Chronic lymphocytic leukemia Prognosis and treatment
Emili Montserrat
Institute of Hematology and Oncology. University of Barcelona
ESH - Hammamet, 28 October 2010
Chronic Lymphocytic Leukemia
• Most frequent form of leukemia in Western world. Incidence: 3-20/100,000
• Median age at diagnosis: 72 yrs• Heterogeneous disease
– Clinically– Biologically
• Accumulation of B lymphocytes – SmIg weak, CD5+, CD19+, CD20 weak, CD23+
• Immune disturbances• Genetic background• No curative treatment
CLL diagnosis
• > 5,000 monoclonal lymphocytes in peripheral blood
• Characteristic immunophenotype– SmIg weak, CD5+, CD19+, CD20 weak,
CD23+
• Not necessary (but useful on many occasions)– Bone marrow aspirate/biopsy– Lymph node histology
CLL: Age at diagnosis<45 45-54
55-64
65-74
>75
Adapted from SEER (1975-2005)
43%
22%
35%
Prognostic Factors in CLL: Why?
• No curative therapy for CLL
• Heterogeneous clinical couse
CLL: natural history
Lymphocytosis Good prognosis
Intermediate prognosis
Bad prognosis
SurvivalNormal
Months
Anemia,
thrombocytopenia
Lymphadenopathy,
enlarged spleen, liver
Overall survival in CLL
Pro
bab
ility
Time (years)
0.8
0.6
0.4
0.2
0
1.0
0 5 10 15 20 25 30 40
Low risk
High risk
Intermediate risk
Relevant Prognostic Factors in CLL
• Classical– Clinical stages– Tumor burden (e.g. WBC count) – LDT
• New– Serum markers (Beta-2 microglobulin)– Cytogenetics– CD38– IGVH mutations– ZAP-70 expression
Prognostic factors vs. Response predictors
• Prognostic factors– predict the natural history of the disease upon no
therapy or no effective therapy– highly dependent on response to therapy
(response to therapy by itself is the most important prognostic factor)
• Response predictors– factors (mainly biological) that predict response to
a given therapy
CLL: Most important biologic response predictors
17p- Resistance to fludarabine, alkylators, rituximab
11q- RR (F< FC < FCR)
Early relapse
From Prognostic Factors to Response Predictors
Diagnosis
Prognostic
Factors
Valuable information
(i.e. risk, frequency of f/u)
No disease activity
Disease activity(Need for therapy)
Response predictors
Risk adapted & Targeted therapy
C. Moreno, E. Montserrat Blood Rev. 2008
Prognostic factors in real life
At diagnosis
• Clinical stages
• LDT
• B2 microglobulinare more than enough!
Before starting treatment
• FISH (TP53 and ATM abnormalities) (17p-, 11 q-)
CLL treatment: when to treat
• General symptoms
• Lymphadenopathy or splenomegaly increasing in size or causing symptoms
• Decreasing hemoglobin levels or platelet counts
• Rapid doubling time
• Autoimmune hemolytic anemia not responsive to corticosteroids
• Hypogammaglobulinemia with infections
CLL treatment: when to treat
• General symptoms
• Lymphadenopathy or splenomegaly increasing in size or causing symptoms
• Decreasing hemoglobin levels or platelet counts
• Rapid doubling time
• Autoimmune hemolytic anaemia not responsive to corticosteroids
• Hypogammaglobulinemia with infections
Biological markers (e.g. cytogenetics, CD38, ZAP-70, IgVH mutations) NOT an indication to
start therapy outside clinical trials
Chemoimmunotherapy (rituximab-based) is the new gold
standard for CLL therapy
Days of course
DrugDose
(mg/m2)Course 1
Courses 2–6
Rituximab 375–500Day 1
(375 mg/m2)Day 1
(500 mg/m2)
Fludarabine 25 2–4 1–3
Cyclophosphamide 250 2–4 1–3
First-line FCR: Dose and schedule
Allopurinol 300 mg/day Tam CS, et al. Blood 2008; 112: 975-980
First-line R-FC: improved OSfollowing CR
Time (months)
120 24 36 48 60 72 84 96 108
Pro
bab
ilit
y
0.8
0.6
0.4
0.2
0
1.0
nPR = nodular PRPR-i = met all criteria for CR except for incomplete recovery of blood countsPR-d = residual disease in blood, nodes, spleen, marrow or other sites
Outcome n p value
CR 217
nPR 31
PR-i 21
PR-d 16
Fail 15
p=0.12
p<0.01
p=0.16
p=0.10
Tam CS, et al. Blood 2008; 112: 975-980
Time (months)
120 24 36 48 60 72 84 96 108
Pro
bab
ilit
y
0.8
0.6
0.4
0.2
0
1.0Protocol n 6-year OS p value
R-FC 300 77%
F±M/C 140 59%
F 190 54%p=0.37
Improved OS with R-FC in first-line CLL(historical comparison)
p<0.001
Tam CS, et al. Blood 2008; 112: 975-980
Confirmatory phase III trials
• REACH Study– Robak et al. J Clin Oncol 2009
• German CLL Study Group CLL8 trial– Hallek et al. Lancet 2010
The CLL-8 trial:R-FC vs. FC in previously untreated CLL
RANDOMISE
R-FC q4wk 3
FC q4wk 3
RESTAGE
R-FC q4wk 3
FC q4wk 3
SD, PD off study
CR, PR
RituximabCycle 1: 375mg/m2
Cycles 2–6: 500mg/m2
Fludarabine25mg/m2 iv, day 1–3
Cyclophosphamide250mg/m2 iv, day 1–3
Untreated B-CLL Binet B requiring
treatment or Binet C ECOG PS 0–1 n=817
Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174
ECOG PS = Eastern Cooperative Oncology Group performance status; q4wk = every 4 weeksSD = stable disease; progressive disease
FC FCR
Evaluable patients
409 408
ORR (%) 80 90
CR (%) 22 44
PFS (median)
~33 m. ~ 52 m.
