Treatment Free Remission in CML: Promise and challengesplan.medone.co.kr/70_icksh2019/data/LS01_Adam_Mead.pdf · 2019. 6. 27. · KR1903977228 Treatment Free Remission in CML: Promise

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Treatment Free Remission in CML: Promise and challengesProfessor Adam MeadConsultant Haematologist at Oxford University Hospitals NHS Foundation Trust and Professor of Haematologyat the University of OxfordOxford, UK

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대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Adam Mead

I currently have, or I have had in the past two years, an affiliation or financial interest with business corporation(s):

(1) Consulting fees, patent royalties, licensing fees ： Celgene, Sanofi, Bristol-Myers Squibb, Gilead, Pfizer, Novartis, CTI BioPharma

(2) Research fundings： Yes, Celgene and Novartis

(3) Others No

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Is CML a ‘sorted’ disease?

3

Improvement in CML patients survival in Oxford from pre- to post-TKI era

Tyrosine Kinase Inhibitors (TKI)

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Survival with CML over timeThe German CML-Study Group experience

4HU, hydroxyurea; IFN, interferon; SCT, stem cell transplantation.German CML Study Group, update 2016: Hehlmann R. Haematologica 2016; 101: 657-659.

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Challenges in CML

5

1. Treatment failure still occurs

Marin et al. 2012

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Challenges in CML

6

1. Treatment failure still occurs2. Early progressions to blast crisis (2-5%)

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Challenges in CML

7

1. Treatment failure still occurs2. Early progressions to blast crisis (2-5%)3. Residual disease propagating cells

Mahon et al. 2017

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Challenges in CML

8

1. Treatment failure still occurs2. Early progressions to blast crisis (2-5%)3. Residual disease propagating cells4. Side effects

Epicace et al. 2012

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Challenges in CML

9

1. Treatment failure still occurs2. Early progressions to blast crisis (2-5%)3. Residual disease propagating cells4. Side effects5. Cost of life-long treatment

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Challenges in CML

10

1. Treatment failure still occurs2. Early progressions to blast crisis (2-5%)3. Residual disease propagating cells4. Side effects5. Cost of life-long treatment (£billions in UK alone over next 10 years)

Why do most patients require lifelong treatment?

Case Presentation• Male, 33 years old• Medications: none• Past medical history: none relevant• Family history: none relevant• Vascular risk factors: none; normal blood pressure• Sokal risk: low• Symptoms: the patient reported a degree of lethargy over

the previous year but had otherwise been well• Presentation: referred following a blood count prior to an

elective urological procedure in July 2011

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Case Presentation (cont)• Blood counts

– Normal white blood cell count but low level basophilia and no circulating blast cells

• Cytogenetic and molecular testing– Bone marrow aspirate showed features consistent with chronic

phase CML (hypercellular with increased myeloid cells and megakaryocytes)

– Cytogenetics showed a variant three-way translocation (9;22;15) with no other chromosomal abnormalities

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• Haemoglobin: 15.5 g/L• White blood cells: 10.2 x 109/L• Platelets: 990 x 109/L• Basophils: 0.4%• Blast cells: None

CML, chronic myeloid leukemia.

Comments About Disease Presentation

• CML should always be considered in cases of isolated thrombocytosis, and where relevant, BCR-ABL1 tested

• The variant translocation does not alter management and is of no prognostic significance

• What are the goals of treatment for this patient:– Prevent disease progression

Complete cytogenetic remission? Major molecular remission (MR3)? Deep molecular remission?

– Minimise TKI associated side effects?– Treatment-free remission– Cure?

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Considerations when selecting 1st line TKI

14

Comorbidities

Cost?

Prevention of disease progression events

Sex

Side effects

Age

Risk stratification

Drug availability

Disease eradication (TFR)

TKI, tyrosine kinase inhibitor.Baccarani M et al. Blood 2013; 122: 872-884.

Molecularanalysis

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Radich JP, et al. J Natl Compr Canc Netw. 2018;16(9):1108–35.

•ELN CML Guidelines 2006, 2009 and 2013….. awaiting update!

•NCCN CML Guidelines 2015, 2017 and 2019

•Some differences between them e.g. at 3 months and 12 months

CML Guidelines

CML, chronic myeloid leukaemia; ELN, European LeukemiaNet; NCCN, National Comperhensive Cancer Network; TKI, tyrosine kinase inhibitor.

NCCN Guidelines Version 1.2019Chronic Myeloid Leukaemia

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Guidelines for monitoring

Radich JP, et al. J Natl Compr Canc Netw. 2018;16(9):1108–35.

CCA, clonal cytogenetic abnormalities; CCyR, complete cytogenetic; FISH, fluorescence in situ hybridization; MMR, major molecular response; Ph, Philadelphia; TKI, tyrosine kinase inhibitor.

NCCN Guidelines Version 1.2019Chronic Myeloid Leukaemia

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Current ELN recommendations for the management of CML

17

Time Optimal response Warning Failure

3 months BCR-ABL ≤10%≤35% Ph+

BCR-ABL >10%36–95% Ph+

No CHR>95% Ph+

6 months BCR-ABL <1%0% Ph+

BCR-ABL 1–10%1–35% Ph+

BCR-ABL >10%>35% Ph+

12 months BCR-ABL ≤0.1% BCR-ABL >0.1–1% BCR-ABL >1%>0% Ph+

Then, and at any time

MMR or better CCA/Ph- (-7, or 7q-) Loss of CHR/CCyRConfirmed loss of MMRMutationsCCA/Ph+

CCA, clonal cytogenetic abnormalities; CCyR, complete cytogenetic response; CHR, complete haematological response;CML, chronic myeloid leukaemia; EFS, event free survival; ELN, European LeukemiaNet; MMR, major molecular response;

OS, overall survival; Ph, Philadelphia.Baccarani M et al. Blood 2013; 122: 872–884.

