LMC Ph+: introduzione
alla patologia, diagnosi,
sintesi delle linee guida,
stato dell’arte e network
internazionali
Mario Tiribelli
Clinica Ematologica di Udine
LMC in fase cronica: presentazione clinica
Asintomatica nel 50% dei casi
Sintomatologia clinica
Astenia
 Febbricola
 Perdita di peso/anoressia
 Senso di distensione
addominale

Laboratorio
Leucocitosi
 Piastrinosi

Faderl S et al, Ann Intern Med 1999; 131:207-219
Goldman JM, Curr Opin Hematol 1997; 4:277-285
Obiettività clinica

Splenomegalia
LMC: le 3 fasi del decorso clinico
Fase cronica
Durata media
4-6 anni
Fase avanzata
Accelerata
Fase blastica
Durata media
sino a 1 anno
Sopravvivenza media
3-6 mesi
Leucemia mieloide cronica – Sospetto diagnostico
leucocitosi con neutrofilia (soprattutto se GB > 20.000 /cc)
presenza di cellule immature circolanti (mieloblasti,
metamielociti)
aumento di basofili e talora eosinofili
piastrinosi (30%)
splenomegalia
Il Cromosoma Philadelphia: la causa della malattia
Traslocazione reciproca
t(9;22)(q34;q11)
t = translocation
q = long arm of chromosom
Proteina di fusione BCR/ABL con
attività tirosin-chinasica che
rappresenta la causa della LMC
Tutto parte da qui..
E arriva qui..
BCR- ABL
PATHWAYS ACTIVATED BY BCR-ABL EXPRESSION
RAS
BCR/ABL
Increased mitogenic signal
NUCLEUS
F-actin
Paxillin
ABL
Cell Cycle
Changes in adhesion
to stromal layer
Inhibition of
apoptosis
Decreased normal ABL function
at nuclear level: genomic instability
Leucemia mieloide cronica…
l’inevitabile destino senza terapia..
Fase
cronica
Fase
accelerata
Crisi blastica
leucemia mieloide cronica
terapia
Fase
cronica
Fase
accelerata
Crisi blastica
„il nulla“
LEUCEMIA : tappe della evoluzione della terapia
leucemia
(1850)
tempo
chemioterapia
(1950)
Ph1 (1960)
tanto…
Trapianto IFN
BCR/ABL PCR
Imatinib (studio IRIS)
Nuovi inibitori TK
11
ALLOGENEIC
TRANSPLANT
IN CML
(THE SEATTLE
EXPERIENCE)
Doney K et al.: Treatment of
chronic granulocytic leukemia by
chemotherapy, total body
irradiation and allogeneic bone
marrow transplantation. Exp
Hematol 6, 1978, 738-747.
Clift and Storb, BMT 1996
SOPRAVVIVENZA IFN vs CHT
STI 571 - Imatinib (Glivec)
Classe: 2-fenilaminopirimidin-derivato
Peso Molecolare: 590 Da
Imatinib: la prima terapia mirata
Druker et al. N Engl J Med (2006) 355: 2408-17
ICSG. N Engl J Med (1994) 330: 820-25
Incidence of CCyR, MMR and CMR (undetectable bcr-abl
at 4.5 log) with Imatinib – the MDACC experience
Kantarjian et al. Cancer 2008
.
12-Month Landmark Analysis
- Hammersmith
96%
74%
n = 121
n = 72
de Lavallade H et al. JCO 2008;26:3358-3363
Routine Methods for Monitoring CML Disease Burden
There are 3 routine methods for measuring
CML disease burden:
Hematologic response (HR)
1)

Measure of blood counts and differentials
1
2
Cytogenetic Response (CyR)
2)

Chromosome-banding analysis of marrow
cell metaphases
Molecular response (MR)
3)

