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Susanne SaußeleSeoul, 15.03.2019

Advances of CML treatment strategy and the prospect

729KR19PR00722-01/Mar2019

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： 홍길동 or Gildong Hong

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.

Survival with CML over timeThe German CML-Study Group experience

German CML Study Group, update 2016

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Surv

ival

pro

babi

lity

Years after diagnosis

n = 3682

Imatinib, 2002 – 2012 (CML IV)5-year survival 90%10-year survival 83%

IFN or SCT, 1997 – 2004 (CML IIIA) 5-year survival 71%10-year survival 61%

IFN or SCT, 1995 – 2001 (CML III)5-year survival 63%10-year survival 48%

IFN, ± HU, 1986 – 1994 5-year survival 53%10-year survival 27%

Hydroxyurea, 1983 – 1994, 5 yr surv. 44%, 10 yr surv. 18%

Busulfan, 1983 – 1994, 5-year survival 38%, 10-year survival 11%

(CML I, II)

(CML IV)

(CML IIIA)

(CML III)

German CML Study IV Relative and Overall Survival, n = 1551

Patients at risk: 1536 (Relative and Overall Survival) 1536 1261 522 218

Years After Diagnosis

Surv

ival

Pro

babi

lity

Relative survival, 10-year probability: 92%, 95%-CI: 89%; 95%

Observed survival, 10-year probability: 82%, 95%-CI: 80%; 84%

Reduced prognosis according to comorbidities (Charlson-Score)

CCI 5+, n = 80, 8-year survival: 48%CCI 4, n = 142, 8-year survival: 75%CCI 3, n= 182, 8-year survival: 82%CCI 2, n =1135, 8-year survival: 91%

Years after diagnosis

Prob

abili

ty o

f sur

viva

l

Saussele et al. Blood 2015

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CML IV: Impact of ACAs on PFS

Fabarius et al., Blood 2011 and Ann Hem 2015

Patients at risk

MR2 n = 1442MMR n = 1442MR4 n = 1358MR4.5 n = 1331MR5 n = 1208

CML IV: Molecular remission levels

Kalmanti et al., Leukemia 2015.

92%89%

81%

72%

59%

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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 need;2nd-3rd line TKIs;SCT

2nd-3rd line TKIs;SCT? New agents?

Switch in order for TFR?

25-30Unsuccessful TFR

25-30Successful TFR

Second stop? Cure?

Tyrosine kinase Inhibitors (TKIs) in CML

• Imatinib

• Dasatinib

• Nilotinib

• Bosutinib

• Ponatinib

New: Asciminib (ABL001)

TKI

Leukemic burden and remission status

1010

> 1012

106

108

Leukemic cells (logarithmic)

MMR (0,1 % BCR-ABL/ABL)MR4 (0,01 % BCR-ABL/ABL)MR4,5 (0,0032 % BCR-ABL/ABL)

Hematological remission

Cytogenetic remission

Moleculae remission

Not detectable

MR5 (0,001 % BCR-ABL/ABL)

Optimal Warning Failure

Baseline NA - HIGH RISK,- CCA/Ph+

(Major route)

NA

3 months Ph+ ≤35% and/orBCR-ABL ≤10%

Ph+ 36%-95% and/orBCR-ABL ≥10%

No CHR and/or Ph+ >95%

6 months Ph+ 0 and/orBCR-ABL <1%

Ph+ 1%-35% and/orBCR-ABL 1%-10%

Ph+ >35% and/orBCR-ABL >10%

12 months BCR-ABL ≤0.1% BCR-ABL 0.1%-1 % Ph+ ≥1% and/orBCR-ABL >1%

Any time BCR-ABL ≤0.1% CCA/Ph- (-7/7q) CCA/Ph+Confirmed loss of MMR

MUTATION

ELN 2013: Response to Treatment First-Line

Baccarani M, et al. Blood 2013

Switch!Wait & monitor closely!

