Convegno Regionale SIE Marche

La Malattia Minima Residua in Ematologia: dalla filosofia alla

pratica

Fano, 15 Novembre 2013

Anna Rita Scortechini, MD, PhD

PCR qualitativa e quantitativa alla diagnosi e nel follow-up

Clinica di Ematologia Università Politecnica delle Marche

La  Genesi  della  Scala  Internazionale  BC

R-­‐AB

L/AB

LIS  

100%  

10%  

1%  

0.1%  

30  pz  nuova  diagnosi  

MMR  

Hughes  TP  et  al.  Blood,  2006  108:28-­‐37  -­‐  Branford  S  et  al.  Leukemia,  2006  20:1925-­‐30  

10%  

1%  

0.1%  

30  pz  nuova  diagnosi  

MMR  

100%  BC

R-­‐AB

L/AB

LIS  

La  Genesi  della  Scala  Internazionale  

Hughes  TP  et  al.  Blood,  2006  108:28-­‐37  -­‐  Branford  S  et  al.  Leukemia,  2006  20:1925-­‐30  

10%  

1%  

0.1%  

100%  BC

R-­‐AB

L/AB

LIS  

La  Scala  Internazionale  Rivisitata  

Cross  NP  et  al.  Leukemia,  2012  26:2172-­‐5  

30  pz  nuova  diagnosi  

MR1  

MR3  

MR2  

0.01%  

0.0032%  

0.001%  

MR4  

MR5  

MR4.5  

0.1%  BC

R-­‐AB

L/AB

LIS  

La  Scala  Internazionale  Rivisitata  

Cross  NP  et  al.  Leukemia,  2012  26:2172-­‐5  

MR3  

La  Scala  Internazionale  Rivisitata  

Cross  NP  et  al.  Leukemia,  2012  26:2172-­‐5  

10%  

1%  

0.1%  

MR1  

MR3  

MR2  

100%  

BCR-­‐AB

L/AB

LIS  

Copie  di  ABL  

10.000  

10.000  

10.000  

La  Scala  Internazionale  Rivisitata  

Cross  NP  et  al.  Leukemia,  2012  26:2172-­‐5  

0.01%  

0.0032%  

0.001%  

MR4  

MR5  

MR4.5  

0.1%   MR3  

10.000  

32.000  

100.000  

BCR-­‐AB

L/AB

LIS  

Copie  di  ABL  

ELN  Defini@ons  of  Response  on  First-­‐Line  Ima@nib:  Role  of  MMR  

Baccarani M, et al. J Clin Oncol. 2009

Optimal Response

Suboptimal Response Failure Warnings

Baseline NA NA NA • High Risk • CCA/Ph+*

3 Months CHR and at least minor CyR (Ph+ ≤ 65%)

No CyR (Ph+ > 95%) Less than CHR NA

6 Months At least PCyR (Ph+ ≤ 35%)

Less than PCyR (Ph+ > 35%)

No CyR (Ph+ > 95%)

NA

12 Months CCyR PCyR (Ph+ 1-35%)

Less than PCyR (Ph+ > 35%)

Less than MMR†

18 Months MMR† Less than MMR†

Less than CCyR NA

Any time Stable or improving MMR†

• Loss of MMR†

• Mutations‡

  Loss of CHR   Loss of CCyR   Mutations§   CCA/Ph+*

• Any rise in transcript levels • CCA/Ph-װ

* CCA/Ph+ = Clonal chromosome abnormalities in Ph+ cells; CCA/Ph+ is a warning factor at diagnosis although its occurrence during treatment (ie, clonal progression) is a marker of treatment failure. Two consecutive cytogenetic tests are required and must show the same CCA in at least two Ph cells. † MMR indicates a ratio of BCR-ABL1 to ABL1 or other housekeeping genes, ≤ 0.1% on the international scale. ‡ BCR-ABL1 kinase domain mutations still sensitive to imatinib. § BCR-ABL1 kinase domain mutations poorly sensitive to imatinib.

