Discontinuación de tratamiento, a quién y cuándo

(1)

Discontinuación de tratamiento, a quién y

cuándo

Juan Luis Steegmann

Hospital de la Princesa

Madrid

Jlsteegmann.hlpr@salud.madrid.org

In 2010, the French Group reported the results of the STIM trial

with 2 year follow-up. They have now patients with 9 years

Etienne, G.

DOI: 10.1200/JCO.2016.68.2914

MRFS

43% by 0,5 y

38% by 2y

38% by 7 y

(2)

Choice in first line. GELMC opinion in 2014

Imatinib 400 mg al día

sería el tratamiento de elección si el

objetivo es la

supervivencia

global o la supervivencia libre de

transformación,dado que existen más datos sobre su perfil de

seguridad

a largo plazo.

Si el objetivo del tratamiento es conseguir

RMC

(RM

4 _{o RM}

4,5

_),

para

una eventual suspensión

del tratamiento, los tratamientos

indicados serían

nilotinib o dasatinib

.

Steegmann, J.L. and L.F. Casado,

Tratamiento de primera línea de la leucemia mieloide crónica

en fase crónica, in Manual para el control y el tratamiento de los pacientes con leucemia

mieloide crónica,

J.L. Steegmann, M.T. Gomez-Casares, and M. Perez-Encinas, Editors. 2014, Euromedice: Badalona ( Spain). p. 43-56.

Eso hizo que ELN 2013 considerase una opción fuera

de ensayos clínicos, aunque con reservas

Treatment discontinuation may be considered in individual

patients, also outside studies, if proper, high-quality, and

certified monitoring can be ensured at monthly intervals.

(3)

Sin embargo

Atención

Seguimiento de los otros ensayos de DC es corto

Las recaídas muy tardías son posibles en el TPH

La toxicidad de imatinib a largo plazo no se vislumbra

peligrosa.

La presión económica es menor con el Imatinib

genérico.

La mayoría de los estudios requerían una duración de ITK de 3

años, estar en RM4.5 , y que hubiese durado 2 años

TKI*

TKI years CMR

QUALITY

CMR

Duration

Confirmed

Times

Confirmed

Central

STIM

1 _I

_{Und. (MR5)}

_y

_{5 cons}

_{Yes (4.7)}

TWISTER

2 _I

_Und.(MR4.5)

_y

_-

_{Yes (4.5)}

A-STIM

3 _I

_Und.

_y

_No

KIDS

4 _I

_Und

_y

₆

_Yes

ISAV

5 _I

₂

_MR4

_y

₃

STOP 2GTKI

6 _{I, D,N}

_Und.(MR4.5)

_y

EUROSKI

7 _{I, D,N}

_y

_{3 cons}

_Yes

ENESTop

8 _{I--> N 3+( 2 vs 1) MR4.5}

_1y

₄

_Yes

ENESTfreedom

9 _N

₂₊₁

_MR4-MR4.5

_1y

₄

_Yes

ENESTpath

10 _{I--> N 2+ (2 vs 3) MR4}

_{1y / 2y}

_4/8

_Yes

STAT 2

11 _{I--> N}

_X+2

_MR4.5

DADI

12 _{I-->D 1 year of D MR4.5}

_1y

₄

*I: Imatinib; N: Nilotinib; D: Dasatinib

Definition of loss of CMR varied across the trials. *UMRD. MR

4

_{or MR}

4.5

1. Mahon FX, et al Lancet Oncol 2010 Nov; 11(11): 1029-1035 2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 4. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 5. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914. 6. Rea D, et al. Blood 2017 Feb 16; 129(7): 846-854.

7. Saussele, S. et al. 2014. Haematologica 99(suppl 1):LB2440. ClinicalTrials.gov. Available at

www.clinicaltrials.gov.