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Importance of achieving ≤10%BCR-ABLIS at 3 months

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• Achieving ≤10% BCR-ABL at 3 months correlates with significantly higher rates of improved PFS and OS

OS, overall survival; PFS, progression-free survival. Marin D et al. J Clin Oncol 2012; 30: 232-238.

≤9,84%

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Survival benefits to reaching ELN3 month milestoneComparison to other landmark analyses at 3 months*

Trial/author(treatment)

Length of analysis

OS with <10% BCR-ABLIS

3 months

OS with >10% BCR-ABLIS

3 monthsHammersmith

Marin1

(imatinib)8 years 93% 57%

CML Study IVHanfstein2†

(imatinib)5 years 94% (>1%–10% BCR-ABLIS)

97% (≤1% BCR-ABLIS)87%

ENESTndSaglio3‡

(nilotinib 300 mg BID)5 years 95.3% (>1%–10% BCR-ABLIS)

94.6% (≤1% BCR-ABLIS)78%

DASISIONJabbour4§

(dasatinib)3 years 96% 86%

ELN, European LeukemiaNet; OS, overall survival. 1. Marin D et al. J Clin Oncol 2012; 30: 232-238; 2. Hanfstein B et al. Leukemia 2012; 26: 2096-2102; 3. Saglio G et al. Abstract 92. Presented at ASH 55th Annual Meeting, December 07-10, 2013. 4. Jabbour E et al. Blood 2014; 123: 494-500

* The table is for an overview only and is not intended for side by side analysis. † Exploratory analysis, descriptive stats only. ‡ These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses. § Post-hoc analysis, descriptive stats only.

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ENESTnd study design

a The ENESTnd study protocol originally called for 5 years of follow-up, which was later extended to 10 years.b Patients randomised to nilotinib 300 mg BID or imatinib who experienced suboptimal response or treatment failure could discontinue core treatmentand enter an extension study in which they received nilotinib 400 mg BID. Patients randomised to nilotinib 400 mg BID were initially permitted to enter the extension study and receive imatinib 400 mg QD; however, a protocol amendment after the 36-month data cutoff removed this option. Survival and progression outcomes during extension study follow-up were included in the “on study” analyses for the core study.BID, twice daily; CP, chronic phase; Ph, Philadelphia; QD, once daily.Larson RA et al. Blood 2014: abstract 4541. Presented at 56th ASH Annual Meeting, December 2014. Novartis Pharmaceuticals Ltd. Tasigna Summary of Product Characteristics. May 2017

Imatinib 400 mg QD (n=283)

Nilotinib 300 mg BID (n=282)RANDOMISE

Nilotinib 400 mg BID (n=281)

Planned follow-up: 10 yearsa,b

N=846

Adults with newly diagnosed(≤6 months) Ph+ CML-CP

1:1:1Stratified by Sokal risk

score

Recommended dose:- 300 mg BID in newly diagnosed patients with CML-CP- 400 mg BID in patients with CML-CP or accelerated phase CML with resistance or intolerance to prior therapy.

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Nilotinib 300 mg BID (n=282)RANDOMISED

3 monthsBCR-ABL level



N=846

217 centres

35 countries

Objectives:PCR Landmark Analysis* to Predict Response & Outcome

Achievement of MMR and MR4.5

PFS (AP/BC or death due to any cause*) OS (death due to any cause*)

(ENESTnd - Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Newly diagnosed patients)

† * These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses.

• On core or extension treatment or during follow-up afterdiscontinuation of treatment.† The licenced dose for nilotinib in newly diagnosed patientswith CML in chronic phase is 300 mg BID.AP, accelerated phase; BC, blast crisis; PCR, polymerase chain reaction; MMR, major molecular response; OS, overall survivalHughes TP et al. Blood 2014; 123(9): 1353–1360.

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ENESTnd: BCR-ABL categories at 3 months*



Patie

nts

(%)

(24 patients)

BCR-ABL level at 3 months

>1−10%(89 patients, 35%)

>1−10%(133 patients, 50%)

≤1%(145 patients, 56%)

≤1%(43 patients, 16%)

91%

9%

67%

33%

0

20

40

60

80

100

≤10% >10%

(88 patients)

* Calculated from total number of evaluable patients with PCR assessments at 3 months. Reasons for unevaluable samples: atypical transcripts (5 patients on nilotinib; 2 patients on imatinib); missing samples (4 patients on nilotinib; 5 patients on imatinib); discontinued (15 patients, inc. 1 progression, on nilotinib; 12 patients, inc. 1 progression, on imatinib).BID, twice daily; PCR, polymerase chain reaction QD, once daily.

Hughes TP et al. Blood 2014; 123(9): 1353–1360.

