Chronic lymphocytic leukemia (CLL) / small lymphocyte

lymphoma (SLL)

Chronic lymphocytic leukemia (CLL) / small lymphocyte

lymphoma (SLL)

Tomáš KozákLecture, pregradual, summer semester 2013

3rd Faculty of Medicine, Charles University in Prague

Tomáš KozákLecture, pregradual, summer semester 2013

3rd Faculty of Medicine, Charles University in Prague

Basic characteristics of CLL and SLLBasic characteristics of CLL and SLL

• Clonal disease with accumulation of proliferating B lymphocytes that met an antigen („experienced“) and that differ by mutational status of genes for V chains of Ig

• CLL: the most frequent leukemia in western hemisphere

• Incidence: 2-15/100 000 in Europe and USA

• Median of age = 65 (cca. 15% <50)

• M:F = 2:1

• Lmyphocytosis of blood, bone marrow, lyphadenopathy, splenomegaly, BM suppression, immunosuppression & autoimmune phenomenons

• Outside of allogeneic SCT incurable, but…

Traditional perception of CLL cloneTraditional perception of CLL clone

Morphology: small lymphocytes, high N/C ration, no prominent nocleoli,99% in G0/earlyG1 phase + poor response to mitogens in vitro

Uniform metabolic inactive clone, primarily defective apoptosis

Silent clone

CLL pathogenesis: proliferation versus apoptosis

CLL pathogenesis: proliferation versus apoptosis

Stromal cells in bione marrow (niches)

IL-6, SDF-1 (stromal cell–derived factor-1)

apoptosis

MCL - 1

Nurse-like cells

in periph. bloodPodle: Chiorazzi N, Ferrarini M, ASH 2006

ProliferatonProliferaton

Unmutated B lymphoproliferation

Galton 1966 : why in ona case has CLL indolent course (20-30 years while in another progressive? „two types of CLL ???“

Hamblin TJ,Blood 1999 a Damle RN, Blood 1999 : yes two types of CLL

50% B CLL

Chronic lymphocytic leukemia: incidence

Redaelli A, et al. Eur J Cancer Care 2004

CLL: incidence according to the age

Redaelli A, et al. Eur J Cancer Care 2004

CLL: typical blood countCLL: typical blood count

CLL/SLL: current terminology according to WHO classificationCLL/SLL: current terminology according to WHO classification

1999: B-CLL, B- PLL, T-CLL, T-PLL SLL

2000: CLL/SLL = always B phenotype

B-PLL: B prolymphocytic leukemia: 2%

T-PLL: T prolymphocytic leukemia: <1%

CD5CD19

CD20

CD23SmIg

CD22

CD79b

CLL: making the diagnosisCLL: making the diagnosis

Persistent lymphocytosis > 5×109/L with chracteristic morphology & monoclonal phenotype:

CD 5+, 19+, 20+, 23+, sIg+- (dim)

• Bone marrow examination: not necessary to make the diagnosis of CLL. If localized SLL: yes

• Další vyšetření: zejména rizikové faktory

…LD, 2m, FISH, mutační stav IgVH, CD38, ZAP70….

• Ultrasonography? CT? In clinical trials

Differential diagnosis („spillover lymphomas“) Differential diagnosis („spillover lymphomas“)

Diff. dg CLL MCL FL HCL

SSpleen + + +/- ++

Morfology dcense Pleomorph various ‘Hairy’chromatin „cleaved“

Imunophenotype

CD5 ++ ++ - -

CD23 ++ - - -

CD79b - + + -

SIg dim strong strong strong

CD10 - - ++ -

Molec. genetics +12; del 13q bcl1 bcl2 various

(cytogenetics) 11q-, 17p- t(11;14) t(14;18)

SLL X CLLSLL X CLL

SLL: • Lymphadenopathy

• No cytopenia due to bone marrow infiltration

• Clonal B lymphocytes in periph. blood < 5 ×109/L

• Diagnosis made by histology of a lymphnode

CLL SLL

CLL and SLL: is there a difference?