8. Hughes, T et al. EHA21 st 2016 meeting LB 237 9. Hochhaus A, et al. Leukemia 2017 Feb 20

10. U.S. NIH. Clinicaltrials.gov. [cited 2013 Sept .http://www.clinicaltrials.gov/. 11. Takahashi , N et al. EHA21st 2016 meeting, P229

(4)

Y con una monitorización mensual durante el 1º año, y cada 2

meses en el segundo

1st year

2nd year Thereafter

Interval

STIM

1 _I

_1m

_2m

_3m

TWISTER

2 _I

_1m

_2m

_3m

A-STIM

3 _I

_1m

_2m

_3m

KIDS

4 _1m

_2m

_3m

ISAV

5 _I

_1m

_2m

STOP 2GTKI

6 _I,

D,N

1m

2-3m

3-6m

EUROSKI

7 _I,

D,N

1-1.5m

3m

DADI

8 _I-->D

_1m

_3m

_6m

*I: Imatinib; N: Nilotinib; D: Dasatinib

Definition of loss of CMR varied across the trials. *UMRD. MR

4

_{or MR}

4.5 1. Mahon FX, et al Lancet Oncol 2010 Nov; 11(11): 1029-1035

2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 4. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 5. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914. 6. Rea D, et al. Blood 2017 Feb 16; 129(7): 846-854.

7. Saussele, S. et al. 2014. Haematologica 99(suppl 1):LB2440. ClinicalTrials.gov. Available at www.clinicaltrials.gov.

8. Imagawa J, et al Lancet Haematol 2015 Dec; 2(12): e528-535.

TKI*

TKI years

CMR

QUALITY

RELAPSE

**

LOSS OF..

N

STIM

1 _I

_{Und. (MR5)}

_CMR

₁₀₀

TWISTER

2 _I

_Und.(MR4.5)

_CMR

₄₀

KIDS

3 _I

₃

_Und.

_MMR

₉₀

KEIO STIM

4 _I

₂

_Und.

_CMR

₄₀

A-STIM

5 _I

_Und.

_MMR

₆₆

ISAV

6 _I

₂

_MR4

_MMR

₁₀₈

STOP 2GTKI

7 _{I, D,N}

_Und.(MR4.5)

_MMR

₅₀

EUROSKI

8 _{I, D,N}

_MR4

_MMR

₈₀₉

ENESTop

9 _{I--> N}

_{3+( 2 vs 1) MR4.5}

_{MR4 or MMR 126}

ENESTfreedo

m

10 _N

₂₊₁

_MR4.5

_MMR

₁₉₀

ENESTpath

11 _{I--> N}

_{2+ (2 vs 3) MR4}

_MR4

₁₀₅₈

STAT 2

12 _{I--> N}

_X+2

_MR4.5

₇₅

DADI

13 _I-->D

_{1 year of D MR4.5}

_CMR

₆₃

*I: Imatinib; N: Nilotinib; D: Dasatinib

Definition of loss of CMR varied across the trials. *UMRD. MR

4

_{or MR}

4.5

1. Mahon FX, et al Lancet Oncol 2010 Nov; 11(11): 1029-1035 2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 4. Matsuki E, et al. Blood 2012;120 (abstr 2788). 5. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 6. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914.

7. Rea D, et al. Blood 2017 Feb 16; 129(7): 846-854. 8. Richter, J. Et al EHA21 st 2016 meeting S145 9. Hughes, T et al. EHA21 st 2016 meeting LB 237 10. Saglio, G et al. EHA21 st 2016 meeting LB 618

(5)

Pero el A-STIM abrió la espita de la pérdida de RMM

TKI*

Definition of relapse triggering treatment

Detectable transcript

Loss of MMR

STIM

1 _I

_{2 consecutive samples}

and a 1-log increase in

the 2nd test

Single test

TWISTER

2 _I

_{2 consecutive samples}

_{Single test}

A-STIM

3 _I

_{Single test}

KIDS

4 _{Two samples within 4 weeks}

ISAV

5 _I

_{2 consecutive samples}

(>0,1% in 1)

STOP 2GTKI

6 _{I, D,N}

_{Single test}

EUROSKI

7 _{I, D,N}

_{Single test}

DADI

8 _I-->D

_{2 consecutive samples}

*I: Imatinib; N: Nilotinib; D: Dasatinib

Definition of loss of CMR varied across the trials. *UMRD. MR

4

_{or MR}

2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 4. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 5. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914. 6. Rea D, et al. Blood 2017 Feb 16; 129(7): 846-854.