OS @ 5 yrs 60% 75%
The CLL-8 trial:R-FC vs. FC in previously untreated CLL
Hallek et al. German CLL Study Group. Lancet 2010; 376 (2): 1164-1174
FCR: some caveats
• Abnormalities of TP53 (10%)
• Patients > 70 years-old (>40%!)
• Impaired renal function
• Viruses (B, C)
• AIHA, DAT-positivity
FCR: some caveats
• All patients progress
• Abnormalities of TP53 (10%)
• Patients > 70 years-old (>40%!)
• Impaired renal function
• Viruses (B, C)
• AIHA, DAT-positivity
FCR is good treatment for many, but not all, patients with CLL
CLL: Treatment of special situations
• TP53 abnormalities/refractory disease (1)
– Allogeneic stem cell transplantation– Alemtuzumab (corticosteroids)– Flavopiridol
(1) Patients not responding or progressing shortly (24-48 m.) after chemoimmunotherapy
CLL: Treatment of special situations
• Elderly patients or patients with comorbidities precluding chemoimmunotherapy
– Chlorambucil – Bendamustine – Lenalidomide – Rituximab + steroids– Trials!
CLL: Treatment of special situations
• Elderly patients or patients with comorbidities precluding chemoimmunotherapy
– Chlorambucil (+ Rituximab)– Bendamustine (+ Rituximab)– Lenalidomide (+ Rituximab)– Rituximab + steroids– Trials!
CLL Therapy 1960-2010Many things have changed…
• From chlorambucil (<10% CR) to chemoimmunotherapy (60%-70% CR)
• Chemoimmunotherapy new gold-standard for CLL therapy
• MRD- negativity CRs correlates with better outcome
• Improved PFS and OS
• Individual, risk-adapted therapy
– 11q- FCR (better than F and FC)
– 17p- Refractory to fludarabine-based
therapies.
Alternatives:
- alemtuzumab
- flavopiridol
- allogeneic stem cell tx
• Individual, risk-adapted therapy
– Patients failing to chemo-immunotherapy have very poor prognosis (median s. < 24 m.)• Allogeneic stem cell transplantation
Others have not…
• CLL continues being an incurable disease!
Others have not…
• CLL continues being an incurable disease!
– Why?
– How to improve on current therapy?
CLL Therapy: not a single target
B-cells
T-cells
Microenvironment
CLL Therapy: not a single target
B-cells
T-cells
Microenvironment
CLL Therapy: not a single target
B-cells
T-cells
Microenvironment
New agents for CLL1
• MoAb– Anti-CD20– Other– Biclonal
• Immunomodulators– Lenalidomide
• Anti Bcl-2– Oblimersen– Obatoclax– ABT-263
• CDK inhibitors– Flavopiridol
• SMIP– TRU-016 (anti-CD37)
• Syk inhibitors– Fostamatinib
• PI3K p110δ inhibitor– CAL-101
• CXCR4/CXCL12 axis inhibitors
(1) List does not intend to be comprehensive (among others, aspirine, valproic acid, green-tea, and ging-seng not included)
New agents in CLL therapy
• New chemotherapies
– Bendamustine
• New anti CD20 monoclonal antibodies
– Ofatumumab, GA101
• Immunomodulators
– Lenalidomide
CLL survival: patients ≤ 65 yearsHospital Clinic, Barcelona
Median survival• 1980–89 (n = 116): 10.0 yrs • 1990–99 (n = 197): 11.4 yrs• 2000–08 (n = 128): NR
p = 0.008p = NS
p = 0.05
2000–2008
1990–19991980–1989
Abrisqueta et al. Blood 2009
1086420Years
1.0
0.8
0.6
0.4
0.2
0.0
Su
rviv
al p
rob
abil
ity