leucemia mieloide cronica - siematologia · leucemia mieloide cronica. bcr-abl loading in cml...

Dati sulla sospensione della

terapia

Gianantonio Rosti, Bologna

Leucemia Mieloide Cronica

BCR-ABL Loading in CML Patients

100%

10%

1%MR4

MR4.5

MMR

STIM study designN=100

STOPSustained CMR

for ≥ 2 years

Start Imatinib

CMR

Q- RT-PCR from peripheral blood

every month in the first year and

every 2 months thereafter

Five BCR–ABL analyses by

Q- RT-PCR during these 2

years

Sixth datapoint checked in

centralized laboratory

Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.

Molecular recurrence: positivity of

BCR–ABL transcript in Q-RT-PCR

confirmed by a second analysis point

indicating the increase of one log in

relation to the first analysis point, at

two successive assessments, or loss

of MMR at one point.

Treatment-free survival

At 60 months 40% ( 95% CI: 30-49)

Median follow up: 55 months (range 9-72)

Mahon, ASH 2013

Follow-up of the non-molecular relapse

patients (n= 39)

• Follow-up: mean 56, median 58 (9-72)

months

• 38 patients are still in CMR i.e., UMRD

(sensitivity > 4.5 log)

• 1 patient died in CMR after 9 months of

imatinib cessation due to myocardial

infarction

£ factors included when p<0.2 in univariate analysis# Acounting for competing risk

Univariate

analysis

P value

Multivariate analysis

(final model)

-

Gender£0.103 0.08

Sokal score£0.0076 0.0037

Interferon 0.2426 -

Time to CMR 0.2880 -

CMR duration 0.2345 -

IM duration£ 0.1357 0.1

Regression model# of molecular relapse at 24 months

STIM: Low Sokal Score and Previous Imatinib ≥ 5 y Are Prognostic For Reduced Relapse Risk

Mahon FX, et al. Blood 2011;118:abstract 603.

Multivariate analysis (Cox model)

Hazard ratio (95% CI) P value

Sokal score 2.555 (1.278 -5.119) 0.008

IM duration (≥ 5 y vs < 5 y) 0.582 (0.340 -0.995) 0.047

At 24 Months:

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al W

ith

ou

t M

ole

cu

lar

Re

lap

se

0 3 6 9 12 15

Sokal Low + IM > 5 y:

Others

68% (95%Cl: 45–83)

33% (95%Cl: 22–42)

18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Months Since Discontinuation of Imatinib

P = .007

Sustained CMR after stopping imatinib

according to duration of CMR before cessation

78% vs. 15%, P = .0002 by Log-rank testTakahashi N et al., Haematologica, 2012; 97:903-06.

Kumari A et al, Blood. 2012 Jan 12;119(2):530-9.

Stem cell persistence is associated with

low BCR-ABL expression

CFUApoptosis

Hypothetical Model of CML persistence and recurrence

versus extinction

Deininger, M. Nat. Rev. Clin. Oncol. advance online publication 1 February 2011;

doi:10.1038/nrclinonc.2011.17

The eradication of the leukemic clone may depend on inherent features of

the disease or on the duration of therapy, or both.

Treatment-free survival

At 60 months 40% ( 95% CI: 30-49)

Median follow up: 55 months (range 9-72)

Mahon, ASH 2013

Summary of treatment suspension trials

Study Therapy Duration of tx

Inclusion criteria and duration

N patients

Primary Endpoint Molecular Relapse Rate

STIM1 (IFN) IM >3 years Stable CMR> 2 years

100 Survival without loss of CMR

61% at 5 year

STIM22 IM >3 years Stable CMR >2 years


38.7% at 1 year

A-STIM3 IM >3 years Stable CMR>2 years

80 Survival without loss of MMR

39% at 3 years

STOP 2G-TKI4 2TKI: I or II line

>3 years Stable CMR >2 years


38.9% at 1 year

TWISTER5 (IFN) IM >3 years Stable CMR>2 years


52.9% at 2 years

EUROSKI IM, 2TKII or II line

>3 years Stable MR4.0>1 year


/

DASFREE DAS I or II line

> 2 years Stable MR4.5>1 year


/

ENEST Freedom

NIL >3 years Stable MR4.5 >1 year


/

ENESTop IMNILNIL

IM NIL >3 years

Stable MR4.5>1 year

117 Survival without loss of MR4.0

/

ENESTPath IMNIL IM 2 NIL 2 vs 3 y

Stable MR4.0 >1 vs 2 years


/

1.Mahon et al ASH 2013. 2.Mahon et al Blood (2013) abs #654 3.Rousselot et al J.Clin Oncol (2013) e-pub ahead of print. 4.Rea etal Blood (2012) abs #916 5.Ross et al Blood (2013) 122:515-522