7. Saussele, S. et al. 2014. Haematologica 99(suppl 1):LB2440. ClinicalTrials.gov. Available at www.clinicaltrials.gov.

8. Imagawa J, et al Lancet Haematol 2015 Dec; 2(12): e528-535.

El porcentaje de pacientes libres de recaída es del 50% -60%

TKI*

TKI years CMR

QUALITY

RELAPSE

**

LOSS OF..

% Relapse

free

months

FU

STIM

1 I

Und. (MR5) CMR

39%

55 TWISTER

2 I

Und.(MR4.5) CMR

45%

42 KIDS

3 I

3 Und.

MMR

62%

26 KEIO STIM

4 I

2 Und.

CMR

55%

23 A-STIM

5 I

Und.

MMR

64%

32 ISAV

6 I

2 MR4

MMR

52%

22 STOP 2GTKI

7 I, D,N

Und.(MR4.5) MMR

61%

EUROSKI

8 I, D,N

MR4

MMR

52%

21 ENESTop

9 I--> N 3+( 2 vs 1) MR4.5

MR4 or MMR

58%

12 ENESTfreedom

10 N

2+1

MR4.5

MMR

52%

12 ENESTpath

11 I--> N

2+ (2 vs 3) MR4

MR4

STAT 2

12 I--> N

X+2

MR4.5

69%

16 DADI

13 I-->D 1 year of D MR4.5

CMR

48%

20 *I: Imatinib; N: Nilotinib; D: Dasatinib

Definition of loss of CMR varied across the trials. *UMRD. MR

4

_{or MR}

2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 4. Matsuki E, et al. Blood 2012;120 (abstr 2788). 5. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 6. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914.

(6)

Variables asociadas con una exitosa discontinuación

en ensayos clínicos

Age

Sex

Sokal

TKI

duration

Time to

UMRD

duration

UMRD

Prior

IFN

Cause

Of DC

STIM

1 -

-

LR

-

NA

TWISTER

2 +

-

LR

-

+

-

NA

KIDS

3 -

-

+

-*

NA

A-STIM

5 -*

-

-*

NA

ISAV

6 +

NE

-

NE

-

NA

STOP

2GTKI

7 -

-

NE

-

NE

-

-EUROSKI

8 NE

NE

+

NA

+

NE

1. Mahon FX, et al Lancet Oncol 2010 Nov; 11(11): 1029-1035 2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 4. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 5. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914. 7. Rea D, et al. Blood 2017 Feb 16; 129(7): 846-854. 8. Richter, J. Et al EHA21 st 2016 meeting S145

1. Twister: Time to UMRD: <244 days vs 244p=0.04;

2. KIDS: TKI Duration: <62m: 40% vs

to UMRD: <29 m ;p=0.15; Duration UMRD: <36m: 48%

36m: 65%;p=0.084

3. A-STIM: Age: <55 :70%; >55:57,5%;p=0.199; IFN yes: 71% vs no: 55% (p=0.061)

4. EuroSKI at 6 m: 5.8 y :43% vs 5.8y : 66%. Duration of MR4: 3.1y :44% vs 3.1y : 62%. OR for duartion was 1.16 ( 1 additional year increases

the chance of staying in MMR at 6m by 16%. The best cut-off for MR4 duartion is more than 3 years

Factors associated with TFR observed in clinical trials.

Bad:

Younger <45 y and positive digital PCR: 0% TFR at 24m

1 High CD86+p Dendritic Cells counts have a higher risk of relapse after TKI

discontinuation

2 Good

High NK-cell

P = 0.017] and CD16+/CD56+ [P = 0.0053]) and NK-cell LGL

(CD56+/CD57+; P = 0.022)

3 Higher NK cells

3 _{, with higher CD56}

dim

_/CD56

bright

_ratio

4 Low + T-cell (P = 0.0022) and CD4+ Treg(P = 0.011)

3 1. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914..

