time to CHR 1 month, to MCyR 2.8 months

*When metaphases unavailable, response was measured by FISH alone

Kantarjian H, et al. Blood. 2009;114: Abstract 1129.

44%* 41%*

57%51%*

77%

0

10

20

30

40

50

60

70

80

90

100

CHR Major CyR Imatinib

resistant

Imatinib

intolerant

CCyR

Pa

tie

nts

%

Bosutinib in CP CML Response (Imatinib Resistant or Intolerant*)

Response (N = 115) N / N evaluable (%)

Hematologic

Complete 34 / 38 (89)

Cytogenetic

Major 23 / 56 (41)

Complete 17 / 56 (30)

Molecular

Major 19 / 58 (33)

Complete 11 / 58 (19)

*Patients had no prior exposure to kinase inhibitors other than imatinib

Cortes J, et al. Blood. 2007;110: Abstract 733.

PonatinibOral pan-BCR ABL TKI with potent activity against

native and mutated BCR-ABL and other kinases

Extensive network of molecular

contacts for optimal fit to the binding

cavity of ABL

Triple bond (yellow) unique structural feature

evades the T315I gatekeeper mutation (blue)

T315I gatekeeper residue


Ponatinib Phase II StudyResponses at Any Time

CP-CMLAP-CML

BP-CML Ph+ ALL

MCyR CCyR MMR MaHR* MaHR MaHR

R/I to das/nil

56% 48% 31% 62% 32% 50%

T315I 72% 70% 58% 61% 29% 36%

Total** 60% 54% 38% 61% 31% 41%

Median time to response, months

2.8 2.9 5.5 0.7 1.0 0.7

*14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders

**Total comprises all eligible patients treated with ponatinib. It excludes 5 patients (3 CP-CML, 2 AP-CML) who were non-cohort

assigned (post-imatinib, non-T315I), but treated; all 5 achieved MCyR


Treatment Options Based on BCR-ABLKinase Domain Mutation Status

*Option for pts with resistance/intolerance to ≥ 2 TKIs†If mutation detected following dasatinib treatment‡No sufficient dose escalation data indicating if mutations with low IC50 are sensitive to high dose imatinib

NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v4.2013

Mutation Treatment options

T315I Ponatinib, omacetaxine, HSCT, or clinical trial

V299L Consider nilotinib, ponatinib or omacetaxine*

T315A Consider nilotinib, imatinib,† bosutinib, ponatinib,

or omacetaxine*

F317L/V/I/C Consider nilotinib, or bosutinib, ponatinib, or

omacetaxine*

Y253H, E255K/V, F359V/C/I Consider dasatinib, or bosutinib, ponatinib, or

omacetaxine*

Any other mutation Consider dasatinib, nilotinib, bosutinib, ponatinib,

high dose imatinib,‡ or omacetaxine*

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. V.1.2016.

Available at: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed May 18, 2016.

Frontline Therapy for CML

How active are newer agents in the

front-line management of CP-CML?

ENESTnd Study Design

N = 846

217 centers

35 countries

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

RANDOMIZE


Follow-up: 5 years; extended to 10 years

after protocol amendment

Patients were stratified according to Sokal risk score at diagnosisBID, twice daily; QD, once daily. Data cutoff: May 22, 2013

ENESTnd 5-year update

Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract 7073.

Cumulative Incidence of MMR

MMR, major molecular response (BCR-ABLIS ≤ 0.1%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

By 1 Yeara By 5 Yearsa

55%, P < .0001

51%, P < .0001

27%

Δ 24% to 28%

60%

77%, P < .0001

77%, P < .0001

Δ 17%

By 4 Yearsa

76%, P < .0001

73%, P < .0001

56%

Δ 17% to 20%

100

0 2 6

90

80

70

60

50

40

30

20

10

0

Pati

en

ts W

ith

MM

R, %

Time Since Randomization, Calendar Years

31




4 5


Data cutoff: May 22, 2013

Larson R, et al. J Clin Oncol. 2014;32(Suppl): Abstract 7073. Hochhaus A, et al. Leukemia. 2016;30(5):1044-1054.

