1

Susanne SaußeleSeoul, 16.03.2019

EHA-KSH Joint Symposium II

Real-world experience of TFR in Europe

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Susanne Saussele

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: BMS, Novartis, Incyte, Pfizer

(2) Research fundings： Yes, BMS, Novartis, Incyte

(3) Others : No

.

Achievements with TKI in CML

• Nearly normal life expectancy compared with the general population

• High percentage of patients reach deep molecular remission (DMR, < MR4)

• Survival is most influenced by ACAs* comorbidities• New perspectives with the concept of “treatment-free

remission” (TFR): life-long treatment not for all patients (possible for about 20% of CML patients?)

*additional chromosomal aberration

CML, chronic myeloid leukemia; MR4, BCR-ABL1 ≤ 0.01% on the International Scale (IS).Hehlmann R, et al. Leukemia. 2017;31(11):2398-2406. Bower H, et al. J Clin Oncol. 2016;34(24):2851-2857. Saußele S, et al. Blood. 2015;126(1):42-49. Saußele S, et al. Leukemia. 2016;30(8):1638-1647.

Cessation of Tyrosine Kinase Inhibitor Treatment in CML

>2500 patients have stopped TKI treatment within studies

Seems to be successful in about 40-55% of patients with stable deep MR (DMR) and several years of TKI treatment

About 85-90% of molecular recurrence appear within 6 months, only few later on

90-95% of patients regain their MR level after restart of treatment

DASFree (N = 84)1 ENESTfreedom (N = 190)2

ENESTop (N = 126)4

TFR after stopping second-generation TKIs

ENEST, Evaluating Nilotinib Efficacy and Safety in Clinical Trials.1. Shah NP, et al. Blood. 2017;130(suppl 1) [abstract 314]. 2. Ross DM, et al. J Cancer Res Clin Oncol. 2018;144(5):945-954.3.

4. Mahon FX, et al. Ann Intern Med. 2018;168(7):461-470. 5. Hughes TP, et al. Haematologica. 2018 [abstract PF377].

Saglio G, et al. Haematologica. 2018 [abstract PF368].

5

48 wk: 58.7%5

96 wk: 56.2%5Tr

eatm

ent-

free

sur

viva

l, %

Time since TFR start, weeksAt risk:events

0 36 48

100

90

80

70

60

50

40

30

20

10

012 24 60 72 84 96 108 120 132 144

Patients Events Censored190 94 96I I I Censored observation

190:0 99:89120:70 95:91 75:93 8:93 0:94

48 wk: 53.1%3

96 wk: 50.9%2

Trea

tmen

t-fr

ee s

urvi

val,

%

Time since TFR, weeksAt risk:events

0 36 48

100

90

80

70

60

50

40

30

20

10

012 24 60 72 84 96 108 120 132 144

Patients Events Censored126 57 69I I I Censored observations

126:0 107:19 76:49 74:51 73:52 71:53 69:54 54:55 32:56 13:57 1:57 0:5772:53

From Shah NP, et al. In: Proceedings from the American Society of Hematology; December 9-12, 2017; Atlanta, GA [abstract 314].

Reprinted from Ross DM, et al. J Cancer Res Clin Oncol. 2018;144(5):945-954. Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

From Annals of Internal Medicine, Mahon FX, et al. 2018;168(7):461-470. Copyright © 2018 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

0 3228242016124 368

Months since dasatinib discontinuation

Mol

ecul

ar re

laps

e-fre

e su

rviv

al, %

100

80

60

40

0

20

Estimated survival95% confidence band

Patients at risk1515222731396184 544

12 mo: 49% (38.0%-59.4%)

Fast kinetics Slower kinetics

0 12 24 36 48 60 72 84 96 108 1200.0001

0.001

0.01

0.1

1

10

100

Time, months

BC

R-A

BL1

/AB

L1IS

, %

MMR

MR4.5

Stop TKIStart TKI

Restart TKI

0 12 24 36 48 60 72 84 96 1080.0001

0.001

0.01

0.1

1

10

100

BC

R-A

BL1

/AB

L1IS

, %

Time, months

Stop TKIStart TKI

MMR

MR4.5

Restart TKI

Undetectable BCR-ABL1with ≥ 32,000 copies of ABL1

MMR lossTreatment-free phase

MMRloss MMR

loss

Kinetics of relapse after TKI discontinuation

6

CML V: Preliminary TFR data

CML V: Molecualr remission rates

• 147 patients in TFR phase. 78% in TFR after 12 months

CML V: Preliminary TFR data

Hochhaus et al., ASH 2018

Prognostic Indicators of Sustained TFR in Clinical Studies

Factor category Factor Prognostic value

Patient Age, sex Only in one small study

Disease Prognostic scores at diagnosis Diverse results

Treatment history and response to therapy

Type of TKI No comparative study, likely no

Depth of deep molecular response (MR4, MR4.5 or even deeper) Intuitively yes, not proven in EURO-SKI

History of suboptimal response or resistance Yes, decreased TFR probabilities

TKI treatment duration Imatinib: Yes, best results if at least 5-6 yearsDasatinib or nilotinib: Not studied yet

Deep molecular response durationImatinib: Yes, best results if at least 3 years in MR4 Dasatinib or nilotinib: not studied yet

Mahon FX, et al. Lancet Oncol. Etienne G, et al. J Clin Oncol. Imagawa J, et al. Lancet Haematol, Rea D, et al, Blood 2017, Hochhaus A, et al. Leukemia. 2017, Saussele et al. Lancet Onc 2018.