2. Schutz, C., et al.,. Leukemia, 2017. 31(4): p. 829-836.

3. Imagawa J et al. Lancet Haematol 2015 Dec; 2(12): e528-535

4. Ilander, M., et al. Leukemia, 2016

(7)

NCCN 2017 Criteria for discontinuation

DC of TKI therapy should only be performed in

consenting patients after a thorough discussion of

the potential risks and benefits

Outside clinical trial, all the criteria of the NCCN

must be met

NCCN Guidelines Version 2.2017. CML

NCCN 2017 Criteria for discontinuation

All of them

NCCN Guidelines Version 2.2017. CML

All of them

Adequate molecular laboratory

Sens.

logs, IS, reports in 2w

Age

Age 18 years or more

BCR-ABL transcript

Quantifiable

BCR-ABL1 transcript

CML past history

1st CP ( No previous AP or BP)

Response to

TKI

No history of resistance to any TKI

Duration of

TKI

therapy

3 years or more

Depth of deep molecular response

MR4 or better

Duration of deep molecular response

monitored in a standardized

laboratory

2 years or more, 4 tests done 3 m apart

Adequate monitoring

Monthly for 6m, Bi-monthly 18m

3-monthly therafter. MR3 is the target?

(8)

NCCN 2017 Criteria for discontinuation

All of them

NCCN Guidelines Version 2.2017. CML

All of them

Previous consultation with a CML

specialist

To review the appropriateness for DC, balancing risks

and benefits

Resumption of TKI

Prompt. It seems to imply that the trigger is loss of

MMR

Adequate monitoring after relapse

Monthly, and every 3 months

( for those with loss of MMR)

Adequate surveillance of patients not

achieving MMR after 6 months

Mutation analysis and monthly monitoring

Reporting to the NCCN panelists

Is strongly encouraged

Any significant AE believed to be related to DC

Progression to AP or BP

EuroVision Logistics

Good, internationally standardized RQPCR laboratory

1 Monthly for 6 months, every 6 weeks months 7 12 and

then every 3 months

2 Capacity to provide RQ-PCR tests every 4-6 weeks, when

required

1 Rapid intervention if BCR-ABL is rising

1 Monitoring required beyond 4 years

1 1. Hughes TP, Ross DM: Blood 2016, 128:17-23

(9)

EuroVision Logistics compared with NCCN

Good, internationally standardized RQPCR laboratory

1 Monthly for 6 months, every 6 weeks months 7 12 and then

every 3 months

2 Capacity to provide RQ-PCR tests every 4-6 weeks, when

required

1 Rapid intervention if BCR-ABL is rising

1 Monitoring required beyond 4 years

1 1. Hughes TP, Ross DM: Blood 2016, 128:17-23

2. Saussele, S., J. Richter, A. Hochhaus and F. X. Mahon (2016). Leukemia 30(8): 1638-1647.

EuroVision Exclusion criteria

Atypical BCR-ABL transcripts

1 Original BCR-ABL transcript type at diagnosis is not known

1 In patients with a prior history of TKI resistance

1 Prior history of accelerated phase or blast crisis

1 _.

ACAS at diagnosis

2 Mutations

2 1. Hughes TP, Ross DM: Blood 2016, 128:17-23.

(10)

EuroVision Exclusion criteria

compared with NCCN

Atypical BCR-ABL transcripts

1 Original BCR-ABL transcript type at diagnosis is not known

1 In patients with a prior history of TKI resistance

1 Prior history of accelerated phase or blast crisis

1 _.

ACAS at diagnosis

2 Mutations

2 1. Hughes TP, Ross DM: Blood 2016, 128:17-23.

2. Imagawa, J

Kimura and D. T. Group (2015). Lancet Haematol 2(12): e528-535.

EuroVision Inclusion criteria

Good laboratory, early intervention

A minimum of 12 months

1 _{or 24 months}

2 _{with MR4}

or better

Long duration of TKI

More than 4 years for imatinib

3 1. Hughes TP, Ross DM: Blood 2016, 128:17-23.

