CHRONIC LEUKAEMIA

IRZA WAHID
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 Chronic leukaemias

AML - ALL CML - CLL

Genesis of Blood Products

Lymphoid Stem Cell CFU-L
B-Cell CFU-B CFU-T T-Cell

Pluripotent Stem Cell

CFU-Eosin

eosinophil

Hemocytoblast

basophil CFU-Bas neutrophil CFU-GM monocyte macrophage platelets CFU-MEG

3

Myeloid Stem Cell CFU-M

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 BCRABL, 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 (7% present with advanced disease)

Clinical features - signs

Splenomegaly (75%) Hepatomegaly (2%) Purpura (16%) Priapism (1% of males)

Lab features

Peripheral blood film

Anaemia 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 :

NAP reduced Serum B12 and transcobalamin increased Serum uric acid increased Lactate dehydrogenase increased Cytogenetic : Philadelphia chromosome

Phases

Accelerated phase

Median duration is 3.5 5 yrs before evolving to more aggressive phases Clinical features

Lab features

Increasing splenomegaly refractory to chemo Increasing chemotherapy requirement 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 (noncurative)

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 Bcellspecific 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
stage 0 I II III IV median survival (years) >10 > 8 6 2 < 2

stage A B C

Binet classification

median survival (years) > 10 7 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