BCR-ABL Categories at 3 Months*

0

20

40

60

80

100

Pa

tie

nts

, %

BCR-ABL Level at 3 Monthsn 176 234 88 24

BCR-ABL >10%

91

67

9

33>1-≤10%

≤1%


Imatinib (n = 264)

Reasons for unevaluable samples included

• Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib

• Missing samples: 4 patients on nilotinib, 5 patients on imatinib

• Discontinuation: 15 patients (including 1 progression) on nilotinib, 12 patients (including 1 progression) on imatinib

*Calculated from total number of evaluable patients with PCR assessments at 3 months

BCR-ABL ≤10%

>1-≤10%

≤1%




20

10

0

5

10

15

20

25

Progressions on Study

Pati

en

ts,

nProgression to AP/BC on Studya

(Including After Treatment Discontinuation)

a Includes progression to AP/BC (excluding clonal evolution) or deaths in patients with advanced CML occurring

on study (on core or extension treatment or during follow-up after treatment discontinuation)

P = .0588


• Two new progressions on study in year 5 (1 in the nilotinib 300 mg BID arm and 1 in the imatinib arm)

• Both patients had BCR-ABL >10% at 3 months

New events in year 5

7.1% 3.5%





PFS and OS on Study(Including After Treatment Discontinuation)a

aIncludes events occurring on core or extension treatment or during follow-up after treatment discontinuation bPatients for whom the principle cause of death was either “study indication” or “unknown” or not reported but

occurred subsequent to a documented progression to AP/BC

Imatinib

400 mg QD

(n = 283)

Nilotinib

300 mg BID

(n = 282)

Estimated 5-year PFS, % 91.1 92.0

Progressions and deaths, n 23 22

Hazard ratio (95% CI) — 0.92 (0.51-1.65)

P value .77

Estimated 5-year OS, % 91.6 93.6

Total deaths, n 21 18

Deaths in patients with advanced

CML, nb 15 6

Hazard ratio (95% CI) — 0.84 (0.45-1.58)

P value — .58

• There were 6 newly reported deaths in year 5

– Imatinib (n = 2): both due to study indication

– Nilotinib 300 mg BID (n = 3): study indication, rectal cancer, and pneumonia




Conclusions• At 5 years of follow-up, rates of event-free survival,

progression-free survival, and overall survival rates are not

significantly different in the two treatment arms

• Nilotinib demonstrated higher rates of early and deeper

molecular response, including MR4.5

• By 5 years, more than half of nilotinib-treated patients had

achieved MR4.5, a key eligibility criterion for many treatment-

free remission studies

• Side effects that appear unique to nilotinib include

pancreatitis, hyperglycemia, EKG changes, and peripheral

arterial occlusive events

42




• Database lock of 24-Mar-2014

• Primary end point: confirmed CCyR by 12 months

– 77% dasatinib vs. 66% imatinib (P = .007)1

DASISION (CA180-056) Study Design

5-year

final resultsRandomizeda


Dasatinib 100 mg QD (n = 259)

• Treatment-naïve

CML-CP patients

(N = 519)

• 108 centers

• 26 countries

• Enrollment:

September 2007-

December 2008

1. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.

DASISION 5-year final study results

aStratified by EURO (Hasford) risk score

Cumulative MMR Rates Over Time

Months Since Randomization

% W

ith

MM

R

Dasatinib 100 mg QD

N

Imatinib 400 mg QD 260

259

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

28%

46%

55%

60%64%

46%

64% 67%

73% 76%

0 6 12 18 24 30 36 42 48 54 60

100

90

80

70

60

50

40

30

20

10

0

P = .0022



Dasatinib 100 mg

QD (n = 259)

Imatinib 400 mg QD

(n = 260)

BCR-ABL at

3 months

≤10%

(84%)

>10%

(16%)

≤10%

(64%)

>10%

(36%)

CCyR, % 94 41 92 59

MMR, % 87 38 81 41

MR4.5, % 54 5 48 12

Best 5-Year Responses by Molecular Response at 3 Months



Dasatinib 100 mg QD

(n = 259)

Imatinib 400 mg QD

(n = 260)

BCR-ABL at 3 months≤10%

(84%)

>10%

(16%)P value

≤10%

(64%)

>10%

(36%)P value

Estimated 5-year

OS, %94 81 .0028 95 81 .0003

Estimated 5-year

PFS, %89 72 .0014 93 72 <.0001

Estimated 5-year

transformation-free

survival, %

97 83 .0004 97 80 <.0001

5-Year Outcomes by Molecular Response at 3 Months

On study treatment and in follow-up after discontinuation of randomized treatment