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Current ELN recommendations for the management of CML

23

Time Optimal response Warning Failure

3 months BCR-ABL ≤10%≤35% Ph+

BCR-ABL >10%36–95% Ph+

No CHR>95% Ph+

6 months BCR-ABL <1%0% Ph+

BCR-ABL 1–10%1–35% Ph+

BCR-ABL >10%>35% Ph+

12 months BCR-ABL ≤0.1% BCR-ABL >0.1–1% BCR-ABL >1%>0% Ph+

Then, and at any time

MMR or better CCA/Ph- (-7, or 7q-) Loss of CHR/CCyRConfirmed loss of MMRMutationsCCA/Ph+

CCA, clonal cytogenetic abnormalities; CCyR, complete cytogenetic response; CHR, complete haematological response;CML, chronic myeloid leukaemia; EFS, event free survival; ELN, European LeukemiaNet; MMR, major molecular response;

OS, overall survival; Ph, Philadelphia.Baccarani M et al. Blood 2013; 122: 872–884.

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IRIS study: EFS according to the 18 month level of response

95%

86%P=0.01

62%58%

0 12 24 36 48 60 72 840

10

20

30

40

50

60

70

80

90

100

% w

ithou

t eve

nt

Months following treatment start

BCR-ABL % (IS)

≤0.1%>0.1–1%>1–10%>10%

EFS, event free survival.Hughes TP et al. Blood 2010; 116: 3758–3765.

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Cumulative incidence of MMR

• Rates of MMR by 6 years remained higher in the nilotinib arms than in the imatinib arm• Nearly all patients still on core treatment at the data cutoff had achieved MMR; in each arm, 4 patients who had not achieved

MMR remained on core treatment at the data cutoff (among these 12 patients, 5 had atypical transcripts at baseline and 7 had a best response of BCR-ABLIS >0.1% to ≤1%)

BID, twice daily; MMR, major molecular response; QD, once daily. Larson RA et al. Blood 2014: abstract 4541. abstract 4541. Presented at 56th ASH Annual Meeting, December 2014.

0 6 12 18 24 30 36 42 48 54 600

20

40

60

80

100

Months Since Randomisationb

Cum

ulat

ive

Inci

denc

e of

MM

R, %

Nilotinib 300 mg BID (n = 282)Nilotinib 400 mg BID (n = 281)Imatinib 400 mg QD (n = 283)

10

30

50

70

90

66 72 78

Δ 24% to 28%

55%;P<0.0001a

By 1 Year

27%

77%; P0<0.0001a

Δ 16% to 18%

79%; P<0.0001a

By 6 Years

61%60%

77%; P<0.0001a

77%; P<0.0001a

Δ 17%

By 5 Years

51%;P<0.0001a

a P values are nominal.b For each arm, the curve stops at the latest time point at which a patient first achieved MMR.

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ENESTnd: Cumulative incidence of MMR by BCR-ABL levels at 3 months (nilotinib 300 mg BID)*

76%

40%

4%

89%

67%

29%

P=0.0001

P=0.0007MMR by 2 years for ≤10% vs >10% BCR-ABL

(80% vs 29%; P<0.0001)

% W

ith M

MR

54Time Since Randomisation (Months)

100

90

80

70

60

50

40

30

20

10

00 12 18 24 30 36 42 48

≤1%>1% – ≤10%>10%

1208924

Patients

60

MMR by 1 year

513 6 9 15 21 27 33 39 45 57

MMR by 2 years

Data cut-off: 27Jul2012.

* These data exclude 25 patients in the nilotinib arm who achieved MMR at or before 3 months. These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses.BID, twice daily; MMR, major molecular response.Hughes TP et al. Blood 2014; 123(9): 1353–1360.

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ENESTnd: Cumulative incidence of MMR by BCR-ABL levels at 3 months (imatinib)*

71%

31%

2%

78%

52%

20%

P=0.0030

P<0.0001

MMR by 2 years for ≤10% vs >10% BCR-ABL(58% vs 20%; P<0.0001)

% W

ith M

MR

54Time Since Randomisation (Months)

100

90

80

70

60

50

40

30

20

10

00 12 18 24 30 36 42 48

≤1%>1% – ≤10%>10%

41133

88

Patients

60

MMR by 1 year

513 6 9 15 21 27 33 39 45 57

MMR by 2 years

Data cut-off: 27Jul2012.

* These data exclude 2 patients in the imatinib arm who achieved MMR at or before 3 months. These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses.MMR, major molecular response.Hughes TP et al. Blood 2014; 123(9): 1353–1360.

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ENESTnd: PFS (AP/BC or death) on study by 5 years by BCR-ABL levels at 3 months*

Nilotinib 300 mg BID Imatinib 400 mg QD

BCR-ABL Level≤1%>1% to ≤10%>10%Censored Observations

Pts Evt Cen145 7 13889 4 8524 6 18

P=0.9814

P=0.0010

PFS by 5 Yearsa

94.6%95.3%

78.3%

100908070605040302010

00 1 2 3 4 5 6

Patie

nts

With

out P

rogr

essi

on, %

Time Since Randomisation, Calendar Years

100908070605040302010

00 1 2 3 4 5 6

Patie

nts

With

out P

rogr

essi

on, %


PFS by 5 Yearsa

P=0.2338P<0.0001

98.5%95.3%

80.1%


Pts Evt Cen43 2 41

133 2 13188 16 72

EMR Failure EMR Failure

• Patients with EMR failure (BCR-ABL >10% at 3 months) have significantly worse 5-year PFS

• Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib

*These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses.aPFS rates reported consider each year to consist of twelve 28-day cycles.BID, twice daily; Cen, censored; EMR, early molecular response;Evt, events; PFS, progression-free survival; Pts, patients;QD, once daily.