.CCA/Ph- = Clonal chromosome abnormalities in Ph- cells װ

Annals of Hematology, 2012

ELN  Defini@on  of  the  Response  to  TKIs  (any  TKI)  as  first-­‐line  treatment  

Baccarani M, et al. Blood 2013

Optimal Warnings Failure

Baseline NA Higt risk or CCA/Ph+, major route

NA

3 Months BCR-ABL ≤ 10% and/or Ph+ ≤ 35%

BCR-ABL > 10% and/or Ph+ 36-95%%

Non-CHR and/or Ph+ > 95%

6 Months BCR-ABL < 1% and/or Ph+ 0

BCR-ABL 1-10% and/or Ph+ 1-35%

BCR-ABL > 10% and/or Ph+ > 35%

12 Months BCR-ABL ≤ 0,1% BCR-ABL > 0,1-1%% BCR-ABL >1% and/or Ph+ > 0

Then, and at any time

BCR-ABL ≤ 0,1% CCA/Ph- (-7, or 7q-)

Loss of CHR Loss of CCYR Confirmed loss of MMR Mutations CCA/Ph+

* CCA/Ph+ = Clonal chromosome abnormalities in Ph+ cells; CCA/Ph+ is a warning factor at diagnosis although its occurrence during treatment (ie, clonal progression) is a marker of treatment failure. Two consecutive cytogenetic tests are required and must show the same CCA in at least two Ph cells. † MMR indicates a ratio of BCR-ABL1 to ABL1 or other housekeeping genes, ≤ 0.1% on the international scale. ‡ BCR-ABL1 kinase domain mutations still sensitive to imatinib. § BCR-ABL1 kinase domain mutations poorly sensitive to imatinib. CCA/Ph- = Clonal chromosome abnormalities in Ph- cells װ

ELN  Defini@on  of  the  Response  to  second-­‐line  therapy  in  case  of  failure  of  ima@nib  

Baccarani M, et al. Blood 2013

Optimal Warnings Failure

Baseline NA No CHR or loss of CHR on imatinib or lack of CyR to first-line TKI or Higt risk

NA

3 Months BCR-ABL ≤ 10% and/or Ph+ ≤ 65%

BCR-ABL > 10% and/or Ph+ 65-95%%

Non-CHR or Ph+ > 95% or new mutations

6 Months BCR-ABL < 10% and/or Ph+ < 35%

Ph+ 35-65%% BCR-ABL > 10% and/or Ph+ > 65% and/or new mutations

12 Months BCR-ABL ≤ 1% and/or Ph+ 0

BCR-ABL 1-10%% and/or Ph+ 1-35%

BCR-ABL >10% and/or Ph+ > 35% and/or new mutations

Then, and at any time

BCR-ABL ≤ 0,1% CCA/Ph- (-7, or 7q-) or BCR-ABL > 0,1%

Loss of CHR or Loss of CCYR or PCyr New mutations Confirmed loss of MMR CCA/Ph+

Marin et al, JCO 2012

Ratio BCR/ABL predittiva a 3 mesi per OS: > 9.84% high risk < 9.84% low risk

•  PaRents  with  transcript  level  of  more  than  9.84%  at  3  months  have  a  significantly  lower  8-­‐y  probabiliRes  of  OS,  PFS,  cumulaRve  incidence  of  CCyR  

•  Transcript  level  of  more  than  1.67%  at  6  months    idenRfies  high  risk  paRents  •  Transcript  level  retains  impact  regardless  need  of  2nd  line    

Cutoff  transcript  levels  to  predict  outcomes  (282  CP,  cutoff  level  tested  at  3,  6,  12,  months,  IMA  400  1st,  nilo,  dasa  2nd)  

Marin  et  al,  JCO  2012  

•  Analysis  by  risk  group  at  3  months:  •  HR:  transcript  level  >9.84%  •  LR:  transcript  level  ≤9.84%  

•  OS:    •  56.9%  vs  93.3%  (HR  vs  LR)  

•  CCyR:  •  47%  vs  91%  (HR  vs  LR)  

•  A  total  of  1303  newly  diagnosed  Ima@nib-­‐treated  pts  were  invesRgated  to  

correlate  molecular  and  cytogeneRc  response  at  3  and  6  months  with  PFS  

(defined  by  absence  of  accelerated  phase,  blast  crisis  and  death  from  any  

reason)  and  OS  (absence  of  death  from  any  reason).  

Molecular  and  cytogene@c  response  levels  at  3  months  of  ima@nib  treatment  are  significantly  associated  with  long-­‐term  progression-­‐free  and  

overall  survival.  