Follow-up

RQ-PCR RQ-PCRevery 3rd month

Screening phase

(confirmationof MR4 in

central lab)

Stop TKIInformedconsent

Year 1 Year 2 Year 3

MR4

≥ 1 year

q4w q6w

≤ 6 weeks

Patients included between May 2012 and December 2014

EURO-SKI design

EURO-SKI ASH 2017

TKI treatment ≥ 3 years

Clinicaltrials.gov. identifier NCT01596114.

Primary endpoint: Molecular recurrence defined as BCR-ABL >0.1% (loss of MMR) at one time point.

Months MRFS (95% CI)6 months 61% (58% - 65%)12 months 55% (51% - 58%)18 months 52% (49% - 56%)24 months 50% (47% - 54%)36 months 47 % (43% - 51%)

EURO-SKI: Method for prognostic testing

Results at 6 months for all patients available

MR4 duration:Odds ratio: 1.13 (95%-CI 1.04-1.23)

MR4 duration, n = 405

6 years MR4 duration:Probability = 0.59(95%-CI: 0.54-0.64)4 years MR4 duration:

Probability = 0.53(95%-CI: 0.48-0.58)

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absolute increase of probability of about 3% / year

• Duration of treatment and of MR4 are highly correlated not allowing a multiple model including both parameters

• In order to investigate the influence the duration of MR4 before treatment stop from total TKI treatment duration was separated

• New variable: TKI treatment duration BEFORE MR4 achievement

TKI treatment and MR4 duration

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Patient 1

TKI treatment 7 years

TKI treatment duration BEFORE MR4

TKI treatment 7 years

Patient 2

MR4 duration: 5.0 years

MR4 duration: 3.0 years

TKI treatment BEFORE MR4

TKI treatment BEFORE MR4

TKI treatment duration BEFORE MR4: 2 years

TKI treatment duration BEFORE MR4: 4 years

TKI before MR4:Odds ratio: 1.04 (95%-CI: 0.93-1.15)

0.2 years duration:Probability = 0.54

10.2 years duration:Probability = 0.62

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TKI treatment duration before MR4

relative increase of probability to stay in MMR about 0.86% / year

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TFR results after failure history prior to stopping?

Réa D, et al. Blood. 2017;129(7):846-854.

STOP 2G-TKI Study: Results

DADI Trial: TFR after Discontinuation of Dasatinib

Imagawa J, et al. Lancet Haematol. 2015;2(12):e528-e535.

• Dasatinib second-line after imatinib

• Patients in MR4.0 for ≥1 year

• Dasatinib restarted at loss of MR4.0

ENESTop study: TFR after discontinuation of second-line nilotinib

1. Hughes TP, et al. ASH 2016 [abstract 792]. Mahon FX, et al. Ann Intern Med. 2018;168:461-470.From Annals of Internal Medicine, Mahon FX, et al. 2018;168(7):461-470. Copyright © 2018 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

2. 20

100

51:0 44:7 31:20 30:21 24:21 16:21 9:21 1:21

30:0 24:6 17:13 16:14 13:14 7:14 2:14 0:1444:0 38:6 28:16 28:16 24:17 13:17 3:17 0:17

0:21

12 24 36 48 60 72 84 96

20

10

0

50

40

30

60

80

70

90

0

Time Since TFR, weeks

IntoleranceResistancePhysician preferenceCensored observations

Pts Evt Cen513044

211417

301627

Patie

nts

with

out l

oss o

f MM

R or

conf

irmed

lo

ss o

f MR4 ,

%

At risk:Events

100

IntoleranceResistance

Physician preference

TKI Withdrawal Syndrome

• First described after imatinib discontinuation• Occurs also after tapered TKI doses prior to discontinuation

and after 2nd generation TKI discontinuation• Onset within 1 to 2 months after TKI discontinuation• Consists in new onset or worsening of osteo-articular pain,

usually mild to moderate, in about 30% of patients• Usually resolves spontaneously or upon analgesics

prescription within a few months• Unrelated to molecular response status• Exact mechanism unknown

Richter et al, 2014; Hochhaus et al, 2017, Ross et al, 2017; Shah et al, 2016

Musculoskeletal pain in TFR

a Reported for patients who remained in the TFR phase for > 96 weeks. Adverse events in the musculoskeletal pain grouping consisted of musculoskeletal pain, myalgia, arthralgia, bone pain, spinal pain, and/or pain in extremities.1. Saglio G, et al. Haematologica. 2018 [abstract PF368]. 2. Hughes TP, et al. Haematologica. 2018 [abstract PF377].