Summary of treatment suspension trials

Study Therapy Duration of tx

Inclusion criteria and duration

N patients

Primary Endpoint Molecular Relapse Rate

STIM1 (IFN) IM >3 years Stable CMR> 2 years


61% at 5 year

STIM22 IM >3 years Stable CMR >2 years


38.7% at 1 year

A-STIM3 IM >3 years Stable CMR>2 years

80 Survival without lossof MMR

39% at 3 years

STOP 2G-TKI4 2TKI: I or II line

>3 years Stable CMR >2 years


38.9% at 1 year

TWISTER5 (IFN) IM >3 years Stable CMR>2 years


52.9% at 2 years

EUROSKI IM, 2TKII or II line

>3 years Stable MR4.0>1 year


/

DASFREE DAS I or II line

> 2 years Stable MR4.5>1 year


/

ENEST Freedom

NIL >3 years Stable MR4.5 >1 year


/

ENESTop IMNILNIL

IM NIL >3 years

Stable MR4.5>1 year

117 Survival without loss of MR4.0

/

ENESTPath IMNIL IM 2 NIL 2 vs 3 y

Stable MR4.0 >1 vs 2 years


/

1.Mahon et al ASH 2013. 2.Mahon et al Blood (2013) abs #654 3.Rousselot et al J.Clin Oncol (2013) e-pub ahead of print. 4.Rea etal Blood (2012) abs #916 5.Ross et al Blood (2013) 122:515-522

DR

BCR-ABL transcripts in patients

remaining in MMR

Patients in MMR without therapy

(median follow-up 17 months: 7-37)n=23

Always undetectable 7/23 (30.4%)

Occasionally detectable on 1 test 8/23 (34.8%)

Occasionally detectable on ≥ 2 consecutive tests 8/23 (34.8%)

STOP 2G-TKI

Rea, ASH2013

Patient characteristics A-STIM* STIM°

Patients, n 80 100

Gender, M/F ratio 0.52 0.6

Median age at diagnosis, y (range) 56 (27 – 78) 62 (29 – 80)

Sokal Score, %

Low risk 52 49

Intermediate risk 27 39

High risk 18 11

Previous therapy, n (%)

Interferon (or IFN/Ara-C) 43 (53.1) 34 (44.9)

Autologous HSCT 3 (3.7) 0

Median duration of imatinib, mo (range) 77 (30 – 145) 50 (36 – 90)

Median duration of CMR, mo (range) 40.1 (20 – 96) 35.5 (24 – 85)

Median follow-up after imatinib

discontinuation, mo (range) 22 (1 – 97) 34 (9 - 50)

Baseline characteristics

in A-STIM and STIM

Mahon FX et al., Lancet Oncol., 2010; 11:1029-35 & Blood 2011; 118 [abstract 603].Rousselot P et al. 2014 JCO

Months

Perc

en

t su

rviv

al

0 12 24 36 48 60 72 84 96 1080

20

40

60

80

100

Kaplan-Meier estimate of TFS defined as loss of

MMR and defined according to STIM criteria after

imatinib discontinuation in 81 CML patients.

37%

65%

P = 0.003

TFS= treatment free survivalRousselot P et al., JCO 2014

How many patients on imatinib achieve deep responses?

