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Chronic Leukemia

Dr. Tjokorda Gde Dharmayuda, SpPD-KHOM

Division of Hematology and Medical Oncology, Faculty of


Medicine, University of Udayana / Sanglah General Hospital
2009

Chronic Lymphocytic
Leukemia
( CLL )

Overview
Definition
Incidence
Etiology
Clinical features and presentation
Diagnosis
Management and prognosis

Definition
Progressive accumulation of mature appearing,
functionally
incompetent,
long-lived B lymphocytes in peripheral
blood, bone marrow, lymph nodes,
spleen, liver and sometimes other
organs.

Incidence
Commonest leukemia in Western
adults (25-30% of all leukemia).
2.5 / 100.000 per annum.
Predominantly disease of elderly
(in over70s, more than
20/100.000).
Median age at diagnosis 65 years.
Ratio of Male : Female = 2:1

Etiology
Unknown
No causal relationship with
radiation, chemicals or viruses.
Small proportion are familial.
Genetic factors suggested by low
incidence in Japanese even after
imigration.
90% of CLL cases have high levels of
BCL-2 which block apoptosis.

Clinical features and presentation


Often asymptomatic; lymphocytosis (> 5.0 x 109/L) on routine

CBC
With more advance disease: lymphadenopathy: painless, often

symmetrical, splenomegaly (66%), hepatomegaly and ultimately


BM failure due to infiltration causing anemia, neutropenia and
thrombocytopenia.
Reccurent infection
Patient with advance disease : weight loss, night sweats,

general malaise
Autoimmune phenomen occur: DAT (+ve) 10-20% cases, warm

antibody AIHA in <50% these cases. Autoimmune


thrombocytopenia in 1-2%.

Diagnosis
CBC

Lymphocytosis > 5.0 x 109/L; usually>20x 109/L;,


occasionally > 400x 109/L;
anemia, thrombocytopenia and neutropenia absent in early
stage CLL;
autoimmune hemolysis with thrombocytopenia can occur in
any stage.

Blood Film

Lymphocytosis with mature appearance; spherocytes;


decrease of platelet if BM failure

Immunophenotyping

Crucial to differentiation from other lymphocytes . First


panel : CD2, CD5, CD19, CD 23 etc.

Bone Marrow

> 30% mature lymphocytes

Lymph Biopsy
Cytogenetics

Management and prognosis


Clinical management
Patients with asymptomatic lymphocytosis simply
require monitoring
Patients with indolent disease : chemotherapy. First line
therapy generally with alkylating agent chlorambucil at
a dose of 6-10mg/day po for 7-14 days in 28 cycles until
disease stabilised (usualy 6 cycles)

Others agent : Purine, cyclophosphamide,


rituximab

Prognosis
CLL remains incurable disease
A minority (10%) develop high grade NHL
(Richter sydrome): median interval from
diagnosis 24 months; associated with all
stages; abrupt onset; chemoresistant; median
survival 4 months.
Second malignancy (skin, colon) occur in up to
20%.

Chronic Myeloid Leukemia


(CML)

* Insidence : 1-1,4/100.000/yrs
* Age: Every age, > adults
Clinical manifestation:
* There are 2 phases:
a. Chronic phase
b. Acute Transformation - blast crisis

Citogenetic
> 95% : Philadelphia chromosome: +ve
Chromosome translocation of 9 dan 22 t ( (,22)
* Fusion oncogen ABL and BCR
* chimeric protein p 210 and 190
cell proliferation
Acute Transformation :
a. Accelerated phase - 6 months
b. Blast crisis several weeks

Biology of CML
Bcr-abl protein is a deregulated
tyrosine kinase with increased activity
Bcr-abl protein leads to malignant
transformation by interference with
control of proliferation, adherence,
and apoptosis

Biology of CML
Disease progression associated with
chromosomal changes in 50-80% cases
Karyotypic evolution may precede
hematologic and clinical manifestations
Frequent changes are trisomy 8,
isochromosome
i(17q), trisomy 19,
additional Ph chromosome
Alterations in tumor suppressor genes

Detection of BCR-ABL
Cytogenetic analysis
Gold standard
Time-consuming, 20-25
metaphases/sample

Translocation of t(9;22) in CML

Faderl, S. NEJM 1999; 341:164


-172

Clinical sign
a. Chronic phase
- Splenomegaly
- Hyperkatabolic state
b. Acute Transformation
- as acute leukemia
Laboratory findings:
a. CBC and blood smear : mild anemia, severe leukositosis,
found every spectrum of granulosit series , which the most
dominat is mielosit dan netrofil
b. BM : hyperseluler

* Acute Transformation :
2/3 - mieloid
1/3 - limfoid
Acute Transformation :
a. Fever
b. Splenomegaly >>
c. Anemia >>
d. Respon of treatment was decrease
e. Blast in peripheral blood > 5%,
blast in BM > 30%

CML-Chronic Phase
Survival by Prognostic Group

Management
Chronic phase
Hydroxiurea
Busulfan (Myleran)
Interferon
STI671 (Imatinib mesylate)
Suportive treatment
Blast Crisis
Treat as acute Leukemia
Bone Marrow Transplantation

Mechanism of action of STI-571

Goldman, J. NEJM 2001; 344:


1084 -1086