Anna Rita Scortechini, MD, PhD SINDROMI MIELOPROLIFERATIVE CRONICHE Ancona,

3° Workshop Regionale
Marchigiano
Ancona,
28 Febbraio – 1 Marzo 2014
SINDROMI MIELOPROLIFERATIVE
CRONICHE
Anna Rita Scortechini, MD, PhD
Clinica di Ematologia
Università Politecnica delle Marche
Risposta molecolare profonda nella leucemia
mieloide cronica: nuovo obiettivo della terapia
Mahon et al, Clinical Cancer Res 2013
ELN Definition of the Response to TKIs
(any TKI) as first-line treatment
Baccarani et al, Blood 2013
Obiettivi terapeutici 2014
Prevenire la progressione
avanzate di emopatia (FA/CB)
alle
fasi
Ottimizzare il raggiungimento di una MR
profonda (Deep Molecular Response: MR3,
MR4, MR4.5, etc ?)
Possibilità di TKIs “stop therapy”
Treatment-Free Remission (TFR)
Why is there a need for new treatment
strategies for newly-diagnosed CML
patients ?
The introduction of IM in CML therapy led to significant
improvements in efficacy and tolerability
However IM is not a suitable treatment for all patients
with CML
Eradication of residual leukemic cells would provide
patients with the possibility of TKIs discontinuation (IM
does not eradicate residual leukemic cells)
Goldman JM, 2012
Today 2014
Five TKIs available for CML
Progressions are rare with IM and less
with 2G-TKIs
What endpoints matter ?
Survival
Survival + TFR
55th ASH Meeting and Exposition
New Orleans, LA
7-10 December, 2013
Update on current monitoring
recommendations in chronic myeloid
leukemia: practical points for clinical
practice
Vivian G. Oehler
Fred Hutchinson Cancer Research Center, Seattle, WA
Perché dobbiamo raggiungere una profonda e persistente
risposta molecolare?
Numerosi dati nella letteratura negli ultimi 3 anni hanno sottolineato
l’importanza di risposte molecolare precoci e profonde.
Una riduzione a 3 mesi del trascritto BCR/ABL < 10% rappresenta uno
strumento accurato per dimostrare l’efficacia della terapia e quindi
rappresenta «milestone» fondamentale nella gestione del paziente
Risposte molecolari precoci sono associate a migliore outcome del
paziente e migliore EFS e PFS.
Una risposta molecolare profonda identifica il paziente candidato a una
discontinuazione della terapia
Vvivian G. Oehler, ASH 2013
Frontline therapy in CML
Only around 13% of CML patients treated with
imatinib are likely to achieve treatment-free
remission (TFR)
Can this be improved with more potent TKIs?
The expectation that more potent TKIs will lead to
more patients achieving TFR is the strongest
justification for frontiline therapy with these agents
ENESTnd 5-Year Update
ENESTnd Update: Nilotinib vs Imatinib
in Patients With Newly Diagnosed CMLCP and the Impact of Early Molecular
Response and Sokal Risk at Diagnosis
on Long-Term Outcomes
G. Saglio, A. Hochhaus, T. P. Hughes, R. E. Clark, H. Nakamae,
D.-W. Kim, S. Jootar, G. Etienne, I. W. Flinn, J. H. Lipton,
R. Pasquini, B. Moiraghi, C. Kemp, X. Fan, H. D. Menssen,
H. M. Kantarjian, and R. A. Larson,
on behalf of the ENESTnd Investigators
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
ENESTnd Study Design
Nilotinib 300 mg BID (n = 282)
N = 846
217 centers
35 countries
R
A
N
D
O Nilotinib 400 mg BID (n = 281)
M
I
Z
E
Imatinib 400 mg QD (n = 283)
Follow-up: 5 years; extended to 10 years
after protocol amendment
•
Patients were stratified according to Sokal risk score at diagnosis
BID, twice daily; QD, once daily.
