CHRONIC LEUKEMIA

IRZA WAHID
5-02-2015
SUBDIVISION OF HEMATOLOGY & MEDICAL ONCOLOGY
DEPARTEMENT OF INTERNAL MEDICINE
FACULTY OF MEDICINE ANDALAS UNIVERSITY
Leukaemias

 What are Leukemias

– Neoplasm of white blood cell and its
precursor
– Clonal proliferations and accumulation of
cells in marrow
– Classify as
 Acute leukaemias  AML - ALL
 Chronic leukaemias  CML - CLL
 Genesis of Blood Products
Lymphoid
CFU-T T-Cell
Stem Cell
CFU-L
B-Cell
CFU-B
Pluripotent
Stem Cell
eosinophil
CFU-Eosin

basophil
Hemocytoblast CFU-Bas
neutrophil
monocyte

CFU-GM macrophage

Myeloid platelets
Stem Cell CFU-MEG

CFU-M
3
Copyright © 2006 by Elsevier, Inc. BFU-E
erythrocyte
 CHRONIC MYELOID
LEUKEMIA (CML)
 Clonal malignant myeloproliferative disorder (MPD)
characterized by increased proliferation of the
granulocytic cell line without the loss of their
capacity to differentiate

 Results in increases in myeloid cells, erythroid cells

and platelets in peripheral blood and marked
myeloid hyperplasia in the bone marrow

 Originate in a single abnormal haemopoietic stem

cell
Introduction- CML

 Incidence :1 per 100,000 (UK)

 Accounts for 7-15% of all leukaemia in
adults
 Median age : 53 years
 All age groups, including children, can
be affected
Introduction- CML

 Etiology
– Not clear
– Little evidence of genetic factors linked to
the disease
– Increased incidence
 Survivors of the atomic disasters at Nagasaki
& Hiroshima
 Post radiation therapy
Leukaemogenesis
 Philadelphia
chromosome is an
acquired cytogenetic
anomaly that is
characterizes in all
leukaemic cells in CML
 90-95% of CML pts
have Ph chromosome
 Reciprocal
translocation of
chromosome 22 and
chromosome 9
 Leukaemogenesis

 BCR (breakpoint cluster region) gene

on chromosome 22 fused to the ABL
(Ableson leukemia virus) gene on
chromosome 9
 Ph chromosome is found on myeloid,
monocytic, erythroid, megakaryocytic,
B-cells and sometimes T-cell proof that
CML derived from pluripotent stem cell
 Leukaemogenesis
 Molecular consequence of
the t(9;22) is the fusion
protein BCR–ABL, which has
increased in tyrosine kinase
activity
 BCR-ABL protein transform
hematopoietic cells so that
their growth and survival
become independent of
cytokines
 It protects hematopoietic
cells from programmed cell
death (apoptosis)
Clinical Features
 Clinical features - symptoms
Asymptomatic in > 20%
Fatigue
Bleeding
Weight loss
Splenic discomfort/fullness
 Clinical features - signs
Splenomegaly (75%)
Hepatomegaly (2%)
Purpura (16%)
Priapism (1% of males)
Lab features

 Peripheral blood film

– Leukocytosis (usu >25 x 109/L, freq> 100
x 109/L
– WBC differential shows granulocytes in all
stages of maturation
– Basophilia
– thrombocytosis
Lab features

 Bone marrow
– Hypercellular (reduced
fat spaces)
– Myeloid:erythroid ratio –
10:1 to 30:1 (N : 2:1)
– Myelocyte predominant
cell, blasts less 10%
– Megakaryocytes
increased & dysplastic
– Increase reticulin
fibrosis in 30-40%
Lab features

 Other lab features :

– Serum B12 and transcobalamin increased
– Serum uric acid increased
– Lactate dehydrogenase increased
– Cytogenetic : Philadelphia chromosome
– PCR : Fusion of BCR ABL gene
Phases
 Accelerated phase
– Median duration is 3.5 – 5 yrs before evolving to
more aggressive phases
– Clinical features
 Increasing splenomegaly refractory to chemo
 Increasing chemotherapy requirement
– Lab features
 Blasts>15% in blood
 Blast & promyelocyte > 30% in blood
 Basophil 20% in blood
 Thrombocytopenia
 Cytogenetic: clonal evolution
Phases

 Blastic phase
– Resembles acute leukaemia
– Diagnosis requires > 20% blast in
marrow
– 2/3 transform to myeloid blastic phase
and 1/3 to lymphoid blastic phase
– Survival : 9 mos vs 3 mos (lym vs
myeloid)
General Management