Saglio G et al. Abstract 92. Presented at 55th ASH Annual Meeting, December 07-10, 2013.

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ENESTnd: OS by 5 years by BCR-ABL levels at 3 months*

Nilotinib 300 mg BID Imatinib 400 mg QDP=0.4871

P

OS by 5 Yearsa


Pts Evt Cen145 6 13989 2 8724 5 19

100908070605040302010

00 1 2 3 4 5 6

Patie

nts

Aliv

e, %


100908070605040302010

00 1 2 3 4 5 6


OS by 5 Yearsa

P=0.087399.2%95.3%

BCR-ABL Level≤1%>1% to ≤ 10%>10%Censored Observations

Pts Evt Cen43 2 41

133 1 13288 16 72

• Patients with EMR failure (BCR-ABL >10% at 3 months) have significantly worse 5-year OS

• Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib

79.5%95.7%97.6%

81.9%

Patie

nts

Aliv

e, %

EMR Failure: 9% of pts

EMR Failure: 33% of pts

P=0.0010

P0<0.0001

*These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses.aPFS rates reported consider each year to consist of twelve 28-day cycles.BID, twice daily; Cen, censored; EMR, early molecular response;Evt, events; OS, overall survival; Pts, patients; QD, once daily.

Saglio G et al. Abstract 92. Presented at 55th ASH Annual Meeting, December 07-10, 2013.

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Progression to AP/BC

Nilotinib 300 mg twice daily (n = 282)

Nilotinib 400 mg twice daily(n = 281)

Imatinib 400 mg once daily(n = 283)

New events reported since the 5-year data cutoff(n=1)

On Core Treatment On Study - ITT

2 3

12 11

6

21

0

5

10

15

20

25 P = .0059b

P = .0185b

P = .0030b

P = .0661b

4.2%1.1%0.7% 7.4%3.9% 2.1%

Adapted from: Hughes, et al 2015a Defined as progression to AP/BC or death due to advanced CML. b P values are nominal.

AP, accelerated phase; BC, blast crisis; n, number; CML, chronic myeloid leukaemiaHughes TP, et al Haematologica 2015. Presentation during EHA20 (abstract only) P288

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Second generation TKIs as first line therapy versus imatinib

• PROs– Reduce the number of

patients failing EMR (<10% BCR-ABL at 3 months)– Reduce the risk of early progression and of

CML-related death – Induce faster and deeper MRs

• CONs– Do not improve OS – May be associated with more long-term toxicities – Are more expensive

What about deeper molecular remissions?

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Should MR4.5 be the new goal of CML therapy?

Levels of molecular response in CML and corresponding leukemia cell burden1

1. Vigil CE et al. Laboratory Medicine 2012; 43: e23–e32. 2. Baccarani M et al. Blood 2013; 122: 872–884.

2

Case presentation: 1L Treatment With Nilotinib

• The patient began treatment with nilotinib immediately and experienced several AEs within the first 6 months; these resolved independently or with a brief interruption in therapy

AE, adverse event; ALT, alanine transaminase; BID, twice daily; ELN, European LeukemiaNet; FISH, fluorescence in situ hybridisation; MMR, major molecular response.

Started nilotinib 300 mg BID

July 2011The patient experienced mild transaminitis (ALT 121IU/L), which settled

without dose adjustment

After 2 months of treatment

2011

After 3 months of treatment

Bone marrow was 13% BCR-ABL1 positive by FISH (reduced from 84/100 cells at diagnosis)

Significant muscle cramps (Grade 2), headache (Grade 1), and rash (Grade 1) developed,

requiring a 5-day treatment interruption

Treatment restarted when symptoms

settled

Peripheral blood BCR-ABL1 showed MMR (0.08%; optimal response according to ELN

recommendations1)

1. European LeukemiaNet. European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML) (online) 2013. Available from: https://www.leukemia-net.org/content/leukemias/cml/recommendations/e8078/infoboxContent10432/PocketCard_UPDATE2013_English.pdf. Last accessed: May 2017. 33

https://www.leukemia-net.org/content/leukemias/cml/recommendations/e8078/infoboxContent10432/PocketCard_UPDATE2013_English.pdf

Treatment discontinued with monthly BCR-ABL1 monitoring

just over 3 years after starting nilotinib (as part of the ENESTfreedom study2)

Long-Term MR4.5 Achieved With Nilotinib

Deep molecular response (MR4.5) was sustained over the following 2.5 years

After 6 months of treatmentComplete cytogenetic response

in bone marrow was achieved (0/200 cells by FISH)

Peripheral blood BCR-ABL1 was undetectable (MR4.5; optimal response according to ELN

recommendations1)

September 2014

2012 2013 2014

1. European LeukemiaNet. European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML) (online) 2013. Available from: https://www.leukemia-net.org/content/leukemias/cml/recommendations/e8078/infoboxContent10432/PocketCard_UPDATE2013_English.pdf. Last accessed: May 2017; 2. Clinicaltrials.gov. Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients (ENESTFreedom) [online] 2016. Available at: https://clinicaltrials.gov/ct2/show/NCT01784068 [Last accessed: May 2017].

MR4.5, BCR-ABL1 ≤ 0.0032% on the International Scale (IS).