Branford et al, Blood 2013;121:3818

Years after commencing imatinib

Cum

ula

tive

Incid

en

ce

%

0

20

40

60

80

100

0 4 5 6 7 81 2 3

Confirmed undetectable MR4.5

52% (CI 43 - 60%)

n=423 patients

37%

Stable

2 years

Deep Molecular Response

Cumulative incidence of MR4.0 342/559 (61%)

Stable MR4.0 (> 18 mos; > 3 samples) 108/559 (19%)

Fluctuating MR4.0 in stable MMR 153/559 (27%)

Episodic MR4.0 (one sample only) 81/559 (14%)

METHODS:

- QPCR every 6 months

- MR4.0: ≤ 0.01% BCR-ABLIS or undetectable BCR-ABL transcript

with ≥10,000 ABL transcripts

GIMEMA CML WPCastagnetti on begalf of GIMEMA , ASH 2013

Factors associated with deep responses

Branford et al, Blood 2013;121:3818

– strongest independent predictor was the

3 month BCR-ABL1 value, P < .001

Years after commencing imatinib

4 5 6 7 81 2 3Cum

ula

tive

Incid

en

ce

%

0

20

40

60

80

100

0

MMR, 78%

>10%, 9%

>0.1-1.0%, 53%

>1-10%, 29%

Stable undetectable MR4.5 for 2 years

n=423

Susan Branford, GOLS 2014

Proportion of Patients With MR4.5

by BCR-ABL Levels at 3 Months

58%

28%

4%

P = .0001

P = .0135

70%

52%

8%

P = .0046

P = .0001

MR4.5 by 4 Yearsa

MR4.5 by 5 YearsaBCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Pts

144

89

24

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6

Pa

tie

nts

With M

R4

.5,

%

Time Since Randomization, Calendar Years

MR4.5 by 4 Yearsa

MR4.5 by 5 Yearsa

65%

24%

5%

P < .0001

P =

.0001

67%

34%

15%

P = .0001

P = .0016

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Pts

43

133

88

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6P

atie

nts

With M

R4

.5,

%


a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

BCR-ABLIS ≤ 1%:

16% of ptsBCR-ABLIS ≤ 1%:

56% of pts

Nilotinib 300 mg BID Imatinib 400 mg QD

Patients with BCR-ABL ≤ 1% at 3 months have significantly higher rates

of MR4.5 by 5 years

More patients achieve BCR-ABL ≤ 1% at 3 months on nilotinib 300 mg

BID vs imatinib

20 Saglio G, et al. Blood. 2013:[abstract 92].

Cumulative Rate of MR4 and MR4.5

% W

ith

MR

4.5

Months

P=0.030

0 12 24 36 48 60

Dasatinib 100 mg QD Imatinib 400 mg QD

MR4 = BCR-ABL (IS) ≤0.01%;

MR4.5 = BCR-ABL (IS) ≤0.0032%;

IS = International Scale.

0

20

10

30

40

50

60

3%

2%

18%

9%

23%

12%

34%

21%

37%

30%

% W

ith

MR

4

Months

P=0.0021

0

20

10

30

40

50

60

12%

5%

28%

17%

35%

22%

47%

35%

0 12 24 36 48 60

53%

42%

MR4 MR4.5

• Treatment discontinuation is a real opportunity:

No exposure to long term toxicities

Better QOL

Reduced costs of treatment

• “CMR” is the absolute prerequisite

• Second generation TKIs allow to a much higher rate of “CMR”

We do not know something relevant:

• Why the duration of TFR is so different?

• Which mechanisms contribute to a sustained TFR?

• TFR rates in a head-to-head comparison of IMA vs 2^ Gen TKIs

• 2^ Gen TKIs: same (long) duration of tx as for ima to allow a long TFR?

• What about the impact of the risk (Sokal/Euro) on TFR duration?

• The added value of IFN or drugs active against leukemic SCs under.

We know that:

Dati sulla sospensione della

terapia

Gianantonio Rosti, Bologna

Leucemia Mieloide CronicaGrazie per l’attenzione

1. Milojkovic D, et al. Blood. 2011;118(21): abstract 605. 2. Goh HG, et al. Leuk ymphoma. 2009;50(6):944-951.3. Koskenvesa P, et al. Blood.

2008;112(11):738 [abstract 2121]. 4. Kuwabara A, et al. Blood. 2010;116(6):1014-1016. 5. Mahon FX, et al. Blood. 2011;118(21): [abstract 603] 6. Rousselot

P, et al. Blood. 2011;118(21): abstract 3781. 7. Goh H-G, et al. Blood. 2011;118(21): abstract 2763. 8. Matsuki E, et al. Blood. 2011;118(21): abstract 3765.