Measurement of BCR-ABL transcript levels
relative to a control gene
3
Correlation Between Response and
Disease Burden Among Detection Methods
Number of Leukemic Cells
1012
1010
109
108
107
106
Cytogenetic
BCR-ABL Transcripts (log10)
1011
Hematologic
Dx
CHR (< 1-log)
CCyR (2-log)
RQ-PCR
MMR (3-log)
≈ 5-log reduction
Time
 BCR-ABL levels measured via RQ-PCR correlate with standard HR and CyR
criteria1-3
 RQ-PCR provides ≥ 3-log greater assay sensitivity than cytogenetics1
CHR, complete HR; Dx, diagnosis; MMR, major MR; RQ-PCR, real-time quantitative polymerase chain reaction.
1. Radich JP. Blood. 2009;114:3376-3381; 2. Baccarani M, et al. Blood. 2006;108:1809-1820; 3. Cross NC, et al. Blood. 1993;82:1929-1936
Glivec… va bene per tutti?
60%
Obiettivo raggiunto
40%
Risultato non soddisfacente
8%
Intolleranza
17%
Resistenza
15%
Perdita risposta
Resistance to treatment

Primary resistance – patient fails to
achieve a desired response to initial
treatment

Secondary resistance – patient with an
initial response to a TKI ultimately
relapses
Optimal Response &
Time Limit to Achieve it
Hematological
1 month  CHR
Cytogenetic
3 - 6 months  CCyR
Molecular
12 (??) months  MMR
Time from start of therapy
European LeukemiaNet 2013 recommendations
OPTIMAL
Baseline
NA
WARNING
- High risk (Sokal, Euro,
Eutos)
- CCA/Ph+ (major route)
FAILURE
NA
3 months
- BCR-ABL ≤ 10%
and/or
- Ph+ ≤ 35%
- BCR-ABL > 10%
and/or
- Ph+ 36-95%
- No 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%
- BCR-ABL >0.1-1%
- BCR-ABL > 1%
and/or
- Ph+ > 0%
12 months
- BCR-ABL ≤ 0.1%
CCA, clonal cytogenetic abnormalities; CHR, complete hematologic response.
Baccarani et al. Blood 2013;122:885-892.
BCR-ABLIS<9.8% in 211/279 pts (76%)
BCR-ABLIS<10% in 501/692 pts (72%)
I farmaci di nuova generazione per la LMC
Inibitori tirosin chinasi di seconda generazione
 Piu potenti di imatinib
 Efficaci nelle mutazioni resistenti a imatinib
 Profili di tossicità differenti da imatinib
Diagnosi
Resistenza o
intolleranza
o
Gli inibitori di seconda generazione
sono in grado di produrre una risposta
efficace in circa il 50% dei pazienti
resistenti o intolleranti a imatinib
diagnosi
Resistenza
o
intolleranza
o
BELA Study Design
Phase 3 open-label trial in
newly diagnosed CP CML
N = 502
139 sites
31 countries
Randomization is stratified based on Sokal risk score and
geographical regions.
R
A
N
D
O
M
I
Z
E
Bosutinib
500 mg/day
n = 250
8-year follow-up
Imatinib
400 mg/day
n = 252
8-year follow-up
1-year analysis
•
Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome–positive (Ph+) CP CML £6 mo
prior, no prior therapy other than hydroxyurea or anagrelide
•
Primary endpoint: complete cytogenetic response (CCyR) at 12 months
Cortes J, ASH 2011
BELA – CCyR Rates at Specified Times on
Therapy: ITT Population
Responders (%)
100
Bosutinib
79% 80%
Imatinib
80
*
60
*
50%
70% 68%
63%
59%
62%
67%
55%
65%
58%
49%
40
25%
20
0
3 months
6 months
9 months
12 months
18 months
24 months
*Indicates a P value <0.05, which was considered statistically significant. P values at all time points with the exception of at
Month 12 were considered exploratory.
Cumulative
by 24 months
BELA – Rates of Treatment Failure:
ITT Population
Patients (%)
15
Bosutinib
13%
Imatinib
10
5
5%
5%
4%
3%
2%
0
a
Treatment failure
Transformation to
AP/BP
Overall deaths
AP, accelerated phase; BP blast phase.
aTreatment failure/disease progression includes both on-treatment transformation to AP/BP and lack of efficacy.
BELA – Treatment-emergent Adverse Events
Reported for ³ 10% of Patients: Safety Population
Bosutinib
(n = 248)
Adverse event, n (%)
Diarrhea
Vomiting
Nausea
Rash
Pyrexia
Upper abdominal pain