34

https://www.leukemia-net.org/content/leukemias/cml/recommendations/e8078/infoboxContent10432/PocketCard_UPDATE2013_English.pdf

Summary and Current Status

• This young patient achieved a very rapid and deep molecular response with first-line nilotinib treatment

• This allowed him to attempt TFR just 3 years after starting treatment for CML

• The patient remains in MR4.5 > 3 years after treatment discontinuation

• The patient has benefitted a great deal psychologically from long-term deep molecular response

• The patient continued to work full-time from diagnosis through treatment to discontinuation

35

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ENESTnd: Cumulative incidence of MR4.5

More patients achieved MR4.5 in each nilotinib arm than in the imatinib armAmong patients still on core treatment at the data cutoff, 30 (nilotinib 300 mg BID), 42 (nilotinib 400 mg BID), and 47 (imatinib) patients had not achieved MR4.5

Kaplan Meier-estimated median times to first MR4.5 were Nilotinib 300 mg BID: 45.5 months (hazard ratio [HR] vs imatinib, 2.0387 [95% CI, 1.5807–2.6295]; nominal P<0.0001)Nilotinib 400 mg BID: 49.8 months (HR vs imatinib, 1.7770 [95% CI,1.3780–2.2915]; nominal P<0.0001)Imatinib 400 mg QD: 61.1 months

0 6 12 18 24 30 36 42 48 54 600

20

40

60

80

100

Months Since Randomisation

Cum

ulat

ive

Inci

denc

e of

MR

4.5 ,

%

Nilotinib 300 mg BID (n=282)Nilotinib 400 mg BID (n=281)Imatinib 400 mg QD (n=283)

10

30

50

70

90

66 72 78

11%; P<0.0001a

7%; P<0.0001a

1%

Δ 6% to 10%

By 1 Year

56%; P<0.0001a

55%; P<0.0001a

33%

Δ 22% to 23%

By 6 Years

31%

By 5 Years54%; P<0.0001a

52%; P<0.0001a

Δ 21% to 23%

a P values are nominal. BID, twice daily; CI, confidence interval; MMR, major molecular response; QD, once daily.Larson RA et al. Blood 2014: abstract 4541. Presented at 56th ASH Annual Meeting, December 2014.

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ENESTnd: Proportion of patients with MR4.5 by 5 years by BCR-ABL levels at 3 months*

58%

28%

4%

P=0.0001

P=0.0135

70%

52%

8%

P=0.0046

P=0.0001

MR4.5 by 4 Yearsa

MR4.5 by 5 YearsaBCR-ABL Level≤1%>1% to ≤10%>10%

Pts1448924

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Patie

nts

With

MR

4.5 ,

%


MR4.5 by 4 Yearsa

MR4.5 by 5 Yearsa

65%

24%

5%

P<0.0001

P=0.0001

67%

34%

15%

P=0.0001

P=0.0016

BCR-ABL Level≤1%>1% to ≤10%>10%

Pts 43

133

88

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Patie

nts

With

MR

4.5 ,

%Time Since Randomisation, Calendar Years

BCR-ABLIS ≤1%: 16% of pts

BCR-ABLIS ≤1%: 56% of ptsNilotinib 300 mg BID Imatinib 400 mg QD

• Patients with BCR-ABL ≤1% at 3 months have significantly higher rates of MR4.5 by 5 years

• More patients achieve BCR-ABL ≤1% at 3 months on nilotinib 300 mg BID vs imatinib

*These Landmark analyses are exploratory and not pre-planned in the protocol. All P values related to these landmark analyses were generated from Kaplan-Meier methods post hoc and not adjusted for multiple comparisons, thus the P values are descriptive only for these analyses.a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.BID, twice daily; QD, once daily.Saglio G et al. Abstract 92. Presented at 55th ASH Annual Meeting, December 07-10, 2013.

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Frequently reported newly occurring or worsening laboratory abnormalities and nonhaematologic AEs

0

5

10

15

20

25

30

35

40

45

50

Nilotinib 300 mg BID (n=279) Nilotinib 400 mg BID (n=277) Imatinib 400 mg QD (n=280)Nonhaematologic AEs

(≥30% in any arm, any grade)Haematologic Abnormalities

(grade 3/4) Biochemical Abnormalities (≥5% in any arm, grade 3/4)

Patie

nts,

%

38

45

19

32

37

23 22

31

41

2023

46

1312

34

3

10

4

10

4

< 1

978

< 1

81010

4

9

3

10

4

22

13

9

151212 10

129

754

AE, adverse event; ALT, alanine aminotransferase; BID, twice daily; QD, once daily.Larson RA et al. Blood 2014:abstract Presented at 56th ASH Annual Meeting, December 2014.

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ENESTnd 6-yr update: cardiovascular events

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Is deep molecular remission important for long term survival?

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CML Study IV: Prognostic impact of deep molecular responses (MR4.5)*

• MR4.5 or better at 4 years predicted survival significantly better than 0.1 to 1% IS (MMR -CCyR)

• No patient with confirmed MR4.5 progressed from Chronic Phase, compared to 13 with CCyr and 9 with MMR1

• No survival benefit of MR4.5 above MR3

*Exploratory analysis , all p values are descriptive only. CCyR, complete cytogenetic response; CML, chronic myeloid leukaemia; MMR, major molecular response.Hehlmann R et al. J Clin Oncol 2014; 32: 415-423

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Treatment free remission:

A new paradigm for CML management

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Published studies on TFR1

• PubMed review of the last 6 years + EHA/ASH/ASCO abstracts of the last 6 years:At least 35 discontinuation studiesAlmost 3,600 patients20 studies on imatinib discontinuation10 studies on nilotinib discontinuation5 studies of dasatinib discontinuation– Only 3 cases of disease progression (incidence

similar to that observed for patients continuing the TKI therapy)

1.. https://www.ncbi.nlm.nih.gov/pubmed/?term=treatment+free+remission+CML. Accessed January 20192. Novartis Pharmaceuticals UK Ltd. Tasigna Summary of Product Characteristics. Sept 2018.

