Transcript Serum Thymidine Kinase as a Prognostic Marker in Early CLL

Chronische lymphatische
Leukämie – Was ist neu?
Michael Hallek
www.dcllsg.de
CLL: Stadium bestimmt Behandlung
Überleben
(Jahre)
Behandlung
indiziert?
A
0-2 Lymphknotenregionen
> 10
Nein
B
>= 3 LKregionen
5
Außer bei
Symptomen oder in
Studien.
C
Hb < 10 g/dl;
Thrombozyten
< 100000
1,5-3
Ja
BinetStadium
Definition
CLL in frühen Stadien
CLL1: DESIGN AND STUDY POPULATION (n = 630)
Binet stage A
877 pts
LDT <12/>12 months
BM diffuse/non diffuse
Risk Stratification
804 pts
Inclusion/Exclusion ok
728 pts
LOW RISK
535 pts
n = 630
TK ≤/> 7 U/L
ß2-MG ≤/> 3.5 mg/L
HIGH RISK W&W
95 pts
HR Fludarabine
98 pts
R
PFS AND OS RELATED TO RISK STRATIFICATION
LR = 522; Events = 262
HR W&W = 94; Events = 75
LR = 527; Events = 42
HR W&W = 93; Events = 19
p<0.001
p<0.001
PFS %
3-year
5-year
10-year
OS %
3-year
5-year
10-year
LR
60
52
17
LR
97
94
82
HR-W&W
26
19
n. a.
HR-W&W
92
81
n. a.
PFS AND OS IN RELATION TO IGVH-STATUS + FISH
p<0.001
p<0.001
p=0.054
PFS mo
17p-
11q-
VHun
/not
17p11q
median
15
19
43
VHmut
/not
17p11q
OS mo
17p-
75
75thper
50
11q-
VHun
/not
17p11q
VHmut
/not
17p11q
78
71
122
Conclusion: Top 10 variables predicting OS and
PFS in untreated, early stage CLL
PFS
Feature at Presentation
OS
HR
Feature at Presentation
HR
Del 11q22-q23 absence/presence
3.219
VH Status mutated/unmutated
6.782
VH Status mutated/unmutated
2.941
ß2-MG ≤3.5/>3.5
4.781
ß2-MG ≤3.5/>3.5
2.927
Del 17p13 absence/presence
4.441
TK ≤10/>10
2.535
TK ≤10/>10
4.364
Lymphocyte count <30.000/ ≥30.000
2.462
Lymphocyte count <30.000/
≥30.000
2.793
LDT <12/>12
2.436
LDT <12/>12 months
2.541
Lymphadenopathy 0/1/ ≥2
2.337
Del 11q22-q23 absence/presence
2.266
Rai stage 0/ ≥1
2.061
Age <60/≥60
2.022
Del 17p13 absence/presence
1.863
Trisomy 12 absence/presence
1.903
LDH <250/≥250
1.831
Sex Female/male
1.705
Cox regression model
(excluding cytogenetics): Overall survival
Parameter
p
TK (≤ / > 7.0)
.045
2.445
1.020
5.857
ß2-MG (≤/> 3.5)
.004
3.670
1.516
8.882
LDT (≥ / < 1 y)
<.001
5.751
2.588
12.783
ALC (< / ≥ 30)
.003
3.614
1.559
8.375
<.001
4.180
1.887
9.260
AGE (<65/≥ 65)
Hazard
95% CI
Major factors predicting an
unfavorable course in Binet stage
A/Rai stage 0 CLL
• Chromosomal aberrations 17p- and 11q• Elevated serum thymidine kinase (> 10
U/L)
• Lymphocyte doubling time < 12 months
• Unmutated IgVH gene
• Expression of cytoplasmic ZAP70
• Elevated surface expression of CD38?
