When to stop TKI in CMLWhen to stop TKI in CML

Three situationsThree situations

Three situationsThree situations When they don’t workWhen they don’t work When they are too toxicWhen they are too toxic When they appear to have affected a cureWhen they appear to have affected a cure

Three situationsThree situations When they don’t workWhen they don’t work When they are too toxicWhen they are too toxic When they appear to have affected a cureWhen they appear to have affected a cure

CML is cured by alloSCT by eradication CML is cured by alloSCT by eradication CML clones via the GVL effect……right?CML clones via the GVL effect……right?

Gratwohl Haem 2006 91:513; Sekhri Leuk Res 2009 33:1291.

Latest reported relapse at 24 years post-allograft

CureCure

Absence of disease-related symptoms Absence of disease-related symptoms and signsand signs

Freedom from progressionFreedom from progression

No need for treatmentNo need for treatment

PermanentPermanent

CMRCMR

Complete Molecular ResponseComplete Molecular Response No detectable BCR-ABL mRNANo detectable BCR-ABL mRNA RQ-PCR method with sensitivity RQ-PCR method with sensitivity ≥4.5-log≥4.5-log Confirmed on two consecutive measurementsConfirmed on two consecutive measurements

Undetectable MRD (UMRD)Undetectable MRD (UMRD) Molecular Undetectable Leukaemia (MUL)Molecular Undetectable Leukaemia (MUL) Treatment free remissionTreatment free remission

Branford Clin Cancer Res 2007 13:7080

CHR

CCR

CMR

MR4.5

Estimated <106 residual leukaemic cells

Less is betterLess is better

Mutations occur stochastically – fewer Mutations occur stochastically – fewer cells means fewer opportunitiescells means fewer opportunities

CML LSCs have increased ROS and CML LSCs have increased ROS and increased mutation rateincreased mutation rate

Imatinib does not correct ROS-induced Imatinib does not correct ROS-induced mutagenesis in the most primitive CML mutagenesis in the most primitive CML cells (mouse model)cells (mouse model)

Bolton-Gillespie Blood 2013 121:4175

AllograftingAllografting

Achievement of UMRD required for EFSAchievement of UMRD required for EFS Relapse risk: UMRD 5%Relapse risk: UMRD 5% detectable MRD 70%detectable MRD 70%

Rate of unstable UMRD is lower than in Rate of unstable UMRD is lower than in imatinib-treated patientsimatinib-treated patients

BCR-ABL DNA not detected in 8/9 BCR-ABL DNA not detected in 8/9 patients in long-term remissionpatients in long-term remission

Radich Blood 1995 85:2632; Mughal BJH 2001 115:569; Lange Leukemia 2005 19:1262; Simoes Blood 2010 116:1329

Ross & Melo ASHEP 2011.

Biology of TFRBiology of TFR

Possible models Possible models for MRDfor MRD

Stopping ImatinibStopping Imatinib

All reported cases of cessation in CCR or All reported cases of cessation in CCR or MMR led to relapse MMR led to relapse Doubling time Doubling time ~~10 days10 days

First reported TFR cases had UMRDFirst reported TFR cases had UMRD

Mahon Blood 2007 109:58; Branford Blood 2012 119:4264

ALLG CML8 studyALLG CML8 studyclinical outlineclinical outline

Clinical trial of withdrawing imatinib from chronic Clinical trial of withdrawing imatinib from chronic phase CML patients with sustained undetectable phase CML patients with sustained undetectable BCR-ABL by RQ-PCR for at least two yearsBCR-ABL by RQ-PCR for at least two years

Close RQ-PCR monitoring for two yearsClose RQ-PCR monitoring for two years

Completed accrual of 40 patients: Completed accrual of 40 patients:

21 patients received IFN before imatinib21 patients received IFN before imatinib

19 patients received imatinib in early CP19 patients received imatinib in early CP

Ross Blood 2013 122:515.

RelapseRelapse

Defined as:Defined as: Loss of MMR (BCR-ABLLoss of MMR (BCR-ABL ISIS >0.1%) >0.1%)

• OROR Any two consecutive positive resultsAny two consecutive positive results

Imatinib re-commenced at previous doseImatinib re-commenced at previous dose

Patients (n=40)Patients (n=40)

Male sex 48%Male sex 48% Median age 61 yearsMedian age 61 years

Median interval (months)Median interval (months) Imatinib prior to study entryImatinib prior to study entry 70 (44-108)70 (44-108) Time to UMRDTime to UMRD 32 (3-73)32 (3-73) UMRD prior to study entryUMRD prior to study entry 36 (24-82)36 (24-82) Follow-upFollow-up 40 (12-72)40 (12-72)

CML8 TFRCML8 TFR

Ross Blood 2013 122:515.

Patient-specific DNA PCRPatient-specific DNA PCRBCR ABL

Years in treatment-free remission

Ross Blood 2013 122:515.

P<0.001P<0.001

10

0.1

0.001

1

0.01

BCR-ABL

DN

A%

Not detected

0.0001

UMRD at study entry

Molecular relapse

UMRD after retreatment

NS

Ross Blood 2013 122:515.

A-STIMA-STIM

Single case of lymphoid blast crisis developing abruptly after regaining UMRD

Started imatinib 10 years after original diagnosis

Rousselot JCO 2014 32:424.