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
Cumulative Incidence of MMR
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
100
By 1 Yeara
Patients With MMR, %
90
By 4 Yearsa
80
By 5 Yearsa
77%, P < .0001
76%, P < .0001
55%, P < .0001
77%, P < .0001
70
73%, P < .0001
60
∆ 17% to 20%
50
∆ 17%
60%
56%
51%, P < .0001
∆ 24% to 28%
40
30
27%
20
10
0
0
1
2
3
4
5
6
Time Since Randomization, Calendar Years
MMR, major molecular response (BCR-ABLIS ≤ 0.1%).
a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
Cumulative Incidence of MR4.5
100
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Patients With MR4.5, %
90
80
70
By 5 Yearsa
By 4 Yearsa
60
54%, P < .0001
By 1
50
Yeara
40
30
11%, P < .0001
40%, P < .0001
52%, P < .0001
37%, P = .0002
∆ 21% to 23%
20
∆ 6% to 10%
10
31%
∆ 14% to 17%
23%
7%, P < .0001
1%
0
0
1
2
3
4
5
6
Time Since Randomization, Calendar Years
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.
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
MR4.5 by 5 Yearsa According to Sokal Risk Score
P = .0004
P = .0082
P = .0148
P < .0001
P = .0105
P = .0041
n=
104
103
(n = 283)
a By
cycle 60 (28 days per cycle).
103
101
101
100
(n = 282)
78
78
78
(n = 281)
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
Studya
Progression to AP/BC on
(Including After Treatment Discontinuation)
P = .0047
New events
in year 5
P = .0588
6
7.1%
Imatinib 400 mg QD (n = 283)
3.5%
Nilotinib 300 mg BID (n = 282)
2.1%
Nilotinib 400 mg BID (n = 281)
Two new progressions on study in year 5 (1 in the nilotinib 300 mg BID arm and 1 in
the imatinib arm)
Both patients had BCR-ABL > 10% at 3 months
a
Includes progression to AP/BC (excluding clonal evolution) or deaths in patients with advanced CML occurring on study (on
core or extension treatment or during follow-up after treatment discontinuation).
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
PFS and OS on Study
(Including After Treatment Discontinuation)a
Imatinib
400 mg QD
(n = 283)
Nilotinib
300 mg BID
(n = 282)
Nilotinib
400 mg BID
(n = 281)
91.1
92.0
95.3
Progressions and deaths, n
23
22
11
Hazard ratio (95% CI)
—
0.92 (0.51-1.65)
0.46 (0.23-0.95)
.77
.03
91.6
93.6
96.0
Total deaths, n
21
18
10
Deaths in patients with
advanced CML, nb
15
6
4
Hazard ratio (95% CI)
—
0.84 (0.45-1.58)
0.46 (0.22-0.98)
P value
—
.58
.04
Estimated 5-year PFS, %
P value
Estimated 5-year OS, %
a
There were 6 newly reported deaths in year 5
Imatinib (n = 2): both due to study indication
Nilotinib 300 mg BID (n = 3): study indication, rectal cancer, and pneumonia
Nilotinib 400 mg BID (n = 1): sepsis
Includes events occurring on core or extension treatment or during follow-up after treatment discontinuation.
for whom the principle cause of death was either “study indication” or “unknown” or not reported but occurred
subsequent to a documented progression to AP/BC.
Saglio G, et al. Blood. 2013:[abstract 92].
b Patients
ENESTnd 5-Year Update
BCR-ABL Categories at 3 Months*
BCR-ABL ≤10%
100
91
80
Patients, %
67
Imatinib (n=264)
Nilotinib 300 mg BID (n=258)
>1- ≤10%
60
BCR-ABL >10%
40
>1- ≤10%
33
≤1%
20
9
≤1%
0
n
176
234
88
24
BCR-ABL Level at 3 Months
•
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.
Saglio G, et al. Blood. 2013:[abstract 92].
