Stopping TKI treatment in CML: Who and when?

13th National CML Patient Forum, Newcastle

11th October 2014

Prof. Mhairi CoplandUniversity of Glasgow / Beatson West of Scotland

Cancer Centre

Questions

• I’ve had CML for a long time and I’m doing fine……..

– Could I stop treatment or take less?– What is the evidence for this?– What are MMR and MR4?– How is DESTINY different?– What will happen in the future?

STopping IMatinib (STIM)

•100 French patients in CMR for at least 2 years

•All were on imatinib for several years

•Some had had previous interferon

•Imatinib stopped, then monthly molecular testing (PCR)

STIM: Stopping imatinib in CMR/MR4

Mahon et al Lancet Oncology 2010

39%

STopping Imatinib (STIM)

•Imatinib resumed as soon as the PCR became positive

•All 61 relapses responded (56/61 back to CMR/MR4)

•No-one had a more serious deterioration in their CML

Ross D M et al. Blood 2013;122:515-522

©2013 by American Society of Hematology

Rate of TFR in all 40 patients.

TWISTER: Stopping imatinib in undetectable disease

TFR = treatment-free remission

STIM: Can we predict who relapses?

Mahon et al Lancet Oncology 2010

Rousselot P et al. JCO 2014;32:424-430©2014 by American Society of Clinical Oncology

61%

65%

29%

55%

43%

Loss of MMR as trigger for restarting TKI therapyLoss of MMR is a practical and safe criterion for restarting TKI therapy

If use STIM criteria……… and restart therapy when BCR-ABL become detectable

Rousselot P et al. JCO 2014;32:424-430

©2014 by American Society of Clinical Oncology

All patients achieve deep molecular responses after re-starting TKI…. But can take time

12 15 18 21 24

Time (months)

CCR

100

1

MMR0.1

CMR/MR4(level of detection)

0.01

30 36 42

BCR-

ABL

PCR

%

Does BCR-ABL need to be negative to stop therapy?

12 15 18 21 24

Time (months)

CCR

100

1

MMR0.1

CMR/MR4(level of detection)

0.01

30 36 42

BCR-

ABL

PCR

%

Does BCR-ABL need to be negative to stop therapy?

….we don’t know

De-Escalation and Stopping Treatment with Imatinib, Nilotinib or sprYcel = DESTINY

• CI – Richard Clark, Liverpool• 2 separate groups; MR4 and MMR; each treated the

same• 84 pts in each group

• 50% treatment dose: IM 200mg; NIL 200mg 2xday; DAS 50mg

• Monitor monthly for 12 months

• If PCR remains below 0.1%, then stop

De-escalate TKI (13 months)

Stop TKI

Check PCR monthly until month 25Check PCR alternate months in months 26-

37

MONTHS

DESTINY: key inclusion criteriaCML in first chronic phase only, aged 18 or over

Demonstration of BCR-ABL1 positivity at or shortly after original diagnosis

Must have received TKI treatment for at least 3 years

At least 3 molecular results over the preceding 12 months, that fit either of the following groups (results from any UK lab are acceptable):

(MR4 group) all the available BCR-ABL1 molecular results over the preceding 12 months are in MR4 (MR4 is defined as a BCR-ABL1/ABL1 ratio of zero, with at least 10,000 ABL1 control transcripts).

(MMR group) some or all BCR-ABL1 molecular results are in MMR (BCR-ABL1/ABL1 ratio of 0.1% or less, but not zero, with at least 10,000 ABL1 control transcripts).

If the results over the preceding 12 months are a mix of MMR and undetectable BCR-ABL1, then the patient is eligible for the MMR but not the MR4 group. 

 

DESTINY: key exclusion criteriaAny molecular result during the preceding 12 months that is not in either MMR or MR4.

Treatment with higher than standard TKI doses ('standard' is defined as imatinib 400mg daily, nilotinib 400mg twice daily or dasatinib 100mg daily), unless as part of a clinical trial of first line therapy, e.g. SPIRIT1.

Patients who switched previous licensed TKI treatment (imatinib, nilotinib or dasatinib) twice or more because of intolerance.

Patients who switched previous licensed TKI treatment (imatinib, nilotinib or dasatinib) because of resistance. Patients treated with lower than standard TKI doses (imatinib 400mg daily, nilotinib 400mg twice daily or dasatinib 100mg daily) for tolerance reasons may be included.

Previous treatment with ponatinib or bosutinib cannot enter. However, patients who received interferon prior to commencing TKI (even if resistant to their interferon) are eligible, provided their response to TKI fits the entry criteria. 

Stage 1

Compare first line intervention

Randomised

Stage 2

Identify partial responders

early

Switch

Stage 3

Identify ‘best’ responders later

Reduce/stop

Primary endpoint: MR3 (MMR) at 3 years

Secondary: sustained MR3

CMR on reduced dose/stop(no more bone marrows!)

EFS, PFS, OSHealth Economics, QoL

SPIRIT 3

RR

Imatinib Imatinib

NilotinibNilotinib

GroupI

GroupN

Imatinib Imatinib

PonatinibPonatinib

PonatinibPonatinib

NilotinibNilotinib

Stage 1Randomise(500 to each

group)

Stage 2Selective

switch(3 months or

later)

Stage 3Reduce dose,

stop(after minimum 3

years)

Primary endpoint

MR3 at 3 years

Imatinib Imatinib

PonatinibPonatinib

PonatinibPonatinib

NilotinibNilotinib

Aim

to re

duce

and

sto

p(if

MR3

for a

t lea

st 1

yea

r)Ai

m to

redu

ce a

nd s

top

(if M

R3 fo

r at l

east

1 y

ear)n=500

n=500

What do you think?