Interferon-Interferon-αα

Mahon JCO 2001 20:214

Stopping of 2G TKIStopping of 2G TKI ENESTopENESTop

MR4.5 after second-line nilotinibMR4.5 after second-line nilotinib One year nilotinib ‘consolidation’ then stop if MRD One year nilotinib ‘consolidation’ then stop if MRD

criteria metcriteria met

ENESTfreedomENESTfreedom MR4.5 after first-line nilotinib (ENESTnd)MR4.5 after first-line nilotinib (ENESTnd) Similar designSimilar design

EuroSKI registryEuroSKI registry

Question #1Question #1

What MRD threshold is good enough to What MRD threshold is good enough to achieve TFR?achieve TFR? UMRD is arbitrary and varies from test to testUMRD is arbitrary and varies from test to test MR4.5 being tested in prospective trialsMR4.5 being tested in prospective trials Probably also depends on Probably also depends on speed speed and and durationduration of of

MRMR

Question #2Question #2

What is the latest that relapse can occur?What is the latest that relapse can occur? How should we monitor patients in TFR?How should we monitor patients in TFR? Latest reported relapse from TFR at 42 monthsLatest reported relapse from TFR at 42 months Latest reported loss of MMR (A-STIM) at 17 Latest reported loss of MMR (A-STIM) at 17

monthsmonths

Question #3Question #3

Why do some people with stable UMRD Why do some people with stable UMRD relapse early while others remain in TFR?relapse early while others remain in TFR? Pre-determined by disease biology?Pre-determined by disease biology? Immune control?Immune control? Persistence of differing subclones or cell types?Persistence of differing subclones or cell types?

ConclusionsConclusions

Some patients appear to be ‘cured’ with Some patients appear to be ‘cured’ with follow-up of >5 years after stopping imatinibfollow-up of >5 years after stopping imatinib

TFR after imatinib is often (or always) TFR after imatinib is often (or always) associated with detectable MRD by highly associated with detectable MRD by highly sensitive BCR-ABL DNA PCRsensitive BCR-ABL DNA PCR

Thank you.Thank you.

Imatinib is still a great drugIRIS and many, many, many

ASH updates

3 year Dasision data Jabbour; Blood 2014

Ischemic heart Ischemic heart diseasedisease

Ischemic Ischemic cerebrovascular cerebrovascular

eventsevents

Peripheral Peripheral arterial arterial diseasedisease

2020

1818

1010

22

00

1616

88

66

44

1414

1212

Nu

mb

er

of p

atie

nts

Nu

mb

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of p

atie

nts

Cardiovascular events (CVE) by 36 months (safety population)Cardiovascular events (CVE) by 36 months (safety population)

Any CVEAny CVE

NilotinibNilotinibMedian exposure, 3.0 yMedian exposure, 3.0 y

Imatinib Imatinib Median exposure on study, Median exposure on study, 2.2 y2.2 y

Crossover to Nilotinib Median Crossover to Nilotinib Median exposure, 1.0 y exposure, 1.0 y

1212

22 22

77

44

001111 11

0 0 11

33

1515

More cases of CVEs were reported in patients More cases of CVEs were reported in patients randomized to nilotinib compared with imatinibrandomized to nilotinib compared with imatinib

What if you do wait until 6 months?

6 month landmark analysis

37 85

3-Month EvaluationRecommended assessments

Level of response achieved

Follow-up assessments

Treatment options

Ongoing monitoring

Ongoing management

Cytogenetics if RQ-PCR using the IS is not available

BCR-ABLIS ≤ 10% or PCyR BCR-ABLIS > 10% or < PCyR

Continue same dose of TKI

Evaluate patient compliance and drug-drug interactions

RQ-PCR every 3 months RQ-PCR at least every 3 months

Switch to alternate TKI (other than imatinib)

OR Continue same dose/dose-escalatea

Continue ongoing monitoring until

12-month evaluation

Proceed according to recommendations for patients with

BCR-ABLIS > 10% or < PCyR at 3 months

RelapseNo relapseEvent

RQ-PCR using the IS

OR Clinical trial

Additional monitoring or mutational

analysis as indicated

Mutational analysis

NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 1.2014.

a Increase dose of imatinib if not candidate for alternate TKI or continue same dose of nilotinib or dasatinib (for patients on first-line nilotinib or dasatinib).

AND Evaluate for HSCT

OPTIMAL WARNING FAILURE

BASELINE NA -HIGH RISK,-CCA/Ph+ (Major route)

NA

3 mo Ph+ ≤ 35% and/orBCR-ABL ≤ 10%

Ph + 36-95% and/orBCR-ABL ≥ 10%

No CHR and/or Ph + > 95%

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

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

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

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

24 mo BCR-ABL ≤ 0.1% BCR-ABL 0.1-1% BCR-ABL > 1%

EUROPEAN LEUKEMIANET 2013RESPONSE TO TREATMENT FIRSTLINE

Baccarani M et al, Blood. 2013 Jun 26. [Epub ahead of print].Yellow = cytogenetic response

00

halving time > 90 days, n=58 (64%)halving time > 90 days, n=58 (64%)halving time ≤ 90 days, n=33 (36%)halving time ≤ 90 days, n=33 (36%)

P P < .0001< .0001

1001009090

5050

101000

66 1212 1818 242433 99 1515 2121

8080

404030302020

70706060

Confirmed undetectable BCR-ABL by 2 years Confirmed undetectable BCR-ABL by 2 years – dynamics of response– dynamics of response

48%

5%

Months after switch to nilotinib Months after switch to nilotinib

91 evaluable patients91 evaluable patients

Cum

ula

tive

inci

den

ce %

Cum

ula

tive

inci

den

ce %

2020For distribution in response to an unsolicited request for medical information pending local NP4 approval.