Tasigna (nilotinib) is the only approved TKI to include TFR data in the current SmPC. When considering discontinuation of nilotinib for TFR, reference should be made to the entry and management criteria described in the SmPC2

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STIM: Stopping imatinib is feasible

Mahon et al. Blood (ASH) 2011; 118: Abstract 603

Surv

ival

with

out m

olec

ular

rela

pse 1.0

0

0.90.80.70.60.50.40.30.20.10.0

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60Months since discontinuation of imatinib

Median follow-up: 34 months (9-50)

Molecular relapses: n=61

Survival without molecular relapse:39% (95% CI: 29-48) at 24 and 36 months

Undetectable BCR-ABL: at least 50 000 copies of the ABL control geneMolecular relapse: defined by 2 positive RQ-PCR results over 1 month showing a significant risein BCR-ABL transcripts; triggers imatinib resumption.

CP-CMLImatinib ≥ 3 yearsUndetectable BCR-ABL ≥ 2 years

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Long-Term Treatment-Free Remission in Patients With Chronic Myeloid Leukemia

in Chronic Phase Following Frontline Nilotinib: Results From ENESTfreedom

Giuseppe Saglio,1 Tamás Masszi,2 María Teresa Gómez Casares,3 Andrzej Hellmann,4Jesper Stentoft,5 Eibhlin Conneally,6 Valentín Garcia Gutierrez,7 Norbert Gattermann,8

Bruno Martino,9 Susanne Saussele,10 Philipp D. le Coutre,11 Francis J. Giles,12

David M. Ross,13 Jerald P. Radich,14 Manu Sondhi,15 Suddhasatta Acharyya,15

Shalini Chaturvedi,15 Véronique Bédoucha,16 Andreas Hochhaus17

1University of Turin, Orbassano, Italy; 2Semmelweis University, Budapest, Hungary; 3Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain; 4Medical University of Gdańsk, Gdańsk, Poland; 5Aarhus University Hospital,

Aarhus, Denmark; 6St James’s Hospital, Dublin, Ireland; 7Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain; 8Universitätsklinikum Düsseldorf, Düsseldorf, Germany; 9Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy;

10III. Med. Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; 11Charité -Universitätsmedizin Berlin, Berlin, Germany; 12Developmental Therapeutics Consortium, Chicago, IL, USA; 13SA Pathology and South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia; 14Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 15Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA;

16Novartis Pharma AG, Basel, Switzerland; 17Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany

144 week follow up , June, 2018

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Methods• ENESTfreedom (NCT01784068) is a single-arm, phase 2 study ENESTfreedom Study Design

52

IS, International Scale; MMR, major molecular response (BCR-ABL1IS ≤ 0.1%); MR4.5, BCR-ABL1IS ≤ 0.0032%; RQ-PCR, real-time quantitative polymerase chain reaction (standardized to the IS).a Sustained DMR defined as the following (in the last 4 quarterly PCR assessments): MR4.5 in the last assessment, no assessment worse than MR4

(BCR-ABL1IS ≤ 0.01%), and ≤ 2 assessments between MR4 and MR4.5. b Patients will be followed up for up to 264 weeks after the last patient entered the TFR phase. c This analysis was based on a cutoff date of October 11, 2017, at which time all patients who entered the TFR phase had completed 144 weeks of TFR, entered the nilotinib reinitiation phase, or discontinued from the study.

• Adults with CML-CP• b2a2 and/or b3a2

transcripts• ≥ 2 years of frontline

nilotinib • MR4.5 at screening

(central laboratory)

Nilotinib consolidation

phase (52 weeks)

TFR phaseb,c

RQ-PCR every 12 weeks

Enro

ll

Sustained DMRa

TFR-2 phaseb

Nilotinib treatment

reinitiation upon loss of

MMR

Nilotinib continuation

phase Sustained

DMRa

No sustained

DMRa

First 48 weeks: RQ-PCR every 4 weeksSecond 48 weeksr: RQ-PCR every 6 weeks

Thereafter: RQ-PCR every 12 weeks

No sustained

DMRa

Prolonged continuation phase

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Treatment Free Survivala

53

a TFS was estimated using the Kaplan-Meier method and was defined as the time from the date of start of TFR to the date of earliest occurrence of an event (loss of MMR, progression to accelerated phase [AP] or blast crisis [BC], death due to any cause up to the end of the TFR phase, or reinitiation of nilotinib due to any cause).b Defined as no loss of MMR and no reinitiation of nilotinib in the first 48 weeks of TFR.