ENESTnd 5-Year Update
OS by BCR-ABL Levels at 3 Months
Imatinib 400 mg QD
Nilotinib 300 mg BID
EMR Failure:
33% of pts
EMR Failure:
9% of pts
100
90
80
70
60
50
40
30
20
10
0
Patients Alive, %
97.6%
95.7% P = .4871
BCR-ABL Level
≤ 1%
> 1% to ≤ 10%
> 10%
Censored
Observations
0
1
2
Pts
145
89
24
Evt
6
2
5
3
81.9% P = .0007
Cen
139
87
19
4
5
6
Time Since Randomization, Calendar Years
OS by 5 Yearsa
100
90
80
70
60
50
40
30
20
10
0
99.2%
95.3%
P = .0873
P < .0001
79.5%
Patients Alive, %
OS by 5 Yearsa
BCR-ABL Level
≤ 1%
> 1% to ≤ 10%
> 10%
Censored
Observations
0
1
2
Pts
43
133
88
3
Evt
2
1
16
Cen
41
132
72
4
5
6
Time Since Randomization, Calendar Years
Patients with EMR failure (BCR-ABL > 10% at 3 months) have
significantly worse 5-year OS
Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib
Cen, censored; EMR, early molecular response; Evt, events; Pts, patients.
a OS rates reported consider each year to consist of twelve 28-day cycles.
Saglio G, et al. Blood. 2013:[abstract 92].
DASISION 4-Year Follow-up
Four-Year (Yr) Follow-Up of Patients (Pts) With Newly
Diagnosed Chronic Myeloid Leukemia in Chronic
Phase (CML-CP) Receiving Dasatinib or Imatinib:
Efficacy Based on Early Response
J. Cortes,1 A. Hochhaus,2 D.-W. Kim,3 N.P. Shah,4 J. Mayer,5
P. Rowlings,6 H. Nakamae,7 M.B. Bradley-Garelik,8 H.
Mohamed,9 H. Kantarjian,1 G. Saglio10
1University
of Texas M.D. Anderson Cancer Centre, Houston, TX, USA;
Jena, Jena, Germany; 3Seoul St. Mary’s Hospital, Seoul,
Republic of Korea; 4UCSF School of Medicine, San Francisco, CA, USA;
5Department of Internal Medicine, Hematology and Oncology, University
Hospital Brno, Brno, Czech Republic; 6Calvary Mater Newcastle Hospital,
University of Newcastle, Australia; 7Osaka City University Hospital, Osaka,
Japan; 8Bristol-Myers Squibb, Wallingford, CT, USA; 9Bristol-Myers Squibb,
Plainsboro, NJ, USA; 10University of Turin, Turin, Italy
2Universitatsklinikum
DASISION 4-Year Follow-up
DASISION (CA 180-056) Study Design
Treatment-naive
CML-CP patients
(N=519)
108 centers
26 countries
Enrollment:
September 2007 ‒
December 2008
aStratified
•
Dasatinib 100 mg QD (n=259)
Randomizeda
Imatinib 400 mg QD (n=260)
by EURO (Hasford) risk score
Primary end point: confirmed CCyR by 12 months
– 77% dasatinib versus 66% imatinib (P=0.007)1
1. Kantarjian H,et al. N Engl J Med. 2010;362:2260-70
DASISION (CA 180-056): NCT00481247; CCyR = complete cytogenetic response.
Long-term
follow-up
DASISION 4-Year Follow-up
Cumulative Rate of MMR
Dasatinib 100 mg QD
100
% With MMR
80
60
Imatinib 400 mg QD
P<0.0001
1.6-Fold higher
likelihood of
achieving MMR
with dasatinib;
HR=1.55
(1.26-1.91)
74%
76%
69%
64%
63%
46%
60%
55%
46%
40
23%
20
0
0
12
24
36
48
60
Months
Hasford Risk Score
MMR = major molecular response,
BCR-ABL (IS) ≤0.1%;
IS = International Scale.
MMR 4-y cumulative rates
Low
Intermediate
High
Dasatinib
90%
70%
65%
Imatinib
69%
63%
52%
DASISION 4-Year Follow-up
Cumulative Rate of MR4 and MR4.5
Dasatinib 100 mg QD
Imatinib 400 mg QD
MR4
MR4.5
P<0.0021
P<0.030
60
60
47%
53%
50
35%
40
42%
28%
35%
30
12%
20
% With MR4.5
% With MR4
50
34%
40
23%
30
30%
18%
20
22%
37%
21%
3%
17%
10
10
12%
9%
5%
0
0
12
0
24
36
Months
MM 4 = BCR-ABL (IS) ≤0.01%
MM 4.5 = BCR-ABL (IS) ≤0.0032%
IS = International Scale.
