Transcript Document

Prognosis and
treatment of Chronic
Lyphocytic Leukemia
Diagnosis of CLL
• Peripheral blood:
>5.0 x 109 B lymphocytes /L
Immunophenotype of CLL cells:
CD5+, CD19+, CD20+, CD23+
(low level expression sIg, CD20,CD79b)
•
•
•
•
Molecular cytogenetics
Mutational status
Serum markers
Bone marrow examination
Prognostic Factors
• 1980s
Clinical: Stage Binet or Rai
• 1990s
Lymphocyte doubling time <12 m
Serum markers: beta-2 microglobulin, thymidine kinase
• 2000>
• Molecular cytogenetics/molecular genetics:
Deletion 11q or 17p
Mutational status:Unmutated IGVH gene,
IGHV3-21 gene
• Flow cytometry: CD38, ZAP-70
• MRD
CLL stage predicts survival and
informs treatment decisions
Rai staging
1: Lymphocytosis with
enlarged nodes
3: Lymphocytosis with anaemia
4: Lymphocytosis with
thrombocytopenia
A: Fewer than three enlarged
nodes/nodal groups, Hb > 100 g/L;
platelets > 100 x 109/L
B: Three or more enlarged
nodes/nodal groups
Hb > 100 g/L; platelets
> 100 x 109/L
C: Hb < 100 g/L; platelets
< 100 x 109/L regardless of
number of lymphoid areas
involved
Begin treatment
2: Lymphocytosis with
enlarged spleen and/or liver
Survival (yrs)
Watch and wait
Low risk Intermediate High risk
0: Bone marrow and blood
lymphocytosis only
Binet staging
14–17
5–7
3
1. Rai KR, et al. Blood 1975; 46:219-234.
2. Binet JL, et al. Cancer 1981; 48:198-206.
Survival according to Binet Stage
1.0
Probability of survival
0.9
0.8
0.7
0.6
0.5
0.4
Binet stage A
Binet stage B
Binet stage C
0.3
0.2
0.1
0.0
0
20
40
60
80
100
Time (Months)
120
140
160
Survival according to FISH and
IGVH Mutation Status
Genomic aberrations (n=325)1
100
100
13q del only
75
12q trisomy
50
11q del
25
Survival (%)
Survival (%)
IgVH mutation status (n=211)2,3
Mutated
75
50
25
17p del
Normal
0
P < 0.0001
Unmutated
0
0
24
48
72
96
120 144 168
Time (months)
0
24 48 72 96 120 144 168 192 216
Time (months)
1. Dohner H, et al. N Engl J Med 2000;343:1910–16.
2. Rai K, et al. Hematology 2001:140–56.
3. Krober A, et al. Blood 2002;100:1410–16.
ZAP-70 Expression

ZAP-70 expression and
IgVH mutation status
ZAP-70 expression and
survival probability
Mutated
80
60
40
20
0
Unmutated
Probability of survival (%)
IgVH
ZAP-70-positive cells (%)

< 20% ZAP-70-positive cells
100
80
60
≥ 20% ZAP-70-positive cells
40
p=0.01
20
0
0
4
8
12
16
20
24
28
32
120
Year after diagnosis
Crespo M, et al. N Engl J Med 2003;348:1764–75.
Treatment is not necessary for
most patients
Percentage of patients
100
80
60
~70%
Asymptomatic at diagnosis
• ~70% of patients1
• Many will never progress
• Treatment is usually not required
40
20
~30%
Symptomatic at diagnosis
• ~30% of patients1
• Shortened life expectancy
• Effective treatment becomes essential
1. Hamblin TJ, et al. Br J Haematol 1987; 66:21–26.
Which patients are eligible for
treatment?
