2012/1/9

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Debate:

CMR as a Therapeutic Goal in CML Patients

Pros台灣大學台成幹細胞治療中心台大醫院內科部血液科

Lin Chien-ting 林建廷Jan 7, 2012

CMR Means…

CMR

Fire lane from

disease progression

May offer “drug-free”

period, and even

chance of cure

Better RFS

Save money if off TKIs

Away from fear of

cancer and better QoL

Deepest response

at present

2012/1/9

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Cumulative Response and Survival

under Imatinib by ITT

Hugues de Lavallade et al. JCO July 10, 2008 vol. 26 no. 20 3358-3363

*EFS by IRIS definition: 81.3%@5yrs

**EFS= IRIS + no MCyR + intolerance

Who will have Who will have

late events?

>1 log reduction@3m predict better *OS

D. Marin et al, JCO 2011. 38:6565, November 7c-CCyRS: current complete cytogenetic response survival 4

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• 1 log reduction@3m

~ CHR@3m

• The first and the only

landmark can predict overall

survival in CML

>1 log reduction (<10%)@3m

predict better *OS

D. Marin et al, JCO 2011. 38:6565, November 7c-CCyRS: current complete cytogenetic response survival 6

What happened to What happened to

them?

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CCyR is Not Good Enough in PFS!

*PFS by landmark molecular response@12m in IRIS

IRIS trial7

Landmark @12m

MMR is Not Good Enough in PFS!

Richard D. Press et al. Clin Cancer Res, October 15, 2007 13; 6136

All achieved MMR at

*RFS by landmark MR@18m

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APL: 前車之鑑--養虎貽患

• RQ-PCR in maintenance stage

predicts relapse in APL

• Goal is “undetectable” PML-

RARα genes� means CMR

Maintenance stage

Carlos Santamaría et al. Haematologica 2007; 92:315-3229

Both 1st and 2nd TKIs can Achieve CMR

Imatinib

Best predictor for cumulative CMR (by

ROC method): ≦0.61%@3m

D. Marin et al, JCO 2011. 38:6565, November 7; Poster 785 (SPIRIT 2 trial)@ ASH 2011

Time from start of therapy (months)

Cumulative incidence of CMR4.5

BCR-ABL/ABL <0.57%, n=62

BCR-ABL/ABL >0.57%, n=66

Dasatinib (SPIRIT2 trial)

Best predictor of *cumulative CMR4.5

(by ROC method): ≦0.57%@3m

20% CML

pts@3m

20% CML

pts@3m48% CML

pts@3m

48% CML

pts@3m

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50

40

30

20

10

0

% with CMR4.5

0 3 6 9 12 15 18 21 24 27 30 33

Time Since Randomization, Months

Nilotinib 300 mg BID

Imatinib 400 mg QD

282

283

n

25%, P < .0001

9%

By 24 months

Larson et al. ASCO 2011; abstract #6511

Cumulative CMR4.5

(ENESTnd Trial)

Better Chance to CMR4.5 for 1st Line TKI

Better Chance to CMR for 2nd Line TKI

20.8%

10.0%

n = 101

n = 100% w

ith

CM

R

Months Since Randomization

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12

Nilotinib

ImatinibP = 0.03

Cumulative CMR with Nilotinib or Imatinib

for “No CMR under Imatinib≥2 yrs” (ENESTcmr Trial@12m)

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CMR Means…

CMR

Fire lane from

disease progression

May offer “drug-free”

period, and even

chance of cure

Better RFS

Save money if off TKIs

Away from fear of

cancer and better QoL

Deepest response

at present

1. Goh HG, et al. Leuk Lymphoma. 2009;50(6):944-951.

2. Koskenvesa P, et al. Blood. 2008;112(11):738 [abstract 2121].

3. Kuwabara A, et al. Blood. 2010;116(6):1014-1016.

4. Mahon FX, et al. Lancet Oncol. 2010;11:1029-1035.

Response at DiscontinuationMolecular and/or

Cytogenetic Relapse, %

CCyR1 100%

MMR2 100%

MMR, CCyR, MCyR3 100%

CMR for ≥ 2 years on imatinib4 60%

CMR is the Lottery to Discontinue TKIs

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Proof of Concept

Stop Imatinib after Durable CMR

STIM TrialMolecular relapse free survival

F. Mahon et al, Lancet Oncol 2010; 11: 1029–35

F. Mahon et al. (STIM) Poster 603 @ ASH 2011

Retreat imatinib:

