1

Presentation on Treatment strategy of CLL: Presentation on Treatment strategy of CLL: Do all CLL patients need treatment?Do all CLL patients need treatment?

Dr. A. Y. Md. NazimDr. A. Y. Md. Nazim

Fellow Trainee-HaematologyFellow Trainee-Haematology

Department of HaematologyDepartment of Haematology

Dhaka Medical College & HospitalDhaka Medical College & Hospital

2

This presentation includes:

CLL definition, Incidence, Clinical features

Diagnosis, Lab-investigation, Staging, Prognostic markers

Classical criteria for treatment,

Conclusion

3

What is chronic lymphocytic leukaemia?

It is a malignant proliferation of

Mature looking

Functionally incompetent

Small lymphocytes

Accumulate in the bone marrow, peripheral blood, lymph nodes, spleen, liver, and sometimes other organ

4

Epidemiology

Commonest leukaemia in Western world (20-30%)Commonest leukaemia in Western world (20-30%)

Predominantly a disease of Predominantly a disease of elderlyelderly

Mean age at diagnosis is 70 yearMean age at diagnosis is 70 year

10% younger than 50 years old10% younger than 50 years old

5

Cause of CLL

Cause of CLL is unknown

No causal relationship with radiation, chemical or viruses

No direct modes of inheritance

Cellular accumulation - basic defect

Defects in intracellular apoptic pathway

90% have high levels of BCL-2

6

Clinical Features

Often asymptomatic at diagnosis

• Painless lymphadenopathy

• Splenomagaly(70%)

• Hepatomegaly(50%)

7

Clinical features Clinical features (contd.)(contd.)

Features of bone marrow failure Anaemia, Thrombocytopenia

Recurrent infection

• Fever and weight loss uncommon

• Para neoplastic syndrome

8

DiagnosisHistory, physical examination & peripheral blood is sufficient for diagnosis of CLL.

9

Diagnosis (Contd.)

Published criteria for CLL Diagnosis:

Peripheral blood lymphocyte count>5000Peripheral blood lymphocyte count>5000 with B cell phenotype consistent with CLLwith B cell phenotype consistent with CLL

Light chain restrictionLight chain restriction

Bone marrow aspirate >30% Bone marrow aspirate >30% lymphocyteslymphocytes

10

Diagnosis (Contd.)

Is bone marrow aspiration necessary for CLL diagnosis?Is bone marrow aspiration necessary for CLL diagnosis?

11

Diagnosis (Contd.)

12

Immunophenotyping findings in CLL

Bcell specific differentiation antigenCD 19+CD 20+CD 22+CD 79a

CD 23+CD 5+ without other pan T marker

sIg weak +

FMC7 -

13

Other laboratory investigations

Hypogammaglobulinaemia

Paraproteinaemia(5%)

Cytogenetic abnormalities in > 80% by FISH

13q-

11q

12+

17p-

14

Other laboratory investigations

LDH

β2 microglobulin

Uric acid

Urea

Creatinine

Eelectrolytes

Imaging as necessary for symptoms

15

Differential Diagnosis• PLL• WM• Leukaemic phase of lymphoma• HCL• Tcell CLL• T-LGL• CTCL

Morphology and Immunophenotyping can differentiate CLL from other LPDs.

16

Do all CLL Do all CLL patients need treatment? need treatment?

Rai clinical Rai clinical staging :Level of risk Stage Median

survival

Low risk 0 Lymphocytosis only > 13 yrs

Intrmediate risk

I Lymphocytosis & lymphadenopathyII Lymphocytosis & Splenomegaly and or Hepatomegaly

5-8 yrs

High risk III Lymphocytosis & anaemia

IV Lymphocytosis & thrombocytopenia 1-2 yrs

17

Do all CLL patients need treatment?Do all CLL patients need treatment?

Binet Binet clinical staging staging:

Stage Clinical features Median survival

A < 3 lymphoid regions enlarged 12 yrs

B 3 or more than 3 lymphoid regions included

5 yrs

C Aanaemia and or thrombocytopenia 2 yrs

18

Variation in prognosis

Median survival of patients with stage A disease or in the low risk group is > 10 years

40% patients progress to advanced disease

50% patients require therapy at some point

25% dying from their disease..

19

Other clinical prognostic factors

Initial lymphocytosis > 50,000

> 5% prolymphocytes

Atypical lymphocyte morphology

Diffuse pattern of infiltrate on trephine

Blood lymphocyte doubling time < 12 months

20

Biologic Prognostic factors

Serum markers:

• Thymidine kinase levels predict disease progression

• Soluble CD-23 levels linked to adverse prognostic • features

• ββ22 microglobulin level shows a positive correlation with

clinical stages

21

CytogeneticsGenetic abnormalities by FISH associated with abnormalities by FISH associated with

progression and poor prognosis in CLL and poor prognosis in CLL

Cytogenetic Abnormality Characteristics of disease

11q23(20% of cases)

Younger age Lymphadenopathyshort survival

12+(15% of cases)

CLL/PL Disease progressionhigh proliferation rate

17p21(7% of cases)

CLL/PL Poor response to therapytransformation

13q(36% of cases)

Excellent prognosis(median survival 133months)

22

IgVH mutational status

IgVH mutational status separates CLL into two different forms of the disease:

IgVH unmutated genes - Progressive disease

IgVH mutated genes - Stable disease

23

Surrogate markers of IgVH mutational status

CD-38 expression - an independent prognostic factor

ZAP-70 expression detected provide stable prognostic information

24

Surrogate markers of IgVH mutational status (Contd)

ZAP-70 and CD-38 may provide complementary prognostic information

Both markers - poorest prognosis

None of the markers - good outcomes

Either of the markers - intermediate

25

Response to therapy

Important prognostic factor for survival

• Higher the degree of response longer the survivalHigher the degree of response longer the survival

• Patients who achieved MRD negative status have a Patients who achieved MRD negative status have a better prognosisbetter prognosis

26

Conclusion

Treatment based on classical criteria (NCI-CLL/WG)

Advanced stage

Symptomatic or unsightly lymphadenopathy

Haemolytic anaemia

Thrombocytopenia

27

Conclusion (Contd.)

Treatment based on classical criteria (NCI-CLL/WG)

• Blood lymphocyte doubling time <6 months

• Prolymphocytic or Richter transformation

Treatment decisions based on biological parameters are justified within clinical trials

28