One imatinib patient and no dasatinib patients transformed between 4 and 5 years

Dasatinib 100 mg QD

(n = 259)

Imatinib 400 mg QD

(n = 260)

BCR-ABL at 3 monthsa≤10%

n = 198

>10%

n = 37

≤10%

n = 154

>10%

n = 85

Transformation to AP/BPb, n (%) 6 (3) 5 (14) 5 (3) 13 (15)

0

5

10

15

20

Pati

en

ts,

n

Overall transformations to AP/BP

4.6%

7.3%

Dasatinib n = 259 Imatinib n = 260

On study During follow-up beyond discontinuation

Transformation to AP/BP CML by 5 Years

aOne dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments bIncluding follow-up beyond discontinuation (intent to treat)



Overall Survival and Progression-Free Survival

Dasatinib100 mg QD

(n = 259)

Imatinib400 mg QD

(n = 260)

Hazard ratio

(95% CI)

Total number of deathsa, n 26 26 -

Estimated 5-year OSa, % (95% CI)

91(87-94)

90(85-93)

1.01 (0.58-1.73)

Estimated 5-year PFSa, % (95% CI)

85(80-89)

86(80-89)

1.06 (0.68-1.66)

• Causes of death were cardiovascular disease (2 dasatinib, 1 imatinib); disease

progression (9 dasatinib, 17 imatinib); infection (11 dasatinib, 1 imatinib); other

malignancy, septic shock and cardiac failure, multi-organ failure, and whole

body swelling (1 each dasatinib); stem cell transplantation complications and

unknown (2 each imatinib); severe chest pain, clinical deterioration and

decrease in performance status, and fatal bleeding (1 each imatinib)

aOn study treatment and in follow-up after discontinuation of randomized treatment


Conclusions

• 5-Year follow-up demonstrates:

– Deeper molecular responses with dasatinib versus imatinib

– More optimal molecular responses with dasatinib versus imatinib

– No significant difference in transformation-free or

overall survival

• Achievement of BCR-ABL ≤10% at 3 months is associated with

significantly higher PFS and OS by 5 years

– BCR-ABL ≤10% at 3 months: dasatinib 84% versus imatinib 64%

By 5 years, 42% of dasatinib-treated patients had achieved

MR4.5, a key eligibility criterion for many treatment-free

remission studies

Side effects that appear unique to dasatinib include pleural

effusion and pulmonary arterial hypertension.


BCR/ABL TKIs

Focus on safety and tolerability

Treatment Options Based on Adverse Event Spectrum of TKIs in CML

BosutinibDiarrhea, nausea/emesis,

rashNilotinib

Pancreatic enzyme ,

indirect hyperbilirubinemia,

hyperglycemia

QT prolongation, cardiovascular

events

Common Effects

Myelosuppression

Transaminase

Electrolyte Δ

DasatinibPleural effusions,

bleeding risk, pulmonary arterial hypertension

Ponatinib

Pancreatic

enzyme , hypertension,

skin toxicity, thrombotic

events

Imatinib

Edema/fluid retention,

myalgia, hypophosphatemia ,

GI effects (diarrhea, nausea)

In addition to grade 3/4 toxicities, it is reasonable to consider changing treatment

for bothersome persistent grade 2 toxicities

BCR-ABL TKIs:Some Distinguishing Features

TKIPleural

effusion

Pulmonary arterial

hypertension

QT prolongation

Hyperglycemia

PancreatitisThrombotic

eventsDiarrhea

LFT abnormalities

Twice daily schedule

Imatinib - - - - - - - + -

Dasatinib ++ + - - - - - - -

Nilotinib - - + ++ + + - + +

Bosutinib - - - - - - ++ ++ -

Ponatinib - - - - + ++ - + -

Management of Hematologic Toxicities With TKIs

• TKIs are not considered strongly myelosuppressive in the

setting of a healthy bone marrow

• TKI-associated cytopenias are most common within 1-3 months

after initiation, are typically transient, and likely reflect disease

reduction prior to adequate hematologic recovery by normal

stem/progenitor cells

• TKI dose interruption for platelet count <50K or absolute

neutrophil count <1K should be considered; retreatment with

lower doses is sometimes employed

Note: Avoid CYP3A4 inducers/inhibitors in all patients on BCR-ABL TKIs

Management of Hematological Adverse Events (AEs): Summary

In general, switch in TKI is not a solution to prolonged

cytopenias. This is a feature of the patient’s normal

stem cell reserve and not the drug.

