Monitoraggio malattia residua nella LLA PH+ e terapia con inibitori

delle tirosin kinasi Maria Ilaria Del Principe

Università Tor Vergata

Roma

COSENZA 23 Novembre 2012

LA Adulti Sono stati fatti passi in avanti ?

Traslocazione t (9; 22)

(q34; q11)

Lee et al., Cancer 2011;117:1583-94

22%  n = 267

n = 1418 43%  

Ph positive Ph negative

Goldstone AH, et al. Blood 2008;111:1827-1833.

MRC UKALL XII/ECOG E2993: OS With Transplantation by Ph

Status

0

25  

50  

75  

100  

OS

(%)

Years  0 1   2 3   4   5  

Segnale  normale  del  Bcr-­‐Abl    Il  dominio  chinasico  a4va  il  

substrato  mediante  fosforilazione  

  L’a4vazione  del  substrato  è  il  segnal  d’inizio  della  cascata  che  culmina  con  la  proliferazione  cellulare  e  sopravvivenza.  

P P P ADP P

P

P P P ATP

SIGNALING

Bcr-Abl

Substrate

Effector

ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate. Savage and Antman. N Engl J Med. 2002;346:683 Scheijen and Griffin. Oncogene. 2002;21:3314.

Ima8nib  Mesylate:    Meccanismo  d’azione.  

  ImaCnib  mesylate  occupa  la  tasca  di  legame  dell’ATP.  

  Impedendo  il  legame  dell’ATP.  

  Non  viene  fosforilato  il  substrato.  

  Inibito  il  segnale  di  proliferazione  cellulare  e  di  sopravvivenza.  

P

P P P ATP

SIGNALING GLIVEC

Bcr-Abl

Savage and Antman. N Engl J Med. 2002;346:683.

Yanada M, et al. Int J Hematol. 2009;89:3-13.

JALSG Study: Allogeneic Transplantation for Ph+ ALL in

the Imatinib Era

EFS

OS

Surv

ival

(%)

Years

1.00

0.75

0.5

0.25

0 1 2 3 4 5

N = 100

0

Alterna8ng  Schedule    (n  =  47)  

Concurrent  Schedule    (n  =  45)  

Induc8on  

P  

ImaCnib   ImaCnib     SCT  

ImaCnib   SCT  

Cons.  1  

IND  1   IND  II  CNS  24  Gy  

C1   SCT  

This research was originally published in Blood. Wassmann B, et al. Blood. 2006;108:1469-1477. © the American Society of Hematology.

Alternating vs Concurrent Imatinib With Chemotherapy

After IND I

Patie

nts

(n)

After IND II Before C1

n = 30

n = 38 n = 39 n = 41

n = 36

n = 25

P = .01

PCR neg. (BM) 7% 5% 26% 27% 19% 52% Alternating Alternating Alternating Concurrent Concurrent Concurrent

Schedule This research was originally published in Blood. Wassmann B, et al. Blood. 2006;108:1469-1477. © the American Society of Hematology.

Alternating vs Concurrent Imatinib With Chemotherapy

50

40

30

20

10

0

This research was originally published in Blood. Vignetti M, et al. Blood. 2007;109:3676-3678. © the American Society of Hematology.

Imatinib Plus Steroids in Older Patients With Ph+ ALL

OS

(%)

Months

100

75

50

25

0 5 10 15 20 25 30 35

GIMEMA LAL0201-B

N = 30

Median age: 69 years (range: 61-83) Hematologic CR: 100% Median survival: 20 months Median DFS: 8 months

0

Imatinib and ABL    

Shah et al., Cancer Cell 2002

BCR-ABL dependent mechanisms  Contact site   P-loop   Activation loop

BCR-ABL independent mechanisms -clonal evolution -disruptions in drug uptake and efflux -activation of alternative signaling pathways

P-loop

Imatinib

Helix αC

Activation loop

DASATINIB

Dasatinib

Single-Agent Dasatinib in Imatinib-Resistant Ph+ ALL

•  Phase I dose-escalation study •  N = 84 •  10 pts with CML in lymphoid blast crisis or Ph+ ALL

–  Major hematologic response: 70% –  All except 1 responders

 Relapse at median of 4 months (range: 1-8)

Talpaz  M,  et  al.  N  Engl  J  Med.  2006;354:2531-­‐2541.  

This research was originally published in Blood. Ottmann O, et al. Blood. 2007;110:2309-2315. © the American Society of Hematology.

Dasatinib in Imatinib-Resistant Ph+ ALL

Free

Fro

m P

rogr

essi

on (%

)

Months

N = 36

100

90

80

70

60

50

40

30

20

10

0 2 4 6 8 10 12

Minimal follow-up: 8 months Median age: 46 years (range: 15-85) Major hematologic response: 42% Complete cytogenetic response: 58%

0

GIMEMA LAL1205: Dasatinib for Newly Diagnosed Adult Patients

With Ph+ ALL •  48  pts,  Ph+  ALL;  median  age:  54  years  (range:  24-­‐76)                        •  Day  1                                                                                                  Day  31      

•  Day  7      2  doses  of  IT  MTX  (Days  22,  43)            

                                                                                                           Frequent  monitoring  of  MRD  

•  34  evaluable  pts  •  Hematologic  CR:  100%  •  Rapid  achievement  of  MRD,  typically  by  Day  22  

Steroids  

Dasa8nib  70  mg  BID  x  12  weeks  

Foà  R,  et  al.  ASH  2008.  Abstract  305.  

BCR-ABL1 Quantitative Analysis (RQ-PCR)

Molecular  monitoring  of  BCR-­‐ABL1  is  vital  to  the  management  of  Ph  +ve  ALL.  Residual  disease  monitoring  usually  commences  once  a  paCent  is  in  cytogeneCc  remission  

and  allows  for  the  assessment  of  response  to  treatment  and  idenCficaCon  of  paCents  at  risk  of  relapse.    

 Level of BCR-ABL1 normalised to ABL1

0.000001

0.00001

0.0001

0.001

0.01

0.1

1

10

26/05

/2009

01/07

/2009

02/09

/2009

09/09

/2009

17/03

/2010

15/06

/2010

13/07

/2010

14/09

/2010

28/09

/2010

04/01

/2011

08/03

/2011

24/05

/2011

21/06

/2011

13/09

/2011

Sample Date

Rat

io o

n lo

g sc

ale

BCR-ABL1: ABL1ratioSensitivity of detection

Target sensitivity

MRD and prognosis

Yanada et al., BJH 2008;143:503-10

Pane et al. Leukemia 2005; 19:628-35

MRD and prognosis  

Pane et al. Leukemia 2005; 19:628-35

MRD and prognosis  

   

   

Chiara Sarlo

Luigi Di Caprio

Francesco Buccisano

Luca Maurillo

Giovanni Del Poeta

Adriano Venditti

Sergio Amadori

Antonella Zucchetto

Pietro Bulian

Francesca Maria Rossi

Riccardo Bomben

Michele Dal Bo

Massimo Degan

Valter Gattei