Response at Time of Treatment

Discontinuation

Patients With Molecular and/or

Cytogenetic Relapse, %

CCyR2 100%

MMR3 100%

MMR, CCyR, MCyR4 100%

CMR for ≥ 2 years on imatinib5-8 ~30%-65%

CCyR, complete cytogenetic response; CMR, complete molecular response;

MCyR, major cytogenetic response; MMR, major molecular response.

Defining Molecular Response Requirements

for Potential Treatment Discontinuation

ENESTnd 5-Year Update

Data cutoff: May 22, 2013

BCR-ABL Categories at 3 Months*

0

20

40

60

80

100

Pati

en

ts, %

BCR-ABL Level at 3 Months

n 176 234 88 24

BCR-ABL >10%

91

67

9

33>1- ≤10%

≤1%

Nilotinib 300 mg BID (n=258)

Imatinib (n=264)

Reasons for unevaluable samples included:

• Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib

• Missing samples: 4 patients on nilotinib, 5 patients on imatinib

• Discontinuation: 15 patients (including 1 progression) on nilotinib, 12 patients (including 1 progression) on

imatinib

*Calculated from total number of evaluable patients with PCR assessments at 3 months.

BCR-ABL ≤10%

>1- ≤10%

≤1%


Characteristics of patients included in the STIM Study

A prospective, multicentre, non-randomized study with 19

participating institutions in France:

•100 patients enrolled between July 2007 and Dec 2009

•Median age (range): 63 years (29–80)

•Gender distribution: 48 males, 52 females

•Patients with previous IFN treatment: 51

•De novo CML patients: 49

•Median follow up: 55 months (range 9-72)

Frequent and sustained drug-free remission in the

Australasian CML8 trial of Imatinib withdrawal

Median follow-up of 42 months (range 15 – 72 months)

Ross DM et al. Blood. 2013 Jul 25;122(4):515-22.

CML-IV: Survival by Confirmed Response at 4 Years

Achievement of confirmed MR4.5 at 4 years predicted significantly

higher survival probabilities at 8 years vs 0.1% to 1% BCR-ABLIS

(92% vs 83%; P = .047)

Hehlmann R, et al., JCO, 2014;32(5):415-423.

0 1

1.0

0.8

0.6

0.2

0

Su

rviv

al

Pro

bab

ilit

y

Time Since Diagnosis, Years

2 3 5 6 7 8

0.4

4

No. at risk

< 0.0032%

8-year survival

9

0.0032%-0.01%

0.01%-0.1%

0.1%-1%

> 1%

198

191

260

55

44

163

149

206

41

32

69

69

106

24

16

40

41

67

17

8

< 0.0032%0.0032% -0.01%0.01%-0.1%0.1%-1%

All patients with primary imatinib (n = 1,194)

4-year survival, 93%

8-year

survival (%)

> 1%

BCR-ABLIS

92

90

88

83

78

NSNSNS

P

.047

.001

MR4.5 at 4 years

No MMR at 4 years

MR4.5 vs no MMR

92% vs 83%, P < .047

Disease burden and cytogenetic response

1012

1011

1010

109

108

107

106

(Complete molecular response)

• Undetectable BCR-ABL mRNA transcript by real-time

quantitative and/or nested PCR in 2 consecutive blood

samples of adequate quality (sensitivity > 104)*

ELN recommendations(optimal response)

CHR 3 months

CCyR 12 months

MMR 18 months

CMR

Number of Leukemic Cells

Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051

Radich JP. Blood. 2009;114:3376-3381

Overall survival

Stable responseNo risk of progression

STOP 2G-GKI experience

2nd generation TKI discontinuation

Rea et al. Blood (ASH) 2012; 120: Abstract 916

0

20

40

60

80

100

0 6 12 18 24 30 36 42

Surv

ival

wit

ho

ut

MM

R lo

ss %

Months since 2G-TKI discontinuation

95% CI: 45.6-76.6)61.1%

Survival without MMR loss at 12 months

• As of November 30, 2012, 39 patients with a minimum follow-up of 6 months

(median 17 months, range: 7-38) were analyzed

– 16/39 patients lost MMR

– Median time to MMR loss was 3 months (1-25)



PFS (AP/BC or Death) on Study

by BCR-ABL Levels at 3 Months

Nilotinib 300 mg BID Imatinib 400 mg QD

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Censored

Observations

Pts Evt Cen

145 7 138

89 4 85

24 6 18

P = .9814

P = .0010

PFS by 5 Yearsa

94.6%95.3%

78.3%

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Pa

tie

nts

Witho

ut P

rog

ressio

n, %


100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Pa

tie

nts

Witho

ut P

rog

ressio

n, %


PFS by 5 Yearsa

P = .2338P < .0001

98.5%95.3%

80.1%

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Censored

Observations

Pts Evt Cen

43 2 41

133 2 131

88 16 72

EMR Failure EMR Failure

Cen, censored; EMR, early molecular response; Evt, events; Pts, patients.a PFS rates reported consider each year to consist of twelve 28-day cycles.