 Patients with intermediate, high-risk, or active disease
have significantly reduced life expectancy and require
effective treatment
 Active disease defined as any of the following:
─ Progressive marrow failure
─ Massive/progressive/symptomatic splenomegaly
─ Massive nodes or progressive/symptomatic lymphadenopathy
─ Progressive lymphocytosis
─ Refractory autoimmune anaemia and/or thrombocytopenia
─ Weight loss, significant fatigue, fever, night sweats
Rai KR, et al. Blood 1975; 46:219-234.
Binet JL, et al. Cancer 1981; 48:198-206.
Tratment of CLL
PAST
PRESENT
Watch and wait
Chlorambucil
CAP
CHOP
Conservative
approach
 CR
 Combined chemotherapy (F+C)
 MAbs: (alemtuzumab, rituximab)
 First-line treatment:
 Chemo + MAb (R-FC, HMP+Cam)
Transplantation programs (auto, allo)
 Fludurabine
FC significantly extends PFS
but has no impact on OS
• Studies
show that fludarabine plus cyclophosphamide
(FC) extends PFS but not OS1–3
PFS1
OS1
50
FC
Clb
Surviving (%)
Progression free (%)
100
FC
F
F
p = 0.00005
0
0
1
p = 0.4
Clb
2
3
Time (years)
4
5
0
1
2
3
4
5
Time (years)
1. Catovsky D, et al. Lancet 2007; 370:230–239.
2. Eichhorst B, et al. Blood 2006; 107:885–891.
3. Flinn IW, et al. J Clin Oncol 2007; 25:793–798.
Rituximab (375) 500 mg/m2 plus chemo improves
survival vs historical controls in first-line CLL
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.
Progression-free survival:
FCR versus FC (CLL8 study)
Median observation time 25.5 months
Cumulative survival
1.0
FCR
0.8
FC
0.6
0.4
0.2
Median PFS: 32.3 months for FC vs 42.8 months for FCR
0.0
p = 0.000007
0
6
12
18
24
30
36
42
48
PFS (months)
Hallek M, Fingerle Rowson G, Fink AM et al. Blood 2008; 112; abstract 325.
54
Conclusion
In CLL patients new prognostic markers are of increasing
importance for novel treatment decisions.
CLL – when to treat
Outline
• Why is that important?
• Theoretical background
–
–
–
–
Glossary
Concept of clinical stages
Evolution modalities
Examples
• What we learned in the past?
• Current gudeliness – how helpfull?
• Call for clinical trials
16
Why is that important?
• If we had efficient and non toxic therapy it would be
logical and self evident to start as soos as diagnosis
is made! The therapy should:
– Prevent progression to full blown disease with end
organ damage, especially BMF and immune deficiency
and/or malfunction etc., thus assuring normal quality
and quantity of life
– Help to repair (reverse) disrupted intrinsic regulation
mechanism(s) and regain the control over
proliferation/apoptosis of neoplastic clone etc.
• However, early treatment studied failed to fullfil what
was hoped, athough effectivly suppressing the
disease, overal benefit is doubtful (and even
questioned), so that “when to treat” question
remains open. WHY?
Theoretical background
• Glossary:
– Early vs advanced disease (related to clinical
stages)
– Stable vs progressive disease (related to
evolution type)
– Prognostic factor – individual predictor of
prognosis (or risk to progress), and large
number of new predictors have been
identified
– Prognostic index – composite predictor of
18
prognosis (or risk to progress)
Concept of clinical stages
stages
death
C
B
Categories,
Not continuous,
Not quantitative,
C is defined by BMF
A
Diagnostic treshold
start
early
advanced
19
Clinical evolution
TTMs
Continuous
Quantitative
death
progressive
DT
stable
start
20
Clinical evolution
(stable)
TTMs
Advanced/stable
9
th. theshold
The level of
advanced is
abitratry!
Early/stable
dg. theshold
0
years
21
Clinical evolution
(progressive)
TTMs
Advanced/ very
progressive
9
Early/ very
progressive
Advanced/progressive
The measurement
of progression require
unbiased parameters!