Imatinib


Most Frequently Reported AEs: First-Line Imatinib

Most common AEs

(by 5 years)

All grade AEs

patients, %

Grade 3/4 AEs

patients, %

Superficial edema 60 2

Nausea 50 1

Muscle cramps 49 2

Musculoskeletal pain 47 5

Diarrhea 45 3

Rash/skin problems 40 3

Fatigue 39 2

Headache 37 <1

Abdominal pain 37 4

Joint pain 31 3

• Only serious adverse events (SAEs) were collected after 2005

• Grade 3/4 adverse events decreased in incidence after years 1-2


IRIS SAEs in Years 6 and 7• No unique, previously unreported AEs attributed to imatinib observed

over the last 24 months (Exception: hepatitis B virus reactivation)

• In years 6 and 7 (n=545), 13 SAEs with suspected relationship to imatinib were reported:

– Congestive heart failure (n = 3): All of the patients had pre-existing cardiac disease prior to study entry

– Second malignancy (n = 3)*

– Myositis (n = 1); elevated CK (n = 1); multiple sclerosis (n = 1)

– Pancreatitis (n = 1); vomiting (n = 1)

– Renal failure (n = 1)

– Dermatitis (n = 1)

*With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population


Management of Common Toxicities With Imatinib

• Gastrointestinal: Take imatinib with a full meal

and a full glass of water

• Muscle cramping: Tonic water (quinine)

• Dose reduction (should not go below 300 mg

daily under most circumstances)

Second-Line Dasatinib in CP-

CML


N = 662 treated

100 mg QD (n = 167)

140 mg QD (n = 167)

50 mg BID (n = 168)

70 mg BID (n = 168)

CP-CML patients ≥18 years with

• Resistance

• Suboptimalresponse

• Intoleranceto imatinib

N = 670 randomizeda

Second-Line Dasatinib: 7-Year Follow-Up

• After 2 years, protocol allowed switching from BID to QD dosing

• Primary endpoint: To compare the MCyR rates of dasatinib when

administered QD vs BID after a minimum follow-up of 6 months

Enrollment period: July 13, 2005–March 13, 2006.a Patients were stratified by imatinib resistance vs imatinib intolerance

7-year

final results

Shah N, et al. Blood. 2014;124: Abstract 520.

Cumulative Incidence Rate of All-Cause Nonhematologic AEs of Special Interest

0 5 10 15 20 25 30 35 40 45 50

Rash

Myalgias/arthralgias

Fatigue

Nausea/vomiting

Diarrhea

Pleural effusion

Hemorrhage

Patients, %

100 mg QD(Any grade)

Other dose groups(any grade)

100 mg QD (Grade ≥3)

Other dose groups (grade ≥3)

• For 100 mg QD, most nonhematologic AEs (all grades) first occurred

within 24 months of treatment


Drug-Related Pleural Effusion and Pulmonary Hypertension Over Time

(Any Grade)

Dasatinib dose

Number of patients (%)

100 mg QD

(n = 165)

Other dose groups

(n = 497)

2-year 5-year 7-year 2-year 5-year 7-year

Pleural effusion 23 (14) 40 (24) 46 (28) 118 (24) 158 (32) 174 (35)

Pulmonary

hypertension0 (0) 0 (0) 3 (2) 5 (1) 8 (2) 13 (3)

Pulmonary

arterial

hypertension

-- 0 (0) 1 (<1) -- 0 (0) 0 (0)


Arterial Ischemic Events Summary: All Treated Patients

Number of patients (%)

100 mg QD

(n = 165)

Other dose groups

(n = 497)

Any

grade

Grade

3/4Grade 5

Any

grade

Grade

3/4Grade 5

Subjects with any

cardiovascular

ischemic eventsa

7 (4) 4 (2) 0 20 (4) 11 (2) 1 (<1)

Myocardial infarction 3 (2) 3 (2) 0 4 (1) 3 (1) 1 (<1)

Angina pectoris 2 (1) 1 (1) 0 12 (2) 6 (1) 0

Coronary artery disease 2 (1) 0 0 1 (<1) 0 0

MedDRA Version 16.1

a Patients may have more than one event within a class


Second-Line Nilotinib in CP-

CML


Imatinib-Resistant or Imatinib-Intolerant Patients 48-Month Follow-Up of Phase II

Trial Hematologic Toxicity

Giles FJ, et al. Leukemia. 2013;27(1):107-112.

