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