Several disease
features besides tumor
load can change
in time (ie, BMF or
immunodefficiency etc)
Early/progressive
0
years
22
Clinical evolution
(acceleration)
TTMs
Advanced/ very
progressive
Factors controlling
progression/stability
should be investigated,
and become therapeutic
targets!
9
Early/ stable
0
APOPTOSIS
RESISTANCE/
ACCUMULATION
ACTIVATION/PROLIFE
RATION
PROGRESSION
STABLE
REMISSION
23
What we learned in the past?
•
•
•
•
Clinical trials in early ‘80
IGCI-01
Franch trials
Meta-analysis
24
IGCI-01 TRIAL DESIGN (1982)
WAIT
EARLY/STA
BLE
TTMS<9
and
DT>12mo
and
No BMF
R
1
HDCLB
B-CLL
ADVANCED/
PR
TTMS>9
or
DT<12mo
or
BMF
R
1
SDCLB
25
Logrank=1.12, NS
Jaksic B, Brugiatelli M,
Nouv Rev Fr Hematol
1988;30:437-442
Surv iv al Function
Complete
Censored
Include condition: STUDY =1 AND TTMS<9
IGCI-01
1,0
1,0
0,9
0,9
0,8
0,8
Surv iv al Function
Complete
Censored
Include condition:
BINET=1
AND STUDY =1
Histogram: BINET
K-S d=,31523, p<,01 ; Lillief ors p<,01
Expected Normal
Include condition: STUDY =1
0,6
IGCI-01 FOLLOW-UP
0,5
0,4
0,3
140
0,7
120
0,6
No. of obs.
0,7
Cumulative Proportion Surviving
Cumulative Proportion Surviving
160
0,5
0,4
100
80
60
0,3
40
0,2
20
0,1
0,1
0
0,0
0,0
0,2
0,5
0
50
100
150
200
250
1,0
1,5
0
50
100
Surv iv al Time (months)
2,5
3,0
150
200
250
Surv iv al Time
Cumulativ e Proportion Surv iv ing (Kaplan-Meier)
Complete
Censored
Include condition: STUDY =1 AND TTMS<9
Cumulativ e Proportion Surv iv ing (Kaplan-Meier)
Complete
Censored
Include condition: BINET=1 AND STUDY =1
1,0
1,0
0,9
0,9
0,8
0,8
Cumulative Proportion Surviving
Cumulative Proportion Surviving
2,0
X <= Category Boundary
0,7
0,6
0,5
0,4
0,3
0,2
0,7
0,6
0,5
0,4
0,3
0,2
p = 0.43159
0,1
p = 0.87522
0,1
0,0
0,0
0
50
100
150
Time (months)
200
250
0
1
0
50
100
150
Time
200
250
0
1
Overall Survival in the First Overall Survival in the Second
Trial
Trial
Dighiero G et al. N Engl J Med 1998;338:1506-1514
CLL Trialists’ Collaborative Group – Meta-analysis
(Journal of the National Cancer Institute, 1999;91:861)
29
What we learned from performed trials:
• No advantage nor harm from alkylator early
treatment
• No survival difference in spite of high response rate
• More than 50% of patients in early stage never
progress!
• Insight into the “natural course” of disease,
awareness of the complex cellular interactions that
control disease progression, bringing up more Q
then A . Need for new approaches! (This has
impact to general th strategy!)
• However, clinical trials of these issues were
30
abandoned, focus moved to new treatments
Current guideliness – how
heplful?
• NCI & iwCLL guidelines
• Indication for treatment: Advanced stages
or BMF, or else + “active”
(progressive/symptomatic) disease
• Criteria are composite, based on different
principles:
– Longitudinal follow-up of quantitative
parameters
– Quantitative (Mass) parameters: defined level!
– Qualitative (symptomatic, response)
31
NCI criteria for active (progressive/symptomatic)
disease
cat
(Hallek, Blood, 2008)
1. Evidence of progressive marrow failure manifested by development of, or worsening of
anaemia and/or thrombocytopenia.