N = 321 All grades (%) Grades 3/4 (%)

Rash 30 2

Pruritus 25 <1

Nausea 24 <1

Fatigue 20 1

Headache 18 2

Vomiting 12 <1

Constipation 12 0

Diarrhea 12 2

Phase II CML-CP: Frequent (>10%) Drug-Related Nonhematologic AEs

Kantarjian HM, et al. Blood. 2007;110: Abstract 735.

N = 321 Grades 3/4 (%)

AST 2

ALT 4

Bilirubin (total) 8

Bilirubin (direct) 5

Creatinine 1

Hypocalcemia 1

Hypomagnesemia <1

Hypophosphatemia 14

Lipase elevation 15

Hyperglycemia 13

Phase II CML-CP: Grades 3/4 Biochemical Laboratory Abnormalities


AST, aspartate aminotransferase, ALT alanine transaminase

N = 321n (%)

QTcF > 60 msec change from baseline 8 (2.5)

QTcF prolongation (> 500 msec) 3 (0.9)

Atrial arrhythmias1 8 (2.5)

Ventricular arrhythmias2 3 (0.9)

Cardiac failure3 5 (1.6)

Myocardial ischemia4 22 (6.9)

Myocardial infarction5 6 (1.9)

Phase II CML-CP: Incidence of Important Cardiac AEs

1. Atrial fibrillation, atrial flutter, supraventricular tachycardia, arrhythmia supraventricular, supraventricular tachyarrhythmia,

supraventricular extrasystoles

2. Ventricular tachyarrhythmia, ventricular flutter, ventricular extrasystoles; one case of ventricular arrhythmia reported in the

originally MAA was later identified as having been reported in error (data entry error)

3. Cardiac failure, cardiac failure congestive, pulmonary oedema, left ventricular dysfunction, ejection fraction decreased

4. Angina pectoris, myocardial ischemia, coronary artery stenosis, coronary artery disease, Arteriosclerosis coronary artery

5. Myocardial infarction, acute myocardial infarction


Second-Line Bosutinib in CP-

CML


Efficacy and Safety of Bosutinib (SKI-606) Among Patients With

Chronic Phase Ph+ Chronic CML

Cortes J, Brümmendorf TH, Kantarjian H, Khoury J, Rosti G,

Fischer T, Tornaghi L, Hewes B, Martin EC, and Gambacorti-Passerini C


EventN (%)

All grades Grade 3/4

Diarrhea 104 (68) 10 (7)

Nausea 65 (43) 1 (1)

Vomiting 42 (28) 4 (3)

Abdominal pain 41 (27) 1 (1)

Rash 37 (24) 10 (7)

Other pain 27 (18) 0

Fatigue 26 (17) 2 (1)

Any fluid retention 17 (11) 1(1)

Bosutinib in CP CML: Non-Hematologic Adverse Events (N = 152)


Bosutinib in CP CML: Other Laboratory Abnormalities

AbnormalityNo. (%)

Grade 3/4

Hypophosphatemia 11 (7)

Elevated ALT 10 (7)

Elevated lipase 6 (4)

Elevated glucose 4 (3)

Elevated INR 4 (3)

Elevated AST 2 (1)

Elevated creatinine 2 (1)

Hypocalcemia 2 (1)


Management of Bosutinib-Related Toxicities

• Diarrhea is common with bosutinib, particularly at the

recommended starting dose of 500 mg daily

• Consider initiating 300-400 mg daily and dose escalate as

necessary and tolerated

• Educate patients that diarrhea is typically self-limited, and

improves substantially within 4-6 weeks; encourage small

meals and limited fluid intake

• Provide patients with prescription anti-diarrheal medications

• Perform monthly hepatic enzyme tests for the first 3 months of

treatment with bosutinib and as clinically indicated; in patients

with transaminase elevations, monitor liver enzymes more

frequently; withhold, dose reduce, or discontinue bosutinib as

necessary

Second-Line (and Beyond)