CLL SLL

CLL and SLL: is there a difference?

≥ Ly 5x109/l≥ Ly 5x109/l < Ly 5x109/l< Ly 5x109/l

CLL = SLL

SLL KS I

SLL KS II

CLL and SLL: is there a difference?

CLL within the familyCLL within the family

• First grade relatives of pts with CLL has higher incidence of CLL and othe lymphoproliferative diseases and other tumours

• The age at diagnosis of their CLL in relatives of pts with CLL is younger but biological behaiviour varies.

15-58% first grade relatives of CLL pts have MBL (monoclonal B lymphocytosis – lymphopathy)

5% of them eventually treated for CLL in 5 years

Monoclonal B lymphocytosis (MBL)Monoclonal B lymphocytosis (MBL)

• B lymphocytes < 5x109/l • Clonal origine ( CD5+, CD20+, FMC5+, SIg)

• No lymphadenopathy, no splenomegaly

• No systemic signs of active lyphoproliferation

Classification according to Rai, Blood 1977Classification according to Rai, Blood 1977

stage signs Survival (years)

0 Lymphocytosis only > 10

I + lymphadenopathy 7 - 9

II +hepato- and/or splenomegaly 5 – 7.5

III Hb < 110 g/l 2

IV Thrombo < 100 x 109/l < 2

Classification according to Binet, Cancer 1977Classification according to Binet, Cancer 1977

Stage signs Medián survival (years)

A Involved areas<3 12

B Involved areas.≥3 5 - 7

C Hb <100g/L or thrombo < 100x109 /L

2 - 4

5 areas: clearly defined

Prognostic factors in CLLPrognostic factors in CLL

• Disease activity

a) Tumor burden:

RAI a BINET

beta 2 mikroglobulin b) Prgogressioon speed: LDT serum TK (thymidine

kinase)

• Qualitative signs a) morfology: prolymphocytes > 10% b) genom: CYTOGENETICS IGVH mutation status ZAP 70 p53 mutation c) phenotype: CD38+, CD49d d) jiné: Gender (F do better than M) Response to treatment

CLL: OS (overall survival) according to stageCLL: OS (overall survival) according to stage

Time (Months)

0 80 100 120 140 16020 40 600.0

0.5

0.6

0.7

0.8

0.9

1.0

0.4

0.3

0.2

0.1

Pro

bab

ilit

y o

f s

urv

iva

l

Binet stage ABinet stage BBinet stage C

LDT (lymphocyte doubling time)LDT (lymphocyte doubling time)

Moeller, Blood 1999

Chromozomal abnormality in patients with CLLChromozomal abnormality in patients with CLL

Döhner et al. N Engl J Med 2000

Karyotype No. of pts. OS (měs.)

17p deletion 23 (7%) 32

11q deletion 56 (17%) 79

Normal 47 (14%) 111

12q trisomy 57 (18%) 114

13q deletion 117 (36%) 133

17p- 13q- +12q

13q- onlyn=117

OSv %

months

11q-n=56

+12n=47

17p-n=23

0 36 72 108 144 1800

20

40

60

80

100

00

00

0

CLL, OS according to cytogenetics

325 pts

Podle Döhnera et al.

13q-, +12, norm.OS %

months

Binet A CLL: OS according to karyotype

11q- or 17p-

0 36 72 108 144 1800

20

40

60

80

100

00

According to Döhnera et al.

CLL : prognosis according to mutational status of IgVH

CLL : prognosis according to mutational status of IgVH

Döhnera, 2001

Clinical course, time of the dg.Clinical course, time of the dg.• Asymptomatic initially in most cases

• Diagnosis often incidental (50 - 80%)

• 80% diagnosed early: Rai 0, I nebo Binet A

• Iniciální symptoms:

lymphadenopathy, organomegaly, cytopenia, „general symptoms of activity of the disease“

CLL – clinical course, developmentCLL – clinical course, developmentProgression

Bone marrow suppression (cytokines!)