Abdominal pain
Headache
Fatigue
Upper respiratory tract infection
Cough
Arthralgia
Myalgia
Muscle cramps
Bone pain
Peripheral edema
Periorbital edema
All grades
173 (70)
80 (32)
80 (32)
59 (24)
45 (18)
35 (14)
33 (13)
32 (13)
32 (13)
29 (12)
23 (9)
18 (7)
14 (6)
11 (4)
10 (4)
9 (4)
3 (1)
Selected adverse events seen more frequently with bosutinib.
Selected adverse events seen more frequently with imatinib.
Grade 3/4
29 (12)
8 (3)
2 (1)
4 (2)
3 (1)
0
3 (1)
2 (1)
3 (1)
0
0
0
0
0
0
0
0
Imatinib
(n = 251)
All grades
62 (25)
39 (16)
91 (36)
47 (19)
31 (12)
18 (7)
17 (7)
28 (11)
34 (14)
20 (8)
27 (11)
31 (12)
30 (12)
56 (22)
26 (10)
28 (11)
37 (15)
Grade 3/4
2 (1)
0
1 (<1)
2 (1)
3 (1)
0
1 (<1)
0
2 (1)
0
0
1 (<1)
2 (1)
0
2 (1)
0
0
Dasatinib and Nilotinib in de-novo CML
DASISION
1,2
ENESTnd 3,4
Dasatinib
100 mg QD
Imatinib 400
mg QD
Nilotinib
300 mg BID
Imatinib
400 mg QD
BCR-ABL ≤ 10%IS at 3 mo.
84%
63%
90.7%
66.7%
CCyR by 1 year
83%
72%
80%
65%
MMR by 2 years
64%
46%
71%
44%
MR4.5 by 4 years
40%
23%
34%
21%
4-yrs rate of progression to
accelerated / blastic phase
3.1%
5.4%
0.7%
4.2%
92.9%
92.1%
93.6%
91.6%
4-yrs survival
Data from different studies. No direct comparison between dasatinib or nilotinib is possible or suggested.
1
Kantarjian et al. N Engl J Med 2010;362:2260-2270. 2 Cortes et al. ASH 2013 3 Saglio et al. N Engl J Med 2010;362:2251-2259.
4 Saglio et al. ASH 2013.
Cumulative incidence of MMR and MR4.5
with frontline Nilotinib and Dasatinib
Giles F et al., EJCI 2012
MR4.5 può essere un preditore di sopravvivenza
La MR4.5 a 4 anni
è stata associata ad una significativamente maggiore probabilità di OS rispetto alla
CCR (8 anni OS, 92% contro 83%).
Hehlman et al, JCO 2013
The evolution of treatment goals in CML
The evolution of treatment in CML
1960
1970
Best
expected
response
1980
1990
2000
2010
Hydroxyurea
IFN
Imatinib
Nilotinib
Nilotinib
Dasatinib
Complete
hematologic
response (CHR)
Complete
cytogenetic
response (CCyR)
Major
molecular
response (MMR)
Earlier and
Deeper
Deeper
molecular
molecular
responses
responses
Tumor
Reductiona
! 10% " 1-log
! 1% " 2-log
! 0.1%IS " 3-log
Tumor Burden
a Compared
with baseline levels.
! 0.01%IS " 4-log
! 0.0032%IS " 4.5-log
! 0.0001%IS " 5-log
CMR4 and beyond
Come valutare il paziente alla
diagnosi?
Su quali elementi basare la
scelta della terapia di prima
linea?
The evolution of treatment goals in CML
The evolution of treatment in CML
1960
1970
Best
expected
response
1980
1990
2000
2010
Hydroxyurea
IFN
Imatinib
Nilotinib
Nilotinib
Dasatinib
Complete
hematologic
response (CHR)
Complete
cytogenetic
response (CCyR)
Major
molecular
response (MMR)
Earlier and
Deeper
Deeper
molecular
molecular
responses
responses
Tumor
Reductiona
! 10% " 1-log
! 1% " 2-log
! 0.1%IS " 3-log
! 0.01%IS " 4-log
! 0.0032%IS " 4.5-log
! 0.0001%IS " 5-log
Tumor Burden
CMR4 and beyond
SURVIVAL
a Compared
with baseline levels.
CURE?
Achieving Deeper Molecular Responses May Be the First Step
to Treatment-Free Remission
Response at Time of TKI
Discontinuation
Patients With Molecular and/or
Cytogenetic Relapse, %
CCyR2
100%
MMR5
100%
MMR, CCyR, MCyR6
100%
DMR for ≥ 2 years on imatinib1,3,7,8
1. Mahon FX, et al. Lancet Oncol. 2010;11:1029-1035.
2. Goh H-G, et al. Leuk Lymphoma. 2009;50:944-951.
3. Goh H-G, et al. Blood. 2011;118:1189 [abstract 2763].
4. Rea D, et al. Blood. 2011;118:277 [abstract 604].
~30%-65%
5. Koskenvesa P, et al. Blood. 2008;112:738 [abstract 2121].
6. Kuwabara A, et al. Blood. 2010;116:1014-1016.
7. Rousselot P, et al. Blood. 2011;118:1615 [abstract 3781].
8. Matsuki E, et al. Blood. 2011;118:1607-1608 [abstract 3765].
STIM1: Patients With Sustained CMR on Imatinib Can Maintain TFR