Ponatinib in CP-CML


Ponatinib in Patients With CML and Ph+ ALL Resistant or Intolerant to

Dasatinib or Nilotinib, or With the T315I BCR‐ABL Mutation: 2-Year Follow‐Up

of the PACE Trial

Cortes J, Kim D-W, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C,

Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio JF, DeAngelo DJ, Abruzzese

E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Lustgarten S, Rivera

VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A,

Hughes TP, Goldman JM, Shah NP, and Kantarjian HM

on behalf of the PACE Study Group


Ponatinib Phase II Study:Hypertension

• 379/449 (84%) patients had elevated BP at baseline (≥140/90, 47%)

• 301/449 (67%) patients experienced any increase in BPa on study

• AEs of hypertension were reported in 109/449 (24%) patients (SAEs in 8/449 [2%])

Baseline blood pressure (BP) (mmHg), NCI CTCAE

Increase in BP on study (single measurement)a

Grade 1 Grade 2 Grade 3

Normal (<120/<80), N = 70 36% 30% 23%

Grade 1 (120-139)/(80-89), N = 167 - 53% 34%

Grade 2 (140-159)/(90-99), N = 157 - - 60%

Grade 3 (≥160/≥100), N = 55 - - -

aAny shift to higher grade (NCI CTCAE v.4.0), based on single BP measurements


N = 449

n (%)

Data as of: 23 July 2012 (USPI) 03 Sep 2013

Median follow-up [exposure]12 months

[340 patient-years]

24 months

[578 patient-years]

Category SAE AE SAE AE

Cardiovascular 21 (5) 29 (6) 28 (6) 41 (9)

Cerebrovascular 8 (2) 13 (3) 18 (4) 25 (6)

Peripheral vascular 7 (2) 17 (4) 16 (4) 28 (6)

Total arterial thrombosis 34 (8) 51 (11) 53 (12) 77 (17)

Ponatinib Phase II Study:

Incidence of Arterial Thrombotic Events Over Time

• 1.7-fold increase in exposure over additional 13 months of follow-up

• Incidence of serious AEs increased from 8% to 12%

• Median time to onset: 215 days (range 3-887 days)

SAE = AE reported as serious by the investigator, per standard criteria


N = 449

n (%)

Data as of: 23 July 2012 (USPI) 03 Sep 2013

Median follow-up [exposure]12 months

[340 patient-years]

24 months

[578 patient-years]

Category SAE AE SAE AE

Cardiovascular 21 (5) 29 (6) 28 (6) 41 (9)

Cerebrovascular 8 (2) 13 (3) 18 (4) 25 (6)

Peripheral vascular 7 (2) 17 (4) 16 (4) 28 (6)

Total arterial thrombosis 34 (8) 51 (11) 53 (12) 77 (17)

Venous Thromboembolism 10 (2) 15 (3) 13 (3) 23 (5)

• In October 2013, inclusion of venous thromboembolism events (3 SAEs in

intervening months) to create vascular occlusion category

Ponatinib Phase II Study:

Incidence of Vascular Occlusive Events Over Time

SAE = AE reported as serious by the investigator, per standard criteria


Management of Ponatinib-Related Toxicities

• Interrupt treatment for grade ≥3 pancreatitis and resume lower

dose or switch to alternate TKI upon resolution of elevated

serum lipase

• Stop treatment in any patient with a vaso-occlusive event

suspected to be related to ponatinib; the use of anticoagulant

therapy has not been investigated in this setting

• Consider an initial dose of 30 mg daily in patients with

cardiovascular risk factors and dose escalate as

tolerated/necessary to 45 mg daily

First-Line Nilotinib in CP-CML


ENESTnd Update: Nilotinib vs Imatinib in

Patients With Newly Diagnosed CML-CP

and the Impact of Early Molecular

Response and Sokal Risk at Diagnosis on

Long-Term Outcomes

Saglio G, Hochhaus A, Hughes TP, Clark RE, Nakamae H,

Kim DW, Jootar S, Etienne G, Flinn IW, Lipton JH,

Pasquini R, Moiraghi B, Kemp C, Fan X, Menssen HD,

Kantarjian HM, and Larson RA

on behalf of the ENESTnd investigators

81


Saglio G, et al. Blood. 2013;122: Abstract 92.