P
2. Massive (ie, at least 6 cm below left costal margin) or progressive or symptomatic
splenomegaly
M, P
Qual
3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy
M, P
Qual
4. Progressive lymphocytosis with an increase of more then 50% over a 2-month period,
or lymphocyte doubling time (LDT) of less then 6 months. LDT can be obtained by
linear regression extrapolation of 2 week over an observation period of 2-3 months. In
patients with initial blood lymphocyte counts of less then 30x109/l LDT should not be
used as single parameter to define a treatment indication. In addition, factors
contributing to lymphocytosis or lymphadenopathy other then CLL (eg, infections)
should be excluded.
P
5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
corticosteroids or other standard therapy
M
Qual
6. Constitutional symptoms defiend as any one or more of the following disease related
symptoms and signs:
a. Unintentional weight loss of 10% within the prevoious 6 months;
b. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual
activities);
M
Qual
0
32
NCI criteria for active (progressive/symptomatic)
disease
cat
(Hallek, Blood, 2008)
1. Evidence of progressive marrow failure manifested by development of, or worsening of
anaemia and/or thrombocytopenia.
P
2. Massive (ie, at least 6 cm below left costal margin) or progressive or symptomatic
splenomegaly
M, P
Qual
3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy
M, P
Qual
4. Progressive lymphocytosis with an increase of more then 50% over a 2-month period,
or lymphocyte doubling time (LDT) of less then 6 months. LDT can be obtained by
linear regression extrapolation of 2 week over an observation period of 2-3 months. In
patients with initial blood lymphocyte counts of less then 30x109/l LDT should not be
used as single parameter to define a treatment indication. In addition, factors
contributing to lymphocytosis or lymphadenopathy other then CLL (eg, infections)
should be excluded.
P
5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
corticosteroids or other standard therapy
M
Qual
6. Constitutional symptoms defiend as any one or more of the following disease related
symptoms and signs:
a. Unintentional weight loss of 10% within the prevoious 6 months;
b. Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual
activities);
M
Qual
0
33
Current guideliness – how heplful
with regard to treatment iniciation
• Based on convention, not EBM
– Why given level of anemia, thrombocytopenia
or limphadenopathy or splenomegaly?
•
•
•
•
Somehow loose, ambigous & imprecise
Allow broad range of variation
Endpoint “Time to treatment” is weak!
However, parameters of “active disease”
can help define treatment goals
• All aspects should be validated (EBM)!
34
∑:Call for clinical rials
• A number of imminent uncertenties should be
addressed in controlled clinical setting
• Pending questions are important for
improving and individualizing treatment
• Translational studies may open new
avenues, number of new parameters should
be validated
• There is a need to develop means to
motivate, support and re-institute
collaborative trials to answer pending open
questions
• Therefore, I call for clinical trials in this area!
35
CLL –
what is the best
1st line therapy ?
CLL active disease criteria
• Evidence of progressive marrow failure (worsening of anemia or
thrombocytopenia)
• Massive (progressive) symptomatic splenomegalia
• Massive nodes or progressive, symptomatic lymphadenopathy
• Progressive lymphocytosis (increase of >50% over 2 months, or
lymphocyte doubling time of < 6 months)
• Autoimmune anemia and/or thrombocytopenia poorly responsive
to standard therapy
• Disease-related symptoms: weigh loss ≥ 10% within 6 months,
significant fatigue (ECOG>2), fever>38,0°C ≥2 weeks, night sweats
for >1 months
Blood,2008. Hallek M et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia:
a report from the international Workshop on Chronic Lymphocytic Leukemia updating the NCI-Working Group
Treatment options for previously untreated CLL
Chemotherapy:
•
Alkylating agents (chlorambucil, cyclophosphamide,
bendamustine)
•
Nucleoside analogues (fludarabine,cladribine, pentostatine)
Immunotherapy - monoclonal antibodies:
•
Rituximab - anti CD20 antibody
•
Alemtuzumab - anti CD52 antibody
Steroids
Chlorambucil
• Alkylating agents used most frequently:
– Chlorambucil
• is used as monotherapy
• optimum dose and schedule have not been defined
CLB
0,4-0,8
mg/kg q 2
wks.