Predic@on  of  PFS  and  OS    by  early  molecular  and  cytogene@c  response  

 (CML  German  trial,  1303  pa@ents)  

Hanfstein  et  al,  Leukemia  2012  

Hanfstein  et  al,  Leukemia  2012  

Hanfstein  et  al,  Leukemia  2012  

mesi  

Hochhaus  A  et  al.  Blood,  2012  Abs:167  

LMC:  MR  a  3  mesi  con  i  2G  TKIs  

(258)

Numero 234  (91%)   24    (9%)  

80%   29%  

4%   17%  

98%   87%  

<10%  

MR3  (@24  m)

AP/BC  (@36  m)

OS  (@36  m)

>10%  

ENESTnd:    pz  in  Fase  Cronica

BCR-­‐ABL  a  3  Mesi  

0

20

40

60

80

100

% o

f Pat

ient

s

BCR-ABL Level at 3 Months

n 234 176 24 88

≤ 10% > 10%

91%

67%

9%

33%

>1-10%

≤1% >1-10%

≤1%

Nilotinib 300 mg BID (N = 258)

Imatinib (N = 264)

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

ENESTnd Landmark Analysis

Hochhaus A, et al. Haematologica. 2012;97(s1):237 [abstract 0584].

PFS*  in  base  a  BCR-­‐ABL  Levels  a  3  mesi    (Nilo@nib  300  mg  BID)  

33

Time Since Randomization (Months)

100

90

80

70

60

50

40

30

20

10

0 0 3 6 9 12 15 18 21 24 27 30 36

≤ 1% > 1% – ≤ 10% > 10%

145 89 24

Pat Evt Cen

5 3 4

140 86 20

Censored observations

95.6% 96.5%

82.9%

* PFS includes both progression events occurring on study drug and also after discontinuation of study drug during follow-up, as well as death due to any cause on study or after discontinuation of study drug during follow-up. After discontinuation of study drug, progression information was prospectively collected every 3 months for up to 5 years.

P = .968

P = .014

P = .0021 between ≤ 10% vs > 10%

% W

ithou

t Pro

gres

sion

or D

eath

Data cut-off: 27Jul2011.

ENESTnd Landmark Analysis

Hochhaus A, et al. Haematologica. 2012;97(s1):237 [abstract 0584].

Overall  Survival  in  base  a  BCR-­‐ABL  Levels    a  3  mesi  (Nilo@nib  300  mg  BID)  

% A

live

33

Time Since Randomization (Months)

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 36

98.8% 96.9% 86.7%

P = .42

P = .006

P = .003 between ≤ 10% vs > 10%

≤ 1% > 1% – ≤ 10% > 10%

145 89 24

Pat Evt Cen

4 1 3

141 88 21

Censored observations

Data cut-off: 27Jul2011.

ENESTnd Landmark Analysis

Hochhaus A, et al. Haematologica. 2012;97(s1):237 [abstract 0584].

Hochhaus  A  et  al.  Blood,  2011  Abs:2767  

LMC:  MR  a  3  mesi  con  i  2G  TKIs  

(235)

Numero

CCyR  (@12  m)

MR3  (@24  m)

AP/BC

>10%  

198  (84%)   37  (16%)  

96%   27%  

76%   16%  

2%   8%  

<10%  

mesi  

DASISION:    pz  in  Fase  Cronica

Predic@ve  value  of  early  molecular  response  in  pa@ents  with  chronic  myeloid  

leukemia  treated  with  first-­‐line  dasa@nib    

David  Marin,1  Corinne  Hedgley,2  Richard  E.  Clark,3  Jane  Apperley,1  LeRzia  Foroni,1  Dragana  Milojkovic,1  Christopher  Pocock,4  John  M.  Goldman,1  and  Stephen  O’Brien2    1Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom; 2Department of Haematology, Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom; 3Department of Haematology, Royal Liverpool University Hospital, Liverpool, United Kingdom; and 4Department of Haematology, East Kent Hospitals National Health Service Trust, Canterbury, United Kingdom

Marin  D  et  al.  Blood,  2012  120:291-­‐4  

mesi  

Marin  D  et  al.  Blood,  2012  120:291-­‐4  

LMC:  MR  a    mesi  con  DASATINIB  

(128)

Numero

CCyR  (@24  m)

MR3  (@24  m)

MR4.5  (@24  m)

>10%  

117  (91%)   11    (9%)  

91%   59%  

80%   14%  

46%   0%  

<10%  

SPIRIT  2:  pz  in  Fase  Cronica  -­‐  CI  di  Risposta

Marin  D  et  al.  Blood,  2012  120:291-­‐4  

LMC:  MR  a    mesi  con  DASATINIB  

>10%  

<10%  

BCR-­‐ABL/ABLIS  

n=11

n=117 n=88

n=40

Marin  D  et  al.  Blood,  2012  120:291-­‐4  

LMC:  MR  a    mesi  con  DASATINIB  

>10%  

<10%  

>2%  

<2%  

BCR-­‐ABL/ABLIS  

n=11

n=117 n=88

n=40

Two-­‐year  Cumula@ve  incidence  of  CCyR,  MR3,  and  CMR4.5  according  to  the  3-­‐month  BCR-­‐ABL1  

transcript  level.    