Immunosupression: hypogammaglobulinemia

Progressive lymphadenopathy

Complication

Autoimmune phenomenons: AIHA/ITP

PRCA (pure red cell aplasia)

Richter´s transformation

Prolymphocytic transformation

Secondary and duplicate malignancies

TREATMENT OF CLL

Patients of the same age use to be differentPatients of the same age use to be different

Indication to start the treatment Indication to start the treatment

Rai III, IV, Binet C alway (almost)

In less advanced stage in the presence of:

• Constitutional symptoms related to CLL

• Progressive bone marrow suppression

• AIHA or ITP not responding to corticosteroids

• Massive or progressive splenomegaly (6cm bellow c. margin)

• Massive or progressive lymphdenopaty ( 10cm)

• Rapidly progressibe lymphocytosis (>50% in 2 months, or expected LDT < 6 m)

Absolute number of lymphocytes is not indication to treatment

Goals of the treatment according to comorbidities & biological ageGoals of the treatment according to comorbidities & biological age

Age50

Quality of life

60 70

Best response and prolonatgtion of the time to next treatment

May be curable by allogeneic HSCT

Best response without progression

Quality of life

Goals of the treatment according to comorbidities & biological ageGoals of the treatment according to comorbidities & biological age

Age50

Quality of life

60 70

Best response and prolonatgtion of the time to next treatment

May be curable by allogeneic HSCT

Best response without progression

Quality of life

MRD -

Treatment - 1. lineTreatment - 1. line

Early phase of the disease

standard treatment 1. line („go go patients“).

• FC = Fludarabin + Cyclophosphamide

High comorbidity index („slow go“)

Progression

‘Watch andwait’

FC+_ Rituximab

Chlorambucil, FCR-lite

AAntigenntigen CD20 CD20AAntigenntigen CD20 CD20

• Hydrofobic phosphoprotein, ~35kd, 167 AMK• Present in 93% B-NHL• Function: Ca channel + cell cyle involvement• Not on early precurors (pro-B) and on plasma cells.

Ref. Einfeld, D.A. 7(3) EMBO Journal 711 (1988)

Cytoplasm

LC1

Rituximab (anti-CD20):structureRituximab (anti-CD20):structure

PF

S

0 1 2 3 4 5

years

R-FC: medián PFS 51,8 months

FC: medián PFS 32,8 měsíce

6x R-FC: influence on progression free survival (PFS)

6x R-FC: influence on progression free survival (PFS)

Hallek M, et al. Blood 2009; 114:Abstract 535.

HR: 0.563 p < 0.001

+ 19 měsíců

0.8

0.6

0.4

0.2

0.0

1.0

CLL: TREATMENT OF RELAPSCLL: TREATMENT OF RELAPS

• First assess risk factor (cytogenetics – 17p?) than decide:

• W&W again, if treatment rrequired:• If remmission > 12 months fludarabine containing

regimen can be used• If fludarabine resistant and suitable to transplant

consider allo HSCT• Alemtuzumab (MabCampath – anti-CD52)• Other treatment: ofatumumab (anti-CD20), R-dexa, R-

CHOP, Bendamustin• CLINICAL STUDIES!!

anti-CD52, Campath-1H, alemtuzumab = MabCampath® anti-CD52, Campath-1H, alemtuzumab = MabCampath®

IgG1 humanised antibody:

– Low immunogenicity

– 150 000 kD

Alemtuzumab: mechanism of actionAlemtuzumab: mechanism of action

Fc Receptor

Alemtuzumab

CD52

Alemtuzumab Membrane attack complex

CD52

1. ADCC 2. CDC

3. lipid raft dependent mechanism

T-PLL, CD3 before trteatment

T-PLL, CD3 after treatment

Supportive treatment in CLL

Prevention & treatment of infection complications

Disease itself

Treatment consequences

• Treatment of cytopenias (immune and non-immune)

• Leukapheresis (usually not needed), splenectomy (rare)

• Screening and prevention of second malignancies

Thank You for AttentionThank You for Attention