Patients with EMR failure (BCR-ABL > 10% at 3 months) have

significantly worse 5-year PFS

Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib


NK CELL COUNTS AT THE TIME

OF IMATINIB DISCONTINUATIONNK cells

No relapse Relapse0

200

400

600

800

CD

3- /C

D5

6+/m

m3

p=0.0135

NK cells CD56dim

No relapse Relapse0

200

400

600

800

CD

3- /C

D5

6dim

/mm

3

p=0.011

NK cells CD56bright

No relapse Relapse0

10

20

30

40

CD

3- /C

D56

bright /m

m3

p=0.366

All No relapse Relapse

Median CD3-CD56+/mm3 (range) 174 (67-727) 233 (70-727) 145 (67-450)

Median CD3-CD56dim/mm3 (range) 162 (55-723) 216 (55-723) 139 (58-438)

Median CD3-CD56bright/mm3 (range) 7 (2-31) 7 (2-30) 8 (2-31)

Delphine Rea et al for STIM Investigators, ASH 2013 (abs 856)



Cumulative Incidence of MMR

MMR, major molecular response (BCR-ABLIS ≤ 0.1%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

By 1 Yeara By 5 Yearsa

55%, P < .0001

51%, P < .0001

27%

Δ 24% to 28%

60%

77%, P < .0001

77%, P < .0001

Δ 17%

By 4 Yearsa

76%, P < .0001

73%, P < .0001

56%

Δ 17% to 20%

100

0 2 6

90

80

70

60

50

40

30

20

10

0

Pati

en

ts W

ith

MM

R,

%


31

Nilotinib 300 mg BID (n = 282)


Imatinib 400 mg QD (n = 283)

4 5




Cumulative Incidence of MR4.5

MR4.5, molecular response ≥ 4.5-logs (BCR-ABLIS ≤ 0.0032%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

By 5 Yearsa

11%, P < .0001

7%, P < .0001

1%

Δ 6% to 10%

31%

52%, P < .0001

54%, P < .0001

Δ 21% to 23%

By 4 Yearsa

40%, P < .0001

37%, P = .0002

23%

Δ 14% to 17%

100

0 2 6

90

80

70

60

50

40

30

20

10

0

Pati

en

ts W

ith

MR

4.5

, %


31




4 5

By 1 Yeara




12

17

233

5

0

5

10

15

20

25

Including Clonal Evolution

Pati

en

ts, n

Progression to AP/BC on Core Treatmenta

a Includes progression to AP/BC or deaths in patients with advanced CML occurring on core treatment.

P = .0059

P = .0185

P = .0009

P = .0085

4.2% 0.7% 1.1% 6.0% 1.1% 1.8%

Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281)

No new progressions on core treatment (excluding or including clonal evolution) in year 5



Disease burden and cytogenetic response

1012

1011

1010

109

108

107

106

(Complete molecular response)

• Undetectable BCR-ABL mRNA transcript by real-time

quantitative and/or nested PCR in 2 consecutive blood

samples of adequate quality (sensitivity > 104)*

ELN recommendations(optimal response)

CHR 3 months

CCyR 12 months

MMR 18 months

CMR

Number of Leukemic Cells

Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051

Radich JP. Blood. 2009;114:3376-3381

Overall survival

Stable responseNo risk of progression

Possibility to discontinue

therapy


Achievement According to 6 Month Response

Muller MC, et al. Blood. 2013: 122(21): [abstract 4008].