At 48 weeks: 53.1%At 96 weeks: 50.9%

At 144 weeks: 48.7%

100

TFS,

%

90

80

70

60

50

40

30

20

10

00 24 48 72 96 120 144 168 192

190: 0 120:70 99:89 95:91 93:93 92:94 77:97 10:97 0:97No. at Risk:Events

Time Since TFR Start, weeks

Patients190

Events97

Censored93

I Censored observations

48-week TFR rate (primary endpoint): 51.6% (98/190)b

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Response to Retreatment

• 91 patients restarted nilotinib treatment after loss of MMR in the main TFR phase

– 90 (98.9%) regained MMR 1 patient discontinued from the study after 7.1 weeks of retreatment

without regaining MMR– 84 (92.3%) regained MR4.5

Of the 6 patients who regained MMR but not MR4.5, 1 remained in the reinitiation phase at the data cutoff, and 5 had discontinued from the study (2 due to AEs, 1 due to physician decision, 1 due to patient decision, and 1 due to lack of efficacy [after regaining and then losing MMR; patient was found to have an F359V mutation6])

54

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Cumulative Rate of MMR Regained in Nilotinib Reinitiation Phase

50% of retreated patientsregained MMR by 7.0 weeks

0/91 44/91 84/91 88/91 89/91 90/91Cumulative n/N0.0 48.4 92.3 96.7 98.9Cumulative % 97.8

100

90

80

70

60

50

40

30

20

10

00 6 12 18 24 30

Patie

nts

With

MM

R R

egai

ned,

%

Time Since Start of Retreatment, weeks

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Safety• Musculoskeletal pain incidence was highest in the first 48 weeks following TKI cessation

and decreased during the second and third 48 weeks of TFR to levels lower than that in the consolidation phase

56

Patients, n (%)

Consolidation Phase

(n = 94)

TFR PhaseFirst 48 Weeks(n = 94)

Second 48 Weeks(n = 94)

Third 48 Weeks(n = 94)

Musculoskeletal pain 15 (16.0) 38 (40.4) 9 (9.6) 4 (4.3)Fluid retention 3 (3.2) 3 (3.2) 5 (5.3) 0

Edema and other fluid retentions 2 (2.1) 3 (3.2) 5 (5.3) 0Severe 1 (1.1) 0 0 0

Hepatotoxicity 2 (2.1) 2 (2.1) 0 0Cardiovascular events 3 (3.2) 2 (2.1) 1 (1.1) 2 (2.1)

Ischemic cerebrovascular events 1 (1.1) 1 (1.1) 0 0Ischemic heart disease 1 (1.1) 0 1 (1.1) 1 (1.1)Peripheral arterial occlusive disease 1 (1.1) 1 (1.1) 0 1 (1.1)

Rash 5 (5.3) 1 (1.1) 2 (2.1) 0Myelosuppression (thrombocytopenia) 1 (1.1) 0 0 0Pancreatitis 1 (1.1) 0 0 0Significant bleeding (GI hemorrhage) 0 0 1 (1.1) 0Cardiac failure 0 1 (1.1) 0 0

GI, gastrointestinal.a Among patients who remained in TFR for > 96 weeks (n = 94). b Each listed AE group includes a predefined set of individual AEs. Reported frequencies include all patients with ≥ 1 new or worsening AE in the group reported during the indicated study period.

AE Groups of Special Interest (all grades)a,b

Criteria for TFR Eligibility Outside of Clinical Trials

57

DMR, deep molecular response; ESMO, European Society for Medical Oncology; SmPC, summary of product characteristics; USPI, United States prescribing information. a Criteria for TFR eligibility in the USPI but not in the SmPC. b According to the USPI, monitor transcript levels in patients eligible for treatment discontinuation using an FDA-authorized test validated to measure molecular response levels with a sensitivity of at least MR4.5. c TKI types not specified. d For patients treated with nilotinib following imatinib, the USPI specifies patients are resistant to or intolerant of imatinib. e According to the USPI, patients treated with first-line nilotinib must maintain MR4.0 for 1 year and achieve MR4.5 in the last assessment prior to TFR; patients receiving second-line nilotinib must maintain MR4.5 for a minimum of 1 year. In clinical trials, for patients treated with first-line nilotinib, sustained DMR was defined as the following in quarterly assessments during the year prior to stopping treatment: no assessment worse than MR4, no more than 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment; for those treated with second-line nilotinib, sustained DMR was defined as no confirmed loss of MR4.5 in quarterly assessments conducted during the year prior to stopping treatment.

1. Hochhaus A, et al. Ann Oncol. 2017;28:iv41-iv51; 2. Tasigna (nilotinib) [summary of product characteristics]. Camberly, UK: Novartis Europharm Ltd.; 2018; 3. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2018.

• CML-CP• Typical BCR-ABL1 transcripts (b2a2 or b3a2) or atypical transcripts

that can be quantified over a 4.5-log dynamic range• Non-high Sokal risk score at diagnosis• Optimal response to first-line therapy

• CML-CP• Typical BCR-ABL1

transcripts (b2a2 or b3a2)• No history of AP/BC or

prior TFR attemptsa

• IS-standardized, accurate, sensitive RQ-PCR• ≤ 4-week turnaround of RQ-PCR results• Ability to perform RQ-PCR tests every 4 to 6 weeks if required• Structured follow-up for rapid intervention in case of rising BCR-

ABL1 transcript levels

• IS-standardized test sensitive to at least MR4.5,b

ESMO1 Tasigna label2,3

Patie

nt

char

acte

ristic

sIn

stitu

tiona

l re

quire

men

ts

• TKI therapy for > 5 yearsc

• Achieved an MR4.5

• Durable DMR (MR4 or MR4.5) for > 2 years

• Nilotinib therapy for ≥ 3 years (first-line or following imatinibd)

• Sustained DMR (MR4.5) for ≥ 1 yeare

DM

R fo

r at

tem

ptin

g TF

R

58

NCCN 2019

What to do if...