GCLLSG
Good tolerability
CLB
40 mg/m2 q
4 wks.
USA
nausea & vomiting
HD-CLB
10
mg/m2/7d q
3-4 wks.
UK
Good tolerability
Jaksic et al. 1988 compared continuous vs. intermittent HD-CLB
HD-CLB
15 mg /cont. EORTC
Good tolerability
- improved RR and OS with continuous HD-CLB
Our experience with
chlorambucil
Patients’ characteristics
• 88 patients 70 M 18 F
• age
• Binet
•
Rai
• TTM
38-88 y (median 64)
A =19 B= 38 C =31
0 =2 1=27 2=38 3=6 4=25
21 < 9
59 > 9
• dose of CLB 10-20 mg daily (median 15 mg)
• Treatment duration 2-20 weeks (median 5)
• 47 (53%) patients received CLB maintenance
Overall survival and time to
treatment
failure
OS-53 months
TTF-20 months
Progression free survival
PFS-15 months
Survival according to stage
OS - 60 vs.44 months
TTF - 30 vs. 11 months
p=0,067
p=0,058
Survival according to age
No difernece in OS
Survival according to TTM
OS- 78 vs. 44 months
p=0,021
Toxicity
• 3 patients had serious infections
• 2 died
• 5 (6%) had severe hematological toxicity, mostly
thrombocytopenia.
• Only 1 patient had severe nausea.
• Our results seem superior to pulse-dosed CLB
• R + HD-CLB continuos ?
Nucleoside analogues
Fludarabine
• most widely studied and most effective purine analogue
Fludarabine monotherapy
• Several phase III studies compared efficacy of fludarabine
monotherapy with CLB , CVP, CHOP
– Fludarabine generally induced higher RR and PFS, no difference in
OS
Fludarabine-based combination
• Different combinations were studied
– cyclophosphamide + fludarabine – the most investigated
– improves RR 69-91%, PFS 31-48 months
– no difference in OS
– acceptable toxicity (neutropenia, thrombocytopenia,
Trials in Previously Untreated CLL
Patients
Referenc
e
Regime
n
Phase
No. Pts.
CR, %
ORR,
%
PFS
Eichhorst
, 2006
Flu
III
164
7
83
20 mo.
164
24
94
48 mo.
137
5
59
19 mo.
141
23
74
32 mo.
387
7
72
10% at 5
y.
194
15
80
10% at 5
y.
Flu +
Cy
Flinn,
2007
Flu
III
Flu +
Cy
Catovsky,
2007
Chl
Flu
III
OS – no difference in any of the trials
Flu +
196
38
94
36% at 5
Monoclonal antibodiesRituximab
• Different combinations studied
– Rituximab + fludarabine
• improved OR, CR and PFS
– Rituximab + fludarabine + cyclophosphamide
• highest OR 90-95%, CR 70-72%
• acceptable toxicity
– Rituximab + fludarabine + cyclophosphamide in reduced doses
(R-FC lite)
• reduced toxicity, results similar to R-FC
– Rituximab + pentostatine + cyclophosphamide
• in patients older than 70 years results are same as in younger
Trials in Previously Untreated CLL
Patients
Referenc
e
Keating,
2005
Hallek,
2008
Regime
n
Phase
No. Pts.
