Chronic lymphocytic leukemia Prognosis and treatment

1
Chronic lymphocytic leukemia Prognosis and
treatment

• Emili Montserrat
• Institute of Hematology and Oncology. University
  of Barcelona

ESH - Hammamet, 28 October 2010
2
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

3
CLL diagnosis

• gt 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

4
CLL Age at diagnosis
22
43
35
Adapted from SEER (1975-2005)
5
Prognostic Factors in CLL Why?

• No curative therapy for CLL
• Heterogeneous clinical couse

6
CLL natural history
Survival

• Lymphocytosis

Normal
Good prognosis
Lymphadenopathy, enlarged spleen, liver
Intermediate prognosis
Bad prognosis
Anemia, thrombocytopenia
Months
7
Overall survival in CLL
Low risk
Probability
Intermediate risk
High risk
Time (years)
8
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

9
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

10
CLL Most important biologic response predictors

• 17p- Resistance to fludarabine, alkylators,
  rituximab
• 11q- RR (Flt FC lt FCR)
• Early relapse

11
From Prognostic Factors to Response Predictors
No disease activity

• Diagnosis
• Prognostic
• Factors
• Valuable information
• (i.e. risk, frequency of f/u)

Disease activity (Need for therapy)
Response predictors
Risk adapted Targeted therapy
C. Moreno, E. Montserrat Blood Rev. 2008
12
Prognostic factors in real life

• At diagnosis
• Clinical stages
• LDT
• B2 microglobulin
• are more than enough!
• Before starting treatment
• FISH (TP53 and ATM abnormalities) (17p-, 11 q-)

13
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

14
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
15
Chemoimmunotherapy (rituximab-based) is the new
gold standard for CLL therapy
16
First-line FCR Dose and schedule
Days of course Days of course
Drug Dose (mg/m2) Course 1 Courses 26
Rituximab 375500 Day 1(375 mg/m2) Day 1(500 mg/m2)
Fludarabine 25 24 13
Cyclophosphamide 250 24 13
Tam CS, et al. Blood 2008 112 975-980
Allopurinol 300 mg/day
17
First-line R-FC improved OSfollowing CR
1.0
Outcome n p value
CR 217
nPR 31
PR-i 21
PR-d 16
Fail 15
0.8
0.6
Probability
0.4
0.2
0
12
0
24
36
48
60
72
84
96
108
Time (months)
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
Tam CS, et al. Blood 2008 112 975-980
18
Improved OS with R-FC in first-line
CLL(historical comparison)
Protocol n 6-year OS p value
R-FC 300 77
FM/C 140 59
F 190 54
1.0
0.8
0.6
Probability
0.4
0.2
0
12
0
24
36
48
60
72
84
96
108
Time (months)
Tam CS, et al. Blood 2008 112 975-980
19
Confirmatory phase III trials

• REACH Study
• Robak et al. J Clin Oncol 2009
• German CLL Study Group CLL8 trial
• Hallek et al. Lancet 2010

20
The CLL-8 trialR-FC vs. FC in previously
untreated CLL
Hallek et al. German CLL Study Group. Lancet
2010 376 (2) 1164-1174
R A N D O M I S E
R ESTAGE

• Untreated B-CLL
• Binet B requiring treatment or Binet C
• ECOG PS 01
• n817

CR, PR
Rituximab Cycle 1 375mg/m2Cycles 26
500mg/m2 Fludarabine 25mg/m2 iv, day
13 Cyclophosphamide 250mg/m2 iv, day 13
SD, PD off study
ECOG PS Eastern Cooperative Oncology Group
performance status q4wk every 4 weeks SD
stable disease progressive disease
21
The CLL-8 trialR-FC vs. FC in previously
untreated CLL
Hallek et al. German CLL Study Group. Lancet
2010 376 (2) 1164-1174
FC FCR
Evaluable patients 409 408
ORR () 80 90
CR () 22 44
PFS (median) 33 m. 52 m.
OS _at_ 5 yrs 60 75
22
FCR some caveats

• Abnormalities of TP53 (10)
• Patients gt 70 years-old (gt40!)
• Impaired renal function
• Viruses (B, C)
• AIHA, DAT-positivity

23
FCR some caveats

• All patients progress
• Abnormalities of TP53 (10)
• Patients gt 70 years-old (gt40!)
• Impaired renal function
• Viruses (B, C)
• AIHA, DAT-positivity

FCR is good treatment for many, but not all,
patients with CLL
24
CLL Treatment of special situations

• TP53 abnormalities/refractory disease (1)
• Allogeneic stem cell transplantation
• Alemtuzumab (corticosteroids)
• Flavopiridol

• Patients not responding or progressing shortly
  (24-48 m.)
• after chemoimmunotherapy

25
CLL Treatment of special situations

• Elderly patients or patients with comorbidities
  precluding chemoimmunotherapy
• Chlorambucil
• Bendamustine
• Lenalidomide
• Rituximab steroids
• Trials!

26
CLL Treatment of special situations

• Elderly patients or patients with comorbidities
  precluding chemoimmunotherapy
• Chlorambucil ( Rituximab)
• Bendamustine ( Rituximab)
• Lenalidomide ( Rituximab)
• Rituximab steroids
• Trials!

27
CLL Therapy 1960-2010Many things have changed

• From chlorambucil (lt10 CR) to chemoimmunotherapy
  (60-70 CR)
• Chemoimmunotherapy new gold-standard for CLL
  therapy
• MRD- negativity CRs correlates with better
  outcome
• Improved PFS and OS

28

• Individual, risk-adapted therapy
• 11q- FCR (better than F and FC)
• 17p- Refractory to fludarabine-based
• therapies.
• Alternatives
• - alemtuzumab
• - flavopiridol
• - allogeneic stem cell tx

29

• Individual, risk-adapted therapy
• Patients failing to chemo-immunotherapy have very
  poor prognosis (median s. lt 24 m.)
• Allogeneic stem cell transplantation

30
Others have not

• CLL continues being an incurable disease!

31
Others have not

• CLL continues being an incurable disease!
• Why?
• How to improve on current therapy?

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CLL Therapy not a single target
T-cells
B-cells
Microenvironment
34
CLL Therapy not a single target
T-cells
B-cells
Microenvironment
35
CLL Therapy not a single target
T-cells
B-cells
Microenvironment
36
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 p110d 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)
37
New agents in CLL therapy

• New chemotherapies
• Bendamustine
• New anti CD20 monoclonal antibodies
• Ofatumumab, GA101
• Immunomodulators
• Lenalidomide

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CLL survival patients 65 yearsHospital
Clinic, Barcelona
1.0
20002008
0.8
19901999
19801989
0.6
Survival probability
0.4

• Median survival
• 198089 (n 116) 10.0 yrs
• 199099 (n 197) 11.4 yrs
• 200008 (n 128) NR

p NS
0.2
p 0.008
p 0.05
0.0
10
8
6
4
2
0
Years
Abrisqueta et al. Blood 2009