ENESTnd Study Design

82

N = 846

217 centers

35 countries



RANDOMIZE


Follow-up: 5 years; extended to 10 years

after protocol amendment

• Patients were stratified according to Sokal risk score at diagnosis

BID, twice daily; QD, once daily.




Newly Occurring or Worsening Grade 3/4 Hematologic and Selected Biochemical Abnormalities

0

5

10

15

20

25

Pati

en

ts,

%

Nilotinib 300 mg BID

(n = 279)

Nilotinib 400 mg BID

(n = 277)

Imatinib 400 mg QD

(n = 280)

New events in year 5

Anemia Neutropenia Thrombocytopenia Lipase ↑ AST ↑ Total bilirubin ↑ Glucose ↑ Cholesterol ↑

6

45

22

1211

9

10

12

4

910

1 1

3

<1

4

9

<1

76

100


Data cutoff: May 22, 2013BID, twice daily; QD, once daily


Selected Cardiovascular Events by 5 Years (All Cause*, All Grades)

• Due to the discontinuation rate, patients had longer exposure to nilotinib than

imatinib

• Approximately 85% of patients with a cardiovascular event had at least 1 risk

factor and were not optimally managed for hyperglycemia and

hypercholesterolemia

*All cause indicates all events, not only those deemed study drug-related by the investigator

IHD, ischemic heart disease; ICVE, ischemic cerebrovascular events; PAD, peripheral arterial disease

Patients with an Event, n

Imatinib

400 mg QD

n = 280

Nilotinib

300 mg BID

n = 279

Nilotinib

400 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

IHD 5 3 2 11 11 0 21 14 7

ICVE 1 1 0 4 3 1 8 5 3

PAD 0 0 0 4 4 0 6 5 1




Management of Nilotinib-Related Toxicities

• Interrupt treatment for elevated lipase in the setting of

abdominal pain and resume lower dose or switch to alternate

TKI upon resolution of elevated serum lipase

• Stop treatment in any patient with a vaso-occlusive event

suspected to be related to nilotinib; the use of anticoagulant

therapy has not been investigated in this setting

• QT prolongation and sudden deaths have been observed with

nilotinib, and regular ECG monitoring is indicated; monitor and

replete K and Mg levels as necessary; avoid nilotinib in patients

with low K, low Mg or long QT syndrome

First-Line Dasatinib in CP-CML


Final Study Results of DASISION (Dasatinib Versus Imatinib in Newly

Diagnosed Chronic Myeloid Leukemia in Chronic Phase [CML-CP])

Cortes J, Saglio G, Shah NP, Baccarani M, Kantarjian H, Mayer J, Nakamae H,

Boqué C, Chuah C, Kim DW, Pavlovsky C, Shah S, Undurraga MS, Wang J,

Ayala M, Casanova L, Bradley-Garelik B, Manos G, and Hochhaus A



• Database lock of 24-Mar-2014

• Primary end point: confirmed CCyR by 12 months

– 77% dasatinib vs. 66% imatinib (P = .007)1

DASISION (CA180-056) Study Design

5-year

final resultsRandomizeda


Dasatinib 100 mg QD (n = 259)

• Treatment-naïve

CML-CP patients

(N = 519)

• 108 centers

• 26 countries

• Enrollment:

September 2007-

December 2008

1. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.


aStratified by EURO (Hasford) risk score


On-Study Drug-Related Nonhematologic AEs (Frequency ≥10%)

• No grade 5 AEs were reported for the nonhematologic AEs listed here

• Pulmonary hypertension was reported in 14 patients in the dasatinib group and 1 patient in the imatinib group

– No patients had pulmonary arterial hypertension per WHO definition

0 5 10 15 20 25 30 35

Vomitting

Muscle spasms

Myalgia

Peripheral edema

Face edema

Nausea

Abdominal pain

Fatigue

Skin rash

Musculoskeletal pain

Headache

Diarrhea

Pleural effusion

Patients, %

Grade 1–2 Dasatinib2

Grade 3–4 Dasatinib

Grade 1–2 Imatinib2

Grade 3–4 Imatinib

Dasatinib

100 mg QD

Imatinib

400 mg QD



Dasatinib 100 mg QD

(n = 258)

Total, n (%) 73 (28)

Grade 1–2 66 (26)

Grade 3–4 7 (3)

Discontinuation due to pleural effusion, n (%) 15 (6)