Efficacy reduced by mutations

Nilotinib: fourmutation hotspots

Dasatinib: threemutation hotspots

Imatinib: >50 mutation hotspots

Thr315

Phe359

Glu255

Tyr253Val299

Thr315

Phe359

Glu255

Tyr253Gln252

Gly25o

Met351Glu355

Phe387His396

Phe382

Asp276

Glu459Phe486

Leu248

Phe317

Phe311

Val379

Val379Val289

Met244

Thr315

Phe317

Mutation hotspots

5 out of the 10 most frequent imatinib-resistant mutations confer resistance to at least one 2GTKI

BCR-ABL1 KD mutation frequency in CML failures and warnings

At diagnosis: only in pts who present in AP/BP

During therapy: in case of Failure and Warning (formerly Suboptimal

response) after having ruled out noncompliance or drug interactions

Conventional (Sanger) sequencing

Soverini et al, Blood. 2011;118(5):1208-15; Baccarani et al, Blood 2013;122(6):872-884

When and how to perform BCR-ABL KD mutation analysis

When and how to perform BCR-ABL KD mutation analysis

Soverini et al, Blood. 2011;118(5):1208-15

Therapy goal(s) for patients with CML in 2018

• Overall survival?

• Molecular remission? MMR or deeper?

• TFR (“treatment-free remission”)?

19MMR, major molecular response.

CML

Imatinib400-800 mg/Tag

Dasatinib100 mg/Tag

Nilotinib 2x300 mg/Tag

Hydroxyurea

Fertility assessment

or or or

BCR-ABL pos

Bosutinib400 mg/Tag

or

Treatment strategy 1st lineOnkopedia (German)

Individual decision

Efficacy

Vs.

Toxicity

By respecting

QoL

Nilotinib, Bosutinib and Dasatinib as First-Line Therapy vs Imatinib

PRO

• Induce faster and deeper MRs (MMR, MR4, MR4.5)

• Reduce the number of patients failing early molecular response (<10% BCR-ABL at 3 months)

• Reduce the risk of early progression and of CML-related death

CON

• Don't statistically improve OS

• Appear to be associated with more long-term toxicities

• Are much more expensive

Relative Toxicity of BCR-ABL-Inhibitors

Druker et al. N Engl J Med. 2006, Nicolini et al. Haematologica (EHA Meeting Abstracts) 2009; 94(s2): Abstract 0630; Shah et al. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 3225. Cortes et al. JCO. 2010; ASCO Ann. Meeting Proc. 28, 15S: 6502,Lipton et al., Lancet Oncology 2016

Severe side effectsImatinib Nilotinib Dasatinib Bosutinib Ponatinib

(Druker et al. 2006)

(Nicolini et al. 2009)

(Shah et al. 2008)

(Cortes et al. 2010)

(Lipton et al. 2016)

Myelosuppression ++ + +++ + +Edema ++ - +++ - -Diarrhea + + + +++ +Hepatic + ++ - +++ +++Glucose/Cholesterol elevation - ++ - - -Arterial thrombotic events - ++ - - +++

• Knowledge Of AE spectrum of different TKIs

• Prevention Comorbidities and co-medication

• Therapy of AEs According to recommendations

• Interactions– E-pocrates

– www.drugs.com

How to minimize side effects

„SCORE“:SystematicCOronaryRiskEvaluation Project

www.escardio.org

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AE-management – DASPERSE trial

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DASPERSE - results

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Treatment-free remission (TFR) in CML

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 patients have molecular recurrence 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].

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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%)

Dasfree: Kinetics of loss and reovery of MMR and MR4.5

TKI Withdrawal Syndrome

• First described after imatinib discontinuation• May also occur 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• Whether tapered TKI doses prior to discontinuation may

attenuate symptoms has not been studied

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].

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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

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.

Summary

• TKIs have substantially improved outcome in CML• 5 TKIs are available for CML treatment so far, efficacy vs. toxicity

taking in consideration QoL• ELN recommendations important for therapy guidance• TFR can be (should be?) a treatment goal for CML patients • DMR duration seems to be the most critical parameter for

successful TFR (EURO-SKI data)• 2nd stop attempts only within trials• 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. 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 DeanElke MatzatRegina Pleil-LöschInge StalljannAstghik Voskanyan

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CooperationsAndreas HochhausMarkus PfirrmannFrancois-Xavier MahonNick CrossThomas ErnstJeroen JanssenJohan RichterHenrik Hjorth-HansenSatu MustjokiKaterina MachovaPanayiotis PanayiotidisDominik WolfAndreas BurchertTim BrümmendorfDong-Wook Kim

Thank you