48
60
2%
0
12
24
36
Months
48
60
DASISION 4-Year Follow-up
Transformation to AP/BP CML by 4 Years
On Study
•
a
Including Follow-up Beyond
Discontinuation (ITT)a
One patient (on imatinib) transformed on study between 3 and 4 years
Yearly evaluation after discontinuation are currently stipulated per protocol; additional information on
patient status may be provided by investigators at other times.
DASISION 4-Year Follow-up
Overall Survival and Progression-Free Survival
Dasatinib
100 mg QD
(n=259)
Imatinib
400 mg QD
(n=260)
Hazard
ratio
19
21
-
Estimated 4-year OS, %
92.9
(89.7-96.1)
92.1
(88.7-95.4)
HR=0.91
(0.49-1.69)
Estimated 4-year PFS,b%
90.0
(86.0-93.9)
90.2
(86.3-94.1)
HR=1.04
(0.58-1.87)
Total number of deaths,a n
aOn-study
treatment and in follow-up after discontinuation of randomized treatment.
bProgression was defined as doubling of WBC count, loss of CHR, increase in Ph-positive
metaphases to >35%, transformation, or death from any cause.
DASISION 4-Year Follow-up
ELN-Defined Molecular Responses1
Dasatinib
100 mg QD
(n=259)
Imatinib
400 mg QD
(n=260)
At 3 months
n
Optimal: BCR-ABL ≤ 10%
Warning: BCR-ABL > 10%
235
198 (84)
37 (16)
239
154 (64)
85 (36)
At 6 months
n
Optimal: BCR-ABL ≤ 1%
Warning: BCR-ABL > 1-10%
Failure: BCR-ABL > 10%
236
164 (69)
46 (19)
26 (11)
238
117 (49)
80 (34)
41 (17)
At 12 months
n
Optimal: BCR-ABL ≤ 0.1%
Warning: BCR-ABL > 0.1-1%
Failure: BCR-ABL > 1%
224
102 (46)
82 (37)
40 (18)
221
66 (30)
82 (37)
73 (33)
1Baccarani
M, et al. Blood. 2013;122:872-84.
ELN = European LeukemiaNet.
Relazione tra riduzione del trascritto a 3 mesi e
outcome clinico a lungo termine
Linea di
trattamento
Follow-up
Agente
Risposta
molecolare a 3
mesi
PFS
OS
Prima linea
DASISION
4 anni
Dasatinib
100 mg/die
<10% vs >10%
BCR/ABL
93,3%
vs
72,9%
95,4% vs
82,9%
Prima linea
ENESTnd
5 anni
Nilotinib
300 mg BID
<10% vs >10%
BCR/ABL
95,2%
vs
82,9%
96,7% vs
86,7%
Marin et al, JCO 2012
Prediction of PFS and OS
by early molecular and cytogenetic response
(CML German trial, 1303 patients)
A total of 1303 newly diagnosed Imatinib-treated pts were investigated
to correlate molecular and cytogenetic 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 cytogenetic response levels at 3
months of imatinib treatment are significantly
associated with long-term progression-free and
overall survival.
Hanfstein et al, Leukemia 2012
Hanfstein et al, Leukemia 2012
The measurement of the transcript level at 3 months in pts. treated
with 1st line Dasatinib is also predictive for outcome, allowing the
dentification of approximately 10% of pts. with low probability of
achieving CCyR and deep molecular responses
Marin et al, Blood 2012
EFS and FFS according to cytogenetic and
molecular response at 3 months
Patients wth poor response at 3 months have significantly
inferior EFS and FFS compared with those with better responses
Jain et al, Blood 2013
Il trascritto al 6°mese non aggiunge informazioni rispetto
al 3° mese che mantiene la sua validità in termini di OS
254 Any BCR-ABL Reduction Below 10% At 6 Months Of Therapy Significantly Improves Outcome
For CML Patients With a Poor Response At 3 Months
Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy: Early Surrogate Markers of Outcome, Long-Term Treatment and Treatment Discontinuation
Susan Branford, PhD1, Nicola Roberts, BSc2*, David T Yeung, BSc, MBBS, FRACP, FRCPA2,3, Haley Altamura, BSc2*, Wendy T Parker, PhD1* and Timothy P. Hughes, MD, MBBS4
Summary of 6-Month Responses Among Patients With
BCR-ABL Level >10% at 3 Months
Dasatinib
100 mg QD
(n=259)
Imatinib
400 mg QD
(n=260)
BCR-ABL at 6 months
Total
≤1%
37
3
10
Transformations
to AP/BP, n
5
-
Deaths from
any cause, n
6
-
BCR-ABL >10%
at 3 months, n
>1-10% >10%
BCR-ABL at 6 months
ND
Total
≤1%
>1-10% >10%
ND
21
3b
85
7
35
37
6c
-
5
-
13
-
3
8
2
-
5
1
14
-
4
8
2
ND = not determined.
