Post on 26-Feb-2021
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