1.0

0 3 41

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Cu

mu

lati

ve i

ncid

en

ce

of

MR

5

Years after diagnosis

52 6 7 8

< 0.1%IS at 4.5 to 7.5 months, n = 255

0.1%-1%IS at 4.5 to 7.5 months, n = 254

1%-10%IS at 4.5 to 7.5 months, n = 211

> 10%IS at 4.5 to 7.5 months, n=107

6 mo

MMR

at 6 mo

No MMR

at 6 mo

RANDOMIZE

Imatinib continue same dose (n = 103)


4-year study

BID, twice daily; CCyR, complete cytogenetic response; MMR, major molecular response; RQ-PCR,

real-time quantitative polymerase chain reaction.

Patients

treated with

imatinib for ≥ 2

years who

achieved CCyR

but have

detectable

BCR-ABLa

(N = 207)

a By RQ-PCR with sensitivity of ≥ 4.5 logs.

Crossover from imatinib to nilotinib for:• Detectable BCR-ABLa at year 2• Treatment failure, confirmed loss of

response

Year 2

Study Schema

The kinetics of molecular relapse

0,001

0,01

0,1

1

10

BCR-ABL / ABL(%)

CyclicNo imatinib

0,001

0,01

0,1

1

10BCR-ABL/ABL (%)

FluctuatingNo imatinib re-treated

0,001

0,01

0,1

1

10

BCR-ABL / ABL(%)

1

3

2Logarithmic

Mahon ASH 2009


in Patients Without MR4.5 at Baseline (ITT analysis)

ITT, intention-to-treat.

Pa

tie

nts

Wit

h M

R4.5

, % P = .0006

By 12 Months By 24 Months

Δ 14%

By 36 Months

Δ 19%

P = .0020

Δ 22%

Nilotinib Imatinib

Crossover to nilotinib

33%

P = .0453

• In a subgroup analysis when only responses up to crossover were counted, 47% versus

24% of patients in the nilotinib and imatinib arms, respectively, achieved MR4.5 (P = .0003)

ENESTcmr 3-year follow-up

Leber B, et al. Blood. 2013;122(21):[abstract 94].

98 989896 9696n

Follow-up of the molecular-relapse patients (n=61)

Among the 57 patients alive another attempt of TKI discontinuation was

proposed for 16 patients in sustained CMR

Patients Treatment in

progress

Molecular response

Sustained treatment 40 27 Imatinib

8 Nilotinib

5 Dasatinib

31 CMR

9 MMR

2nd Stop without molecular

relapse9 NA 7 CMR

2 MMR

2nd Stop with molecular relapse 7 5 Imatinib

1 Nilotinib

1 Dasatinib

3 CMR

1MMR

No response*

3rd Stop 1 NA 1 CMR

No treatment 1 NA 1 CMR

Deaths 4 stroke,

mesothelioma,

gastric carcinoma,

elderly woman

general deterioration

Strategies to Try to Silence / Eradicate

Ph+ Stem Cells

- Ph+ stem cell eradiction may occur

spontaneously after TKI therapy in some cases

(how many?)

- It may be “stimulated” by immunomodulatory

agents like IFN

- We may try to force it:

- Through vaccination processes

- Adoptive immunotherapy with antibodies directed

against Ph+ Stem cells antigens (IL1R*)

- Drugs affecting stem cell activated pathways

*Fioretos et al. Blood (ASH) 2010.

+ imatinib

CD

34-P

E

CFSE

- imatinib

CML Stem Cells are Resistant to Imatinib: Experimental Approaches

Imatinib/GF insensitive CML stem cells

Graham. Blood 2002;99(1):319-25 (modified)

Reversible G1 arrest –anti-proliferative effect“accumulation”

10mM 10x IC50+/- GFs

Recruitment out of niche/into cycle:+ IFN-alpha+ Plerixafor +/- G-CSF+ PLGF-Inhibitor....

Targeting of quiescent LSC:+ JAK2 Inhibitors.+ IFN-alpha+ Vaccination+ Autophagy inhibitors+ earlier acting TKIs

Clonal exhaustion:Telomerase inhibitors

JAK2-Mediated Extrinsic Survival of CML Stem Cells

Stromal cells protect CML stem/progenitors cells by producing cytokines which

activate JAK2 pathway: rational for combining Bcr-Abl and JAK2 inhibitor

Traer E, Mackenzie R, Snead J et al. Blood 2010; 116: abstract 199

leucemia mieloide cronica - siematologia · leucemia mieloide cronica. bcr-abl loading in cml...

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