• All sensitive

• 56/61 (92%) re-gain CMR

~41%@2yrs

~39%@3yrs

15

F. Mahon et al, Lancet Oncol 2010; 11: 1029–35

IFN *Gender

*Sokal score *Imatinib duration

51%,

35%,

12%

16

X

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No Ethnic DifferenceJapan KEIO STIM Trial

• 30 pts

• Relapse-free survival@6m: 46.8%

• TKI retreated pts remained sensitive

Eri Matsuki et al. (Japan) Poster 3765 @ ASH 201117

Discontinuation of Dasatinib or Nilotinib in CML:

French CML Group (FILMC)

D. Rea et al. (FILMC group) Poster 604 @ ASH 201118

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Can We eliminate Leukemic Stem Cells?

• Biphasic α(months),

β(years)

• Steeper β, better

survival

• Quiescent stem cells

are key point

Neil P. Shal et al. Clin Cancer Res November 1, 2011 17; 6605

ms yrs19

Normal Stem Cells

Stem

Cell

Apoptosis

Self-renewalQuiescence

Differentiation

20

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Leukemic Stem Cells

Stem

Cell

Apoptosis

Self-renewalQuiescence

Differentiation

FTY720– PP2A activator

(PP2A is tumor suppressor)

XBMS-214662

(cytotoxic farnesyl

transferase inhibitor)

X

21

BMSNovartis

Give it a Try to Make Plateau…

• After several years, trials data will be mature.

• “Can I stop TKI?”, patient may ask.

??

?

22

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Curative Intent Treatment– 633 Policy

Induction of CMR Consolidation of CMRHope sustained CMR, and

operational cure

2 yrs 2 yrs 2 yrs

Diagnosis Off TKI

More intensive TKI

Stem cell targeting

Immunotherapy

Combination

? ?

>1 log reduction@3m predict OS

23

Low risk: off TKI

Intermediate risk: off TKI?

High risk: go on TKI

?

CMR Means…

CMR

Fire lane from

disease progression

May offer “drug-free”

period, and even

chance of cure

Better RFS

Save money if off TKIs

Away from fear of

cancer and better QoL

Deepest response

at present

2012/1/9

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現在不會溺水,

但我寧可踩在乾地上

Imatinib Nilotinib Dasatinib

AE % (Any Gr)

Edema 36 9

Pleural effusion 0 10 (all mild)

Headache 10 14 12

Skin rash 17 31 11

Nausea 20 11 8

Vomiting 10 5 5

Myalgia 12 10 6

Lab abnormal% (Gr3-4)

Lipase↑ 0 6 0

LFT ↑ 1 4 <1

Bilirubin↑ 0 4 1

Sugar ↑ 0 6 0

Pregnancy D D D

26

Adverse events profile 略有不同,

但其實半斤八兩

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Feel Like Normal, and Better QoL

• At least, some pts can be “drug free” for years

– Better QoL

– Fell like normal

可以交男女朋友可以結婚可以不要避孕可以生小孩可以哺乳…

27

Fabio Efficace et al. Blood October 27 2011 vol. 118 no. 17 4554-4560

CMR Means…

CMR

Fire lane from

disease progression

May offer “drug-free”

period, and even

chance of cure

Better RFS

Save money if off TKIs

Away from fear of

cancer and better QoL

Deepest response

at present

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花錢? 還是省錢?

10% pts may be eligible for STIM trial

(By Mahon data)

x 40% sustained CMR after off TKIs

x每人年藥費

=省下 $$$$$$$$$$元

29F. Mahon et al, Lancet Oncol 2010; 11: 1029–35

每個陌生人都有等他回家的人

他….跟我們一樣….無價之寶

30

2012/1/9

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Conclusions

Think How to Move More People into CMR

• Not only a fire lane

– Better relapse free survival

• But also a gift

– May offer “drug-free” period, and even chance

of cure

– Away from fear of cancer and better QoL

• Save money if off TKIs

• Need your “big hands”!

CMR:

Midway of Cure

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