CLL7 protocol of the GCLLSG/FCLLSG
Patients at Binet stage A or B without symptoms
Aim and Rationale: Complete (MRD-) eradication of early high risk disease
Assessment of 4
prognostic factors:
• 11q- or 17p- deletion
• Unmutated IgVH-Status
• Serum thymidine kinase >
10 U/L
• Lymphocyte doubling time <
12 months
Low risk:
< 2 factors
positive
watch and wait
2/3 of patients
FCR
High risk: 2 or
more factors
positive
1/3 of patients
watch and wait
Ältere (komorbide) Patienten mit
CLL in fortgeschrittenen Stadien
CLL5 protocol for elderly patients with
advanced CLL
CLL, > 65 years, untreated,
Binet stage C or symptomatic
A/B
6 x Fludarabine
phosphate
F 25 mg/m², Days 1–5
q 28 days
Chlorambucil
(up to a maximum of 12
months)
Clb 0.4 mg/kg body weight
increasing 0.1 mg up to
0.8 mg/kg body weight
q 15 days
CLL5 protocol
Overall Survival (OS)
1.0
0.9
random
F
CLB
F-censored
CLB-censored
Cum Survival
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
Overall survival in months
Median OS: F 45.8 months; Clb 63.6 months
p = 0.15
CLL5 protocol
Cause of death
5%
6%
25%
3%
66%
CLL related
Treatment related
Secondary disease
Unknown
31%
54%
10%
Clb arm: 32 patients died
F arm: 42 patients died
CLL related
Treatment related
Secondary disease
Unknown
Jüngere (fitte) Patienten mit CLL in
fortgeschrittenen Stadien
First-line R-FC: improved OS
following CR
1.0
Outcome
Probability
0.8
0.6
n
p value
CR
217
nPR
31
PR-i
21
PR-d
16
p=0.16
Fail
15
p=0.10
p=0.12
p<0.01
0.4
0.2
0
0
12
24
36
48
60
72
84
96
108
Time (months)
nPR = nodular PR
PR-i = met all criteria for CR except for incomplete recovery of blood counts
PR-d = residual disease in blood, nodes, spleen, marrow or other sites
Tam CS, et al. Blood 2008;112:975–80
F±P vs F±M/C vs R-FC: improved survival with
rituximab (historical comparison)
Outcome
1.0
Probability
0.8
n
6-year OS
F
190
54%
F±M/C
140
59%
R-FC
300
77%
p value
p=0.37
p<0.001
0.6
0.4
0.2
0
0
12
24
36
48
60
72
84
96
108
Time (months)
Tam CS, et al. Blood 2008;112:975–980
CLL8: first-line treatment of CLL
6 x FCR
Final staging
and follow-up
6 x FC
Final staging
and follow-up
817 untreated
patients with
Binet B/C CLL
randomised
 In January 2008, the DSMB concluded that the study
had reached the primary endpoint (PFS, difference of
at least 35% at 2 yrs)
 FCR is the superior study arm
CLL2M
study design II
Protocol amendment 1
Second to fourth-line therapy
First-line therapy
81 patients
119 patients
6 cycles BR
6 cycles BR
Bendamustine 70mg/m2 day 1-2
q4wks, cycle 1-6
Bendamustine 90mg/m2 day 1-2
q4wks, cycle 1-6
Rituximab 375 mg/m2 day 0, cycle 1
500 mg/m2 cycle 2-6
Rituximab 375 mg/m2 day 0, cycle 1
500 mg/m2 cycle 2-6
BR GCLLSG – FCR Wierda
BR
CLL2M GCLLSG
FCR Wierda et al.,
JCO 2005
% of patients
% of patients
Number of patients
62
177
Median number of
pretreatment
2 (1-3)
2 (1-10)
ORR
77.4%
73%
CR
14.5%
25%
nPR
1.6%
16%
PR
61.3%
32%
Patients characteristics
Efficacy
TTP/OS
28 months/42 months
Response by pretreatment
Pts (N)
ORR (%) CR
Fludarabine sensitive
41
70.7%
Fludarabine refractory
9
77.8%
-
Pts (N)
ORR (%) CR(%)
108
76%
37
59%
5%
BR GCLLSG – FCR Wierda
BR CLL2M
GCLLSG
FCR Wierda et al.,
JCO 2005
% of all cycles
% of all cycles
N cycles
328
529/539/745
Neutropenia CTC 3+4
12.2%
62 %
Thrombocytopenia CTC 3+4
9.1%
17%
Major infection
5.2%
5%
Safety
Anemia
6.1% (of all cycles)
24% (of all pts)
PCP prophylaxis applied
none by routine
none by routine
Antiviral prophylaxis applied none by routine
none by routine
Growth factors applied
none by routine
none by routine
CLL 10 protocol of GCLLSG
Fludarabin
Cyclophosphamid
Rituximab
(FCR)
Fludarabine 25 mg/m² i.v., days 1-3
Cyclophosphamide 250 mg/m², days 1-3,
Rituximab: 375 mg/ m2 i.v. day 0, cycle 1
Rituximab: 500 mg/m² i.v. day 1, cycle 2-6
R
Bendamustin
Rituximab
(BR)
Bendamustine 90mg/m² day 1-2
Rituximab 375 mg/m² day 0, cycyle 1
Rituximab 500 mg/m² day 1, cycyle 2-6
Similar efficacy of BR in comparison to FCR?
Lower toxicity rate of BR?
3rd generation of trials of the GCLLSG:
Risk, stage and fitness adapted
Inactive Binet A
Active disease + all Binet C, not del(17p)
CLL12
CLL10
CLL11
Go Go
Slow go
Which is the best score to define
high risk?
no
W&W
yes
W&W
treat
BR
FCR
Disease (MRD) eradication?
Longer survival?
CLB
CLB + R
Symptom control?
longer disease-free survival?
CLL Treatment 2008
Binet Stage
Fitness
First line treatment
GCLLSG trial
A, asymptomatic B
Irrelevant
None
CLL7CLL12
Go Go
FCR (BR, FR, FCA)
Del(17p): FCA AlloTx
CLL10
Slow Go
CLB, Bendamustine F (+C?
+R?, reduced dose)
CLL11
Fitness
Second line
GCLLSG trial
Go Go
Alemtuzumab, FC-A Allo
Tx
CLL2O, CLL2L,
CLLX2
Slow Go
Alemtuzumab (17p-),
Bendamustine (+R), RCHOP, lenalidomide?
CLL2O, CLL2P
Go Go &
Slow Go
Repeat first line
C, symptomatic B
Relapse
Early (< 1 year) =
refractory disease
Late (> 1 year)