22

ENESTfreedom1

Patie

nts,

%

16.0

40.4

9.64.3

0

10

20

30

40

50

60

Consolidation First 48weeks of

TFR

Second 48weeks of

TFR

Third 48weeks of

TFR

Patie

nts,

%

ENESTop2

10.3

51.5

19.111.8

0

10

20

30

40

50

60

Consolidation First 48weeks of

TFR

Second 48weeks of

TFR

Third 48weeks of

TFR

Frequency of adverse events in the musculoskeletal pain grouping following cessation of first-line or second-line nilotiniba

WARNINGS!!!!

3 alerts:• One patient in A-STIM developed a BC after restarting TKI

and re-achievement of MMR; no exact data• One patient in ENESTFreedom developed a mutation

after restarting nilotinib; no follow-up after switch to other TKI

• One patient in stopping 2nd generation TKI developed sudden BC after during stopping; BCR-ABL level already increases to 0.4%, treatment restart was slightly postponed due to holidays.

Rea personal communication

Other important preconditions before stopping

institutional:• PCR according to international scale available• Make sure that PCR results are immediately available in your

center and communicated to patients

Patient characteristics:• Optimal 5 years (minimum 3!?) on TKI

and 3 (minimum 1!?) years in DMR• Typical transcript• No resistance, mutation, warning or failure history

Patient case

Where are we now with CML therapy?100 CML patients

10 Primaryresistance

10 Secondary Resistance

20-30 between0.01 and 1% BCR-ABL

50-60 In DMR(<0.01% BCR-ABL)

Urgent medical need2nd 3rd line TKIsSCT?

2nd 3rd line TKIsSCt? New agents? SCT?

Switch in order for TFR?

25-30Unsuccessful TFR

25-30Successful TFR

Second stop? Cure?

Increase possible, e.g. IFN? ENDURE

Only within trialsNAUTDasstop2

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Recruiting studies in Germany

TKI

ENDURE - CML-IXRandomized phase II Ropeg-IFN maintenance study

major inclusion/exclusion criteria• 3 x confirmed MR4 or better in

the last 13 months• > 3 years of TKI therapy (IFN

possible)• no prior TKI resistance• no allogenic stem cell

transplantation

R1:1

TKI0 1 2 3 4 5 6 7.5 9 10.5 12 13.5 1516 17 18 19 20 21 2224 36 48 60

100µg s.c. bi-weekly

0 1 2 3 4 5 6 7.5 9 10.5 12 13.5 15 17 19 21 24 36 48 60

d d d d d d d d dd

d d d d d d d d d

50µg

treatment: none, surveillance

surveillance

Arm: A

Arm: B

BCR-ABL monitoring

BCR-ABL monitoring

Start EOS

month:

month:

EOToff studyfollow up.months36, 48, 60

d

d

A. Burchert

AOP2014

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

RQPCRConfirming

MR4.5

Stop TKI

Year 1 Year 2+3

q4w q6w every 3rd month

≤ 2 weeks

Follow-up

within EURO-SKI

outside EURO-SKI but fulfilled EURO-SKI rules

outside EURO-SKI not fulfilling EURO-SKI rules

Patients with unsuccessful 1st discontinuation

stable MR4 for at least one yearand MR4.5 for at least 0.5 year

Informed consent

Nilotinib 600mg/d for at least 2 years

Any TKI for at least1 one years

Nilotinib treatment phase

Treatment –free remissionphase

Study start

NAUT - study design

Summary

• TFR can be a treatment goal for a substantial portion of patients with CML

• DMR duration seems to be the most critical parameter for successful TFR (EURO-SKI data)

• Careful selection of patients• Second stop only within trials recommended• Trials listed under CML-Allianz.de

– first stop: ENDURE– Second stop: NAUT, Endure, Dasstop– planned: Registry

• Future goal: to increase the number of patients in TFR

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Thank youCML-Excellenzzentrum

III. Medizinischen Klinik in Mannheim(Prof. Dr. W.-K. Hofmann)

Diagnostik und wissenschaftliches Labor Prof. Dr. Alice FabariusPD Dr. Birgit SpießPD Dr. Wolfgang SeifarthDr. Ute Kossak-RothDr. Nicole NaumannKatrin AckermannMelanie BauerHeike BraunElena FeldeNorbert GaluschekCarolin HöltingSusanne Keppler-GernerVanessa LeinsDiana RoseIrina Tarnapolskaja

Studienzentrale MCCDr. Janna KirchhoffDr. Katharina KohlbrennerDr. Catherine Sodan-BoyerSabine DeanNicole Kautz-VielleElke MatzatRegina Pleil-LöschInge StalljannHeike StammlerAstghik Voskanyan

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CooperationsAndreas HochhausMarkus PfirrmannFrancois-Xavier MahonNick CrossThomas ErnstJeroen JanssenJohan RichterHenrik Hjorth-HansenSatu MustjokiKaterina MachovaJuan Luis Steegman

Thank you

Panayiotis PanayiotidisDominik WolfAndreas BurchertTim BrümmendorfSimona SoveriniGianantonio RostiGuiseppe SaglioMichele BaccaraniJoelle GuilhotSusan BranfordTim Hughes