2. Takahashi , N et al. EHA21st 2016 meeting, P229

3. Saussele, S., J. Richter, A. Hochhaus and F. X. Mahon (2016). Leukemia 30(8): 1638-1647.

(11)

No se necesita ensayo clínico, pero sí

recomendaciones

The absence of a suitable trial should not preclude a patient

from stoppingTKI treatment, but outside the structure of a

clinical trial, it would be useful to have

consensus

recommendations

to guide those clinicians for whomTFR

represents a new area of practice

1. Hughes TP, Ross DM: Blood 2016, 128:17-23.

Hughes & Ross criteria for attempting TKI

discontinuation

Hughes TP, Ross DM: Blood 2016, 128:17-23.

Green

Yellow

Red

Adequate institution

Yes

-

No

Sokal score at diagnosis

Non-high

High

-BCR-ABL transcript at diagnosis

Typical

b2a2 or b3a2

Atypical, but can be

accurately quantified

Not quantifiable

CML past history

CP

Resistance or KD

mutation

Prior AP or BC

Response to first line TKI

Optimal

Warning

Failure

Duration of TKI therapy

> 8 years

3 8 years

< 3 years

Depth of deep molecular response

MR4.5

MR4.0

Not in MR4.0

Duration of deep molecular response

monitored in a standardized laboratory

> 2 years

1 2 years

< 1 year

All green cells: strong recommendation to consider TKI withdrawal

Any yellow: only in high priority circumstances (e.g. significant toxicity or planned pregnancy

Any red: TKI withdrawal not recommended except in clinical trial

(12)

Y los franceses, apoyan a los australianos

We might accept stoppingTKIs if molecular follow-up is

performed according to international recommendations by

using selection criteria recently proposed by Hughes and Ross

but only for IM.

Etienne, G.

DOI: 10.1200/JCO.2016.68.2914

UNA OPINIÓN CRÍTICA SOBRE LA DEFINICIÓN

DE RECAÍDA

(13)

¿Por qué se escogió la pérdida de la RMM como criterio de

recaída ?

80 Patients

51 Cont.MMR

Cont.CMR

23 Occasional

Pos

12 Fluctuating

CMR

16

29 Loss MMR

Early:11

Late: 18

Only 1 patient developed Progression

1 _{after losing}

MMR

Porque en el A-STIM se observó que la RMC podía ser fluctuante

Rousselot P, et al. J Clin Oncol 2014 Feb 10; 32(5): 424-430.

mayor en los ensayos en los que se esperó a perder la RMM

TKI*

TKI years

CMR

QUALITY

RELAPSE

**

LOSS OF..

PROB OF

REGAINING

CMR

***

STIM

1 I

Und. (MR5)

CMR

92 %

TWISTER

2 I

Und.(MR4.5) CMR

NR

KIDS

3 I

3 Und.

CMR

NR

KEIO STIM

4 I

2 Und.

CMR

94 %

A-STIM

5 I

Und.

MMR

84 %

ISAV

6 I

2 MR4

MMR

NR

STOP 2GTKI

7 I, D,N

Und.(MR4.5) MMR

87 %

EUROSKI

8 I, D,N

MR4

MMR

NR

ENESTop

9 I--> N

3+( 2 vs 1) MR4.5

MR4 or MMR

94 %

ENESTfreedom

10 N

2+1

MR4.5

MMR

89 %

ENESTpath

11 I--> N

2+ (2 vs 3) MR4

MR4

ONGOING

STAT 2

12 I--> N

X+2

MR4.5

100 %

DADI

13 I-->D

1 year of D MR4.5

CMR

97%

*I: Imatinib; N: Nilotinib; D: Dasatinib

Definition of loss of CMR varied across the trials. *UMRD. MR

4

_{or MR}

2. Ross DM, et al Blood 2013 Jul 25; 122(4): 515-522. 3. Lee SE et al Haematologica 2016 Jun; 101(6): 717-723. 4. Matsuki E, et al. Blood 2012;120 (abstr 2788). 5. Rousselot P et al J Clin Oncol 2014 Feb 10; 32(5): 424-430. 6. Mori S, et al Am J Hematol 2015 Oct; 90(10): 910-914.