Marin  D  et  al.  Blood,  2012  120:291-­‐4  

1.  Soglia  del  2%  a  3  mesi  sembra  più  appropriata  per  2G  TKIs  

2.  Soglia  10%  a  3  mesi  parrebbe  più  indicaRva  della  risposta          ad  IM  della  soglia  1%  a  6  mesi  

La  MR  Precoce:  soglie  e  tempisRche  

3.  Soglia  10%  a  3  mesi  sembra  definire  probabilità  di  risposta          a  2G  TKIs  in  pazienR  resistenR  o  intolleranR  ad  IM  

Neelakantan  P  et  al.  Blood,  2013  121:2739-­‐42  

LMC:  più  importante  MR  a    o  a    mesi?  

b-­‐> b   a-­‐> a  

93%  

56%  (66%)   (21%)  

(274)

Neelakantan  P  et  al.  Blood,  2013  121:2739-­‐42  

LMC:  più  importante  MR  a    o  a    mesi?  

b-­‐> b   a-­‐> a  

a-­‐> b  b-­‐> a  

93%  

83%  

56%  (66%)   (21%)  

(11%)   (2%)  

(274)

Il  trascribo  al  6°mese  non  aggiunge  informazioni  rispebo    al  3°  mese  che  man@ene  la  sua  validità  in  termini  di  OS  

1.  Soglia  del  2%  a  3  mesi  sembra  più  appropriata  per  2G  TKIs  

2.  Soglia  10%  a  3  mesi  parrebbe  più  indica@va  della  risposta          ad  IM  della  soglia  1%  a  6  mesi  

La  MR  Precoce:  soglie  e  tempisRche  

3.  Soglia  10%  a  3  mesi  sembra  definire  probabilità  di  risposta          a  2G  TKIs  in  pazienR  resistenR  o  intolleranR  ad  IM  

1.  Soglia  del  2%  a  3  mesi  sembra  più  appropriata  per  2G  TKIs  

2.  Soglia  10%  a  3  mesi  parrebbe  più  indica@va  della  risposta          ad  IM  della  soglia  1%  a  6  mesi  

La  MR  Precoce:  soglie  e  tempisRche  

3.  Soglia  10%  a  3  mesi  sembra  definire  probabilità  di      risposta  a  2G  TKIs  in  pazien@  resisten@  o  intolleran@  ad  IM  

 Raccomandazioni  ELN  2013  

  Terapia prima linea: imatinib, nilotinib, dasatinib   Eliminata la categoria dei pazienti sub-ottimali

  Rimangono quindi: pazienti ottimali, fallimenti (elevato rischio di progressione), warnings (precedenti pazienti subottimali che richiedono un più attento monitoraggio citogenetico e molecolare)

 A 3 mesi: ottimale BCR-ABL< 10%; warning BCR-ABL>10%

  A 6 mesi: ottimale BCR-ABL <1% o CCR; warning BCR-ABL tra 1-10%; fallimento BCR-ABL> 10%

  A 12 mesi: ottimale MMR o oltre MMR; warning BCR-ABL tra 0,1-1%; fallimento BCR-ABL> 1%.

Baccarani  et  al  Blood  2013  

Cosa  abbiamo  raggiunto  con  dasa@nib/nilo@nib  in  prima  linea?  

   Riduzione degli eventi di resistenza (EFS)

 Riduzione del rate di progressioni (PFS)

 Risposte più profonde con possibile discontinuazione futura

 

         Efficacia  della  seconda  generazione  in  prima  linea  

Obiegvi  terapeu@ci  2013  

  CCyR entro i 6 mesi

  MMR più rapida (entro 12 mesi)   risposte molecolari più profonde

CONCLUSIONI  (1)

  Identificare precocemente i pazienti (3°mese ad

outcome non ottimale (indipendentemente dall’inibitore scelto)

 Ottenere risposte molecolari più rapide e profonde, con conseguente riduzione del rate di progressione in

crisi blastica (vantaggio in EFS e PFS)

 Possibile discontinuazione (partecipazione a trial clinici controllati dopo ottenimento di una MR4.5

persistente)

CONCLUSIONI  (2)

Obiegvi  terapeu@ci  2013  

Grazie