CR, %
ORR, %
Median
PFS
(months
)
FCR
II
300
72
94
NR
FC
III
409
27
88
32
408
52
95
43
FCR
Kay, 2007
PCR
II
64
41
91
31
Kay, 2008
PR
II
33
30
79
12
Reynolds,
2008
PCR
III
92
7
45
Not Rep
58
Not Rep
OS – no difference in any of the trials
FCR
92
17
Our experience with rituximab in
CLL
• Rituximab 375 mg/m2
–
–
–
–
–
–
–
monotherapy
COP
CHOP
CLB
FND
FC
F
2
8
4
11
15
4
1
Patients’ characteristics
–
–
–
–
–
–
–
45 patients:
29 M 16 F
age
41-82 y (median 60)
Rai
0=2 1=13 2=15 3=1 4=14
Binet
A=5
B=25
C=15
TTM
<9=18
>9=15
0-5 line of therapy (median 1)
time from dg. 0-60 mo (median 10)
• Alive 33
Dead 12
• Follow up 6-44 months (median 17)
Response to therapy
1st
line therapy
1.linija
TOTAL
Sveukupno
47%
53%
14%
32%
KR
PR
NR
54%
2nd
therapy
2.line
linija
20%
24%
56%
PREŽIVLJAVANJE
Overall survival
n=15
1st line therapy
100
80
n=44
All patients
Sveukupno
n=25
%
60
1. linija
2nd line therapy
40
2. linija
20
0
0
3
6
9
12
15 18
21
months
mjeseci
24 27
30 33
36
Toxicity
• Acute infusion reaction
– 1 death
• Anaphylaxis during 2. infusion
• M, 78 y, R-CVP, 5.
• Infection grade 3/4
– 1. line
– >1. line
0/15
7/29
Monoclonal antibodies
• Alemtuzumab –anti CD 52
– first monoclonal antibody approved for treatment of CLL in USA,
– alemtuzumab compared with pulse-doses of chlorambucil in untreated
patients improved
• PFS,OR and CR
• time to alternative treatment
• increased minimal residual disease-negative remissions
• predictable and manageable toxicity
Hellman et al. 2007 alemtuzumab vs. CLB
• OR 83% vs. 55%, CR 24 vs 2 %, PFS 14,6 vs 11,7 months,TTF 88 vs
36 weeks
New drugs
Bendamustine
• promising results
• significant toxicity
– Knauf et al 2008 compared bendamustine versus chlorambucil
• ORR 68% vs. 31% , PFS 21,6 months vs. 8,3 months , sever infection
8% vs 3%
• ongoing trial bendamustin + rituximab vs FCR
Lenalidomide
• immunomodulatory drug
• dosing regimen not yet defined
• continuous low dose may be most effective and less toxic
Steroids
• high dose methylprednisolon + rituximab
Conclusions
• Advances in the treatment of chronic lymphocytic leukemia
improved
– overall response rates
– complete response rates
– progression free survival
• However, there is still no difference in overal survival.
• CLL remains incurable with standard therapies.
• Thus, more effective therapy is needed, particularly for patients with
high-risk CLL.
Conclusions
• The “best” initial treatment for CLL depends on desired
goals.
– disease control vs. disease eradication
– higher tolerability vs increased toxicity
• FC results in best RR and PFS but without affecting OS
• Chlorambucil is a viable alternative, specially if given
continuously in high doses
• Rituximab is not toxic, can be combined with any
chemotherapy and improves RR ,CR and PFS
– Therefore FCR > FC and R-HD-CLB > HD-CLB
•
Role for alemtuzumab – frontline or consolidation,
Thanks
• Division of Hematology
–
–
–
–
–
–
–
prof. dr B. Labar
doc. dr S. Zupančić-Šalek
doc. dr M. Mrsić
dr I. Radman-Livaja
dr D. Sertić
dr R. Serventi-Seiwerth
dr D. Dujmović
– prof. dr D. Batinić
– K. Dubravčić
–
–
–
–
prof. dr M. Sučić
dr M. Marković-Glamočak
dr S. Ries
dr K. Gjadrov-Kuveždić
– prof. dr M. Nola †
– dr I. Ilić
– dr S. Dotlić