(14)

Sin embargo, una comparación simple tiene riesgos: los ensayos

tienen algunas diferencias

ENESTstop

ENESTfreedom EURO-SKI

Tratamiento anterior

Nilotinib

2ª línea

Nilotinib 1ª

línea

Imatinib 1ª

linea

(94%)

N

126

190

760 % Female

56

50

48 Edad

56

55

60 Dx-entrada ( años)

6,5 (3-22)

2,7(2-6,7)

7,7(3-23)

Duración ITK

7(4-14)

3,6(2,7-7,4)

7,6(3-14)

Duración RM4,5*/RM4** 1,7*

1,5*

4,7**

7. Richter, J. Et al EHA21 st 2016 meeting S145 8. Hughes, T et al. EHA21 st 2016 meeting LB 237 9. Saglio, G et al. EHA21 st 2016 meeting LB 618

4-5 logs

Células

leucémicas

2 log

10

13

10

12

10

11

10

9

10

8

10

7

10

6

10

5

10

4

10

3

10

2

10

0 1 log

3 log

10

13

10

12

10

11

10

9

10

8

10

7

10

6

10

5

10

4

10

3

10

2

10

0 Células

leucémicas

PRE DISCONTINUATION

El número estimado de células leucémicas residuales en

MR4.5 : en el rango de 10

6 _{( 1.000.000)}

(15)

El número estimado de células leucémicas residuales en

RM2 : en el rango de 10

11 _{(100.000.000.000)}

Células

leucémicas

10

13

10

12

10

11

10

9

10

8

10

7

10

6

10

5

10

4

10

3

10

2

10

0

10

13

10

12

10

11

10

9

10

8

10

7

10

6

10

5

10

4

10

3

10

2

10

0 Células

leucémicas

PRE DISCONTINUATION

RELAPSE

4-5 logs

2 log

1 log

3 log

RATIO

0,1%: RM3 ( RMM)

0,01%: RM4

0,0032: RM4,5

0,001%: RM5

100%

1%

0,1%

0,01%

0,0032%

0,0001%

Jlsteegmann ®

Es decir, después de nuestros esfuerzos

por conseguir RMC, ¿volvemos a la casilla

de salida?

(16)

Conclusión

Las variables más fuertes: Riesgo previo, duración

del tratamiento, duración de la RMC.

La definición de recaída no está clara.

Si le preguntan a un investigador de EuroSki, RMM

Si me preguntan a mí, ya lo saben, RMC.

Preguntas

Cinética de la recaída

1 Células stem leucémicas residuales y recidiva

Una pregunta interesante, por contestar

2 _{, y que esperamos responda}

ENESTpath

Inmunología previa y posterior a la suspensión.

PCR digital

*

Clones Ph1 negativos tras suspensión.

1. Ross, D.M., et al.,Blood, 2013. 122(4): p. 515-22.

2. Chomel, J.C., et al., Oncotarget, 2016. 7(23): p. 35293-301.

(17)

Unos criterios a discutir

Verde

Institución adecuada

Si

Sokal al diagnóstico

No alto

Transcrito BCR-ABL al diagnóstico

Típico

b2a2 or b3a2

Fase de la LMC

FC

Respuesta al 1º ITK

Óptima

Duración de ITK

a

Tipo de respuesta

RM4.5

Duración de la RMC

Y mejor si

1. IFN previo

2. Obtención rápida de la RMM

3. Mujer

4. Tempo para RMC menor de 1 año

(18)

GRACIAS

THANK YOU !

¡GRACIAS!

MADRID, GRAN VIA

Could

made dissapear the Ph+

leukemic stem cell?

Against

Late relapses are possible after decades of BMT

1 The excess of risk of overt CML in atomic bomb

survivors remained elevated more than 40 years

1 Kinetic studies

Mathematical models of HSC extinction.

Absence of known Graft v Leukemia effect

in vitro are immunosuppressants

1. Bansal, A. and J. Radich, Is cure for chronic myeloid leukemia possible in the tyrosine kinase inhibitors era? Curr Opin Hematol, 2016. 23(2): p. 115-20 2. Holyoake, T. and D. Vetrie, The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood, 2017. 129(12):1595-1606)(12): p. 1595-1606 3. Etienne, G., et al., Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol, 2017. 35(3): p. 298-305.