Dose interruptions due to pleural effusion, n (%) 45 (61)

Dose reductions due to pleural effusion, n (%) 30 (41)

Median time to first grade 1–2 pleural effusion,

weeks (range)114 (4–299)

Median time to first grade 3–4 pleural effusion,

weeks (range)175 (114–274)

Characteristics and Management of Pleural Effusion

• 9 (12%) dasatinib-treated patients had therapeutic thoracentesis

• 9 out of 14 dasatinib-treated patients with pulmonary hypertension also had

pleural effusion



• At 5 years of follow-up in DASISION, recurrent pleural effusions were reported

– 46 out of 73 patients had recurrent pleural effusions

• Pleural effusion did not impair the ability of patients to obtain a response

– Of patients with pleural effusion, 96% had cCCyR, 82% had MMR, and

50% had MR4.5

Pleural Effusion by Year of Treatment

0

2

4

6

8

10

≤1 y >1 y–≤ 2 y >2 y–≤ 3 y >3 y–≤ 4 y >4 y–≤ 5 y

Pati

en

ts,

%

8%

5%4%

5% 5%

BCR-ABL (IS) ≤0.1%;

MR4.5 = BCR-ABL (IS) ≤0.0032%



Arterial Ischemic Events Regardless ofRelationship to Study Therapy

Treated patients, n (%)

Dasatinib 100 mg QD

(n = 258)

Imatinib 400 mg QD

(n = 258)

Any

grade

Grade

3/4

Grade

5

Any

grade

Grade

3/4

Grade

5

Any ischemic event 12 (5) 7 (3) 2 (1) 6 (2) 3 (1) 1 (<1)

Cardiovasculara 10 (4) 5 (2) 2 (1) 4 (2) 2 (1) 1 (<1)

Transient

ischemic attack2 (1) 2 (1) 0 0 0 0

Peripheral arterial

occlusive disease0 0 0 2 (1) 1 (<1) 0

aIncludes myocardial infarction, angina pectoris, coronary artery disease, and acute coronary syndrome.

• Cardiovascular ischemic events occurred in 7 out of 10 patients within 1 year of

dasatinib initiation



Management of Pleural Effusion With Dasatinib

• Pleural effusions can occur anytime following

initiation of dasatinib

– More common in age >60 years

– Associated with higher trough levels of drug

• Tend to accumulate slowly

• Educate patients regarding concerning symptoms

• If chest X-ray confirms symptomatic pleural effusion,

interrupt TKI; for severe effusions, refer for

therapeutic thoracentesis; for mild/moderate

effusions, short course of diuretics/steroids can be

beneficial; after resolution, use lower dose of

dasatinib or alternate TKI


Management of Pulmonary Arterial Hypertension (PAH) With Dasatinib

• Anecdotal reports of largely reversible pulmonary

arterial hypertension with dasatinib have surfaced;

incidence estimated to be ~0.5%

• If unexplained breathless develops on dasatinib,

consider echocardiogram; if indicative of increased

pulmonary arterial pressure, refer to cardiology for

consideration of right heart catheterization (gold

standard for diagnosis); discontinue dasatinib in

individuals with confirmed PAH


• BCR-ABL TKIs have transformed chronic phase CML to a

manageable chronic condition in the vast majority of cases

– Excessive delays in diagnosis/treatment of chronic phase

CML can be highly detrimental to long-term outcomes

– Effective monitoring is required to maximize therapeutic

outcomes

– Better medical therapies are required for blast phase CML

• Timely recognition and treatment of TKI resistance is

necessary to maximize therapeutic outcomes

– Certain BCR-ABL kinase domain mutants may respond

preferentially to a particular TKI

BCR-ABL TKIs have distinct AE profiles to be aware of

• Attempts to develop safer therapies for patients with the

BCR-ABL/T315I mutation are ongoing (eg, ABL001)

Conclusions (I)

• CML represents a triumph of precision medicine, and the

outlook for chronic phase CML patients is highly favorable as a

result of TKI therapy

• As a consequence of dramatically improved long-term

outcomes, the prevalence of CML has increased

- With the favorable outlook, it is increasingly important to

minimize serious and irreversible toxicities and maximize

quality of life

Conclusions (II)

Practical Guidance for the Management of CML in 2016 · 1.6 0.9 0.8 0.5 0.3 0 2.0 0.4 • KM...

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