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After Discontinuation, Some Patients May Show Fluctuations in MRD

CML patient in CP31 years oldLow risk Sokal score

Rousselot P;2016 John Goldman Conference.

KR1803789669

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Patients who met stringent criteria for attempting TFR in the ENESTnd study after 5 years of treatment1

37.9%

Nilotinib 300 mg BID

21.6%

Imatinib 400 mg QD

TFR, treatment-free remission1. Hochhaus A. et al, American Society of Hematology 2015 (poster) P2781

Adapted from: Hochhaus A. et al, ASH 2015 (poster) P2781

ENESTnd

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CML, chronic myeloid leukaemia; TFR, treatment-free remission; TKI, tyrosine kinase inhibitor. 1. Clark R et al. Abstract S423. Presented at 22nd European Haematology Association, 22-25 June 2017, Madrid, Spain. 2. Novartis. Tasigna 150 mg summary of product characteristics. 2017; 3. Novartis Pharmaceuticals UK Ltd. Tasigna Summary of Product Characteristics. May 2017.

DESTINY: 24 months data (EHA 2017)1

NOTE: Dose de-escalation is not in line with SmPC recommendations for discontinuation for attempting TFR with nilotinib. Tasigna (nilotinib) is the only approved TKI in CML with TFR data included in the current SmPC. When considering discontinuation of nilotinib in attempting TFR, reference should be made to the entry criteria and the management requirements as detailed in the current SmPC.2,3

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Patient pathways with first line imatinib

65


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So why do many patients in deep molecular remission fail TFR?

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Challenges in CML

67

1. Treatment failure still occurs2. Early progressions to blast crisis (2-5%)3. Residual disease propagating cells4. Side effects5. Cost of life-long treatment (£billions in UK alone over next 10 years)


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CML stem cells (CML-SCs)

CML-stem cells

PRESENTATION

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CML-stem cells

PRESENTATION

TKIs

REMISSION

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CML-stem cells

PRESENTATION

TKIs

REMISSION

Stop TKIsor

Resistance

RELAPSE

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CML-stem cells

PRESENTATION

TKIs

REMISSION

Stop TKIsor

Resistance

RELAPSE

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Single cell analysis

Separation of homogeneous CML-SCs from normal HSCs?


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?

Single cell analysis

Separation of homogeneous CML-SCs from normal HSCs?

Identify heterogeneity in CML-SCs?


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Single cell sort

CD34

CD38

Single Cell RNA-Seq of CML stem cells:Workflow

Lysis Buffer

Lin-CD34+CD38-

Smart-seq 2

Picelli S. et al., Nat Prot, 2014.

cDNA generation BCR-ABL scoreand sequencing

qPCR

+ BCR-ABL +ve cells

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- 18 chronic phase CML patients pre-TKI treatment- Over 1500 Lin-CD34+CD38- cells analysed for presence of BCR-ABL- BCR-ABL frequencies 9% to 98%- 478 BCR-ABL +ve and 386 BCR-ABL –ve cells selected for sequencing- CML-SC burden correlates with clinical features (WBC, Hgb, spleen

size)

CML-SCs at diagnosis

Aim for > 1 million mapped reads in >80% of cellsDeeper sequencing does not improve dropout rates

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Heterogeneity in the stem cell compartment in CML

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CML-SCs are more proliferative than normal HSCs

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CML-SCs are more proliferative than normal HSCs

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CML-SCs at diagnosis

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CML-stem cells

PRESENTATION

TKIs administration

REMISSION

CML-SCs at remission

- 20 CML patients 3 months to 5 years post-TKI initiation- Over 3000 cells analysed to detect 243 BCR-ABL +ve cells- BCR-ABL frequencies 0.5% to 45%

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Distinct clusters of CML-SCs at remissiontSNE using top 500 informative genes by random forest analysis

Normal HSCs= 232 cells; Diagnosis+ = 478 cells; Remission+ = 243 cells;Remission+ class A = 122 cells; Remission+ class B = 121 cells

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Enriched in B > A Enriched in A > B

QUIESCENCE HSCPROLIFERATION

Distinct clusters of CML-SCs at remission

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Group A remission cells are enrichedwith time on TKI

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Group A remission cells are enrichedwith time on TKI

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Summary

• Why do most patients require lifelong TKI treatment?

Most patients fail to achieve DMR required for TFR Many patients achieving sustained DMR fail TFR

• Single cell analysis of CML stem cells reveals biology underlying failure of TFR

• Single cell genomics in clinical medicine Accurate disease classification Prognostic risk stratification Minimal residual disease detection Identification of biomarkers Therapeutic target discovery

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Supat Thongjuea

Acknowledgments

Sten Eirik Jacobsen

Petter WollTiphaine Bouriez

Single Cell PCR FacilityNeil AshleyKarolinska InstitutetRickard SandbergAsa SegerstolpeHong Qian

Flow Cytometry FacilityPaul SoppSally-Ann Clark

University of HelsinkiSatu Mustjoki

Nikolas Barkas

Bioinformatic Analysis

Lauren JamiesonChristopher BoothRuggiero NorfoAlba Rodriguez-MeiraAll other lab members!

Alice Giustacchini

Novartis UK

Documents

Treatment Free Remission in CML: Promise and challengesplan.medone.co.kr/70_icksh2019/data/LS01_Adam_Mead.pdf · 2019. 6. 27. · KR1903977228 Treatment Free Remission in CML: Promise