Results for principal objective: Estimated rate of TFR at 6 months was 45% (95% CI,
34-55)1

After a median follow-up of 55 mo, molecular relapse had occurred in 61 patients2
• 58 relapses occurred during the first 7 mo
• 3 late relapses occurred at mo 19, 20 and 22
Survival Without CML Treatment
100
Estimated TFR at
60 months:
90
80
40%
(95% CI, 30%-49%)
70
60
50
40
30
20
10
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Months Since Discontinuation of Imatinib
STIM1 provided the first demonstration of the feasibility of TFR following TKI therapy in a large
cohort of patients with sustained deep molecular response
1. Mahon FX, et al. Lancet Oncol. 2010;11:1029-1035.
2. Mahon FX, et al. Blood. 2013;122(21):[abstract 255].
È possibile aumentare i pazienti eleggibili per il TFR?
100
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
90
Patients With MR4.5, %
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
Δ 21% to 23%
20
Δ 6% to 10%
10
31%
Δ 14% to 17%
23%
7%, P < .0001
1%
0
0
1
2
3
4
5
6
Time Since Randomization, Calendar Years
No patient who achieved MR4.5 on any arm progressed to AP/BC
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].
CML and the PATH TO CURE
Coming back to the new ELN
recommendations…
OPTIMAL
WARNING
FAILURE
3 months
- BCR-ABL ≤ 10%
and/or
- Ph+ ≤ 35%
- BCR-ABL > 10%
and/or
- Ph+ 36-95%
- No 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%
IF several studies have reported that a BCR-ABL >10%
at 3 months is associated with an inferior survival,
WHY was that BCR-ABL level not taken as an
indication of failure mandating a change of therapy?
Not only the level but also the
dynamics!
BCR-ABL %IS
CCyR
MMR
Baseline
3° month 6° month 9° month 12° month
Overall survival according to the RELATIVE*
BCR-ABL reduction within 3 months
*These results are expressed as BCR-ABL/GUS ratio
Hanfstein et al. EHA 2013