CHRONIC LEUKEMIAS

CHRONIC LEUKEMIAS Chronic myelogenous (granulocytic)

leukemia Is characterized by an unregulated

proliferation of myeloid elements in the bone marrow, liver and spleen, leading to marked leukocytosis and organomegaly.

Incidence 20% of all leukemias Primarily affects adults 25-60 years old, with a

peak incidence at 40-59.Etiology, pathogenesis and physiology

May occur after anything that can induce chromosomal aberrations such as ionizing radiation, alkylating agents, and exposure to other biologically active chemicals

CHRONIC LEUKEMIASAppears to be a clonal hematopoietic stem cell disorder 90% of CML have a Philadelphia (Ph’) chromosome

(reciprocal translocation between chromosome 22 and chromosome 9 by cytogenetic karyotype studies.

A BCR/ABL hybrid gene is created when the breakpoint is in the major breakpoint cluster region of chromosome 22. The gene product (p290) has enhanced tyrosine kinase activity that results in Increased granulocyte-colony stimulating factor Increased platlet derived growth factorSuppression of apoptosis in hematopoietic cells

The remaining 5-10% are positive for the translocation using more sensitive DNA studies such as RT-PCR or fluorescent in situ hybridization

The Ph’ chromosome is found in all hematopoietic cells except T lymphocytes (and sometimes B lymphocytes)

The Ph’ cells have a growth advantage over normal cells

PHILADELPHIA CHROMOSOME IN CML

PHILADELPHIA CHROMOSOME

CHRONIC LEUKEMIAS

The progeny of the original malignant cell, after 2-6 years, eventually replace the normal hematopoietic elements and become the prominent cell

By the time the disease becomes clinically evident, nearly all the myeloid cells in the bone marrow are Ph’ +

As the disease progresses, the Ph’ + cells undergo additional chromosomal aberrations and the patients ultimately terminate in a blast crisis.

Note - A Philadelphia chromosome generated by a break in the minor breakpoint region of chromosome 22 resulting in a fusion protein product, p190, may be seen in AML. The clinical course of the disease occurs in three

stagesAsymptomatic, proliferative stage – Ph’+ cells

appear in the bone marrow and the peripheral leukocyte count is normal

CHRONIC LEUKEMIAS

The symptomatic, chronic stage occurs after about 6.3 years – at this stage the peripheral leukocyte count is increased and immature granulocytes appear in the peripheral blood.

The hyperproliferation is easily controlled with chemotherapy, but the remission is only temporary and patients still have Ph’+ cells in the bone marrow.

Accelerated or acute stage – this is also called a blast crisis (>30% blasts in the bone marrow)Cellular proliferation is uncontrollable and

resembles AML.The medium survival is 10 weeks

Signs and symptoms Malaise Fatigue due to anemia Fever

CHRONIC LEUKEMIAS Weight loss Sweating Bone aches and fullness in upper abdomen due

to expansion of the bone marrow and organomegaly

Bleeding, petechiae, ecchymoses from abnormal platlets

Lab features Leukocytosis and anemia; ¾ have WBC

counts> 100 x 109/L Normal appearing granulocytes at all stages of

maturation are seen in the peripheral smear (they are not functionally normal, however); < 10% are blasts and promyelocytes

Many have a thrombocytosis with variation in shape; platlet function is frequently abnormal

Low to absent leukocyte alkaline phosphatase activity (Low LAP score)

CML

CML – ABNORMAL PLATLET

CML – BLAST TRANSFORMATION

CHRONIC LEUKEMIAS

Treatment Median survival from the time of diagnosis

used to be ~ 3 years The prognosis is better if the WBC count is

lower and the % of blasts is low Chemotherapy with a single agent has been

used and ~ 75% in the chronic phase of the disease go into remission. However, Ph’+ cells remain in the bone marrow

Bone marrow transplants during the chronic phase (high dose chemo/radiotherapy followed by infusion of normal, compatible bone marrow) used to be the best therapy

A new drug, Gleevec, is now available and it specifically targets the BCR/ABL gene product. The Ph’ + cells are destroyed, while normal cells are unaffected

CHRONIC LEUKEMIAS

Eosinophilic leukemia Is this a distinct entity or a variant of CML?30-70% eosinophils with a WBC count > 30

x 109/L and a shift to the leftThe prognosis is poor with a median

survival of < 1 year Basophilic leukemia

Is this a distinct entity or a variant of CML? Is extremely rare with 40-80% basophils and a

left shift

CHRONIC LEUKEMIAS

Chronic lymphocytic leukemiaThis is predominantly a disease of the

elderly; > 90% are over 50 and 2/3 are over 60; male:female is 2:1

Is characterized by peripheral and bone marrow lymphocytosis and a survival of a few years to > 10 years

This is a B cell abnormalityThe lymphocytes appear normal, but are

immunologically incompetent. However, some functionally normal B cells remain and