 Discussion with family

– The disease & diagnosis
– Prognosis
– Choices of treatment
 Cytotoxic drug vs bone marrow transplant
 Side effect
CML - principles of
treatment
 Relieve symptoms of hyperleukocytosis,
splenomegaly and thrombocytosis
– Hydration
– Chemotherapy (bulsuphan, Hydoxyurea)
 Control and prolong chronic phase (non-
curative)
– alpha interferon+chemotherapy
– imatinib mesylate
– chemotherapy (hydroxyurea)
CML - principles of
treatment

 Eradicate malignant clone (curative)

– allogeneic transplantation
– alpha interferon ?
– imatinib mesylate/STI 571 ?(Thyrosine
kinase inhibitor)
 Chronic lymphocytic leukemia

 Is characterised by the accumulation of

nonproliferating mature-appearing
lymphocytes in the blood, marrow, lymph
nodes, and spleen

 In most cases, the cells are monoclonal B

lymphocytes that are CD5+

 T cell CLL can occur rarely

Chronic lymphocytic leukemia

 Is the most common form of leukemia in

North America and Europe, but is extremely
rare in the Orient

 Typically occurs in older patients, with the

highest incidence being in those aged 50 to
55 years

 Affects men twice as often as women

Etiology

 The cause of CLL is unknown

 There is increased incidence in farmers,

rubber manufacturing workers, asbestos
workers, and tire repair workers

 Genetic factors have been postulated to play

a role in high incidence of CLL in some
families
Clinical findings
 Approximately 40% of CLL patients are
asymptomatic at diagnosis
 In symptomatic cases the most common
complaint is fatigue
 Less often the initial complaint are enlarged
nodes or the development of an infection
(bacterial)
 Clinical findings
 Most symptomatic patients have enlarged lymph
nodes (more commonly cervical and
supraclavicular) and splenomegaly
 Hepatomegaly may occure
 Less common manifestation are infiltration of
tonsils, mesenteric or retroperitoneal
lymphadenopathy, and skin infiltration
 Patients rarely present with features of anemia,
and bruising or bleeding
 Laboratory findings
 The blood lymphocyte count above 5,0 G/L
 In most patients the leukemic cells have the
morphologic appearance of normal small
lymphocytes
 In the blood smears are commonly seen
ruptured lymphocytes (“basket” or “smudge”
cells)
 Careful examination of the blood smear can
usually differentiate CLL, and the diagnosis can
be confirmed by immunophenotyping
 Laboratory findings
 Clonal expansion of B (99%) or T(1%) lymphocyte
– In B-cell CLL clonality is confirmed by
 the expression of either  or  light chains on the cell surface
membrane
 the presence of unique idiotypic specificities on the immunoglobulins
produced by CLL cells
 by immunoglobulin gene rearrangements
 typical B-cell CLL are unique in being CD19+ and CD5+
 Hypogammaglobulinemia or agammaglobulinemia are
often observed
 10 - 25% of patients with CLL develop autoimmune
hemolytic anemia, with a positive direct Coombs’ test
 The marrow aspirates shows greater than 30% of the
nucleated cells as being lymphoid
The diagnostic criteria for CLL
1) A peripheral blood lymphocyte count of
greater than 5 G/L, with less than 55% of
the cells being atypical
2) The cell should have the presence of Bcell-
specific differentiation antigens (CD19,
CD20, and CD24) and be CD5(+)
3) A bone marrow aspirates showing greater
than 30% lymphocytes
 Differential diagnosis
 Infectious causes
– bacterial (tuberculosis)
– viral (mononucleosis)
 Malignant causes
– B-cell
– T-cell
 leukemic phase of non-Hodgkin lymphomas
 Hairy-cell leukemia

 Waldenstrom macroglobulinemia

 large granular lymphocytic leukemia

Staging
 Rai Classification for CLL
– 0 - lymphocytosis (>5 G/L)
– I - lymphocytosis + lymphadenopathy
– II - lymphocytosis + splenomegaly +/-lymphadenopathy
– III - lymphocytosis + anemia (Hb <11g%) +/-
lymphadenopathy or splenomegaly
– IV - lymphocytosis + thrombocytophenia (Plt <100G/L)
+/- anemia +/-lymphadenopathy +/- splenomegaly
Staging

 Binet Classification for CLL

– A. < 3 involved areas, Hb > 10g%, Plt > 100G/L
– B. > 3 involved areas, Hb > 10g%, Plt > 100G/L
– C. - any number of involved areas, Hb < 10g%,
Plt < 100G/L
 Prognosis

 Rai classification  Binet classification

stage median survival stage median survival
(years) (years)
0 >10 A > 10
I > 8 B 7
II 6 C 2
III 2
IV < 2
 Treatment

– Alkylating agents (chlorambucil, cyclophosphamide)

– Nucleoside analogs (cladribine, fludarabine)

– Monoclonal antibodies

– Bone marrow transplantation

– And systemic complications requiring therapy

 antibiotics
 immunoglobulin
 steroids
 blood products
Thank you