aData are provided only for patients who remained on therapy through 6 months and had a molecular assessment at
the indicated time point.
bWith dasatinib, 3 patients discontinued between 3 and 6 months because of toxicity (n=2) and pregnancy (n=1).
cWith imatinib, 6 patients discontinued between 3 and 6 months because of progression (n=1), toxicity (n=1),
noncompliance (n=1), patient request (n=1), loss to follow-up (n=1), and unknown reasons (n=1).
34
3M
EUROPEAN LEUKEMIANET 2013
RESPONSE TO TREATMENT
FIRSTLINE,
You &
can
also
Wait
monitor
Switch!
wait
& closely!
monitor
more
IMATINIB, NILOTINIB,
and DASATINIB
more closely!
OPTIMAL
BASELINE
3 mo
6 mo
NA
WARNING
-HIGH RISK,
-CCA/Ph+
(Major route)
FAILURE
NA
Efficacy of
Ph+ ≤ 35% and/or
Ph + 36-95% and/or
No CHR and/or
switching
is
not
BCR-ABL ≤ 10%
BCR-ABL ≥ 10%
Ph + > 95%
yet
demonstrated
Ph+ 0 and/or
Ph + 1-35% and/or
Ph + > 35% and/or
BCR-ABL < 1%
BCR-ABL 1-10%
BCR-ABL > 10%
12 mo
BCR-ABL≤ 0.1%
BCR-ABL 0.1-1 %
Ph + ≥ 1%, and/or
BCR-ABL > 1%
24 mo
BCR-ABL ≤ 0.1%
BCR-ABL 0.1-1%
BCR-ABL > 1%
Yellow = cytogenetic response
Baccarani M et al., submitted comm.
Evoluzione degli obiettivi terapeutici
Ph+ CML
Diagnosis
CHR
CCyR
MMR
Not
sufficient
OS
PFS & EFS
Baccarani et al., J Clin Oncol. 2009;27(35):6041-6051.
MR 4.5
MR4.5 and TFR
Achieving the CMR is the first step to the discontinuation
Discontinuations by patients with less than CMR are less successful
Response at Time of Treatment Patients With Molecular and/or
Discontinuation
Cytogenetic Relapse, %
CCyR1
100%
MMR2
100%
MMR, CCyR, MCyR3
100%
CMR for ≥ 2 years 4
61%
CCyR, complete cytogenetic response; CMR, complete molecular response;
MCyR, major cytogenetic response; MMR, major molecular response.
1. Goh HG, et al. Leuk Lymphoma. 2009;50(6):944-951.
2. Koskenvesa P, et al. Blood. 2008;112(11):738 [abstract 2121].
3. Kuwabara A, et al. Blood. 2010;116(6):1014-1016.
4. Mahon FX, et al. Abstract 255. 2013 ASH meeting
TKIs discontinuation
40% of patients in deep molecular response maintained this result after IM
discontinuation
A significant difference in the cumulative incidence of stable MR4.5 was
observed
according to BCR/ABL1 value at 3 months
Treatment-free Remission Studies Supported by Novartis
Novartis is supporting
8 TFR studies, including:
– 4 company-sponsored trials
• ENESTpath
• ENESTop
• ENESTgoal
• ENESTfreedom
– 4 investigator-initiated trials
Conclusioni
Identificare precocemente i pazienti ad outcome non ottimale
(indipendentemente dall’inibitore scelto).
Una riduzione a 3 mesi del trascritto BCR/ABL < 10% rappresenta lo
strumento più accurato per dimostrare l’efficacia della terapia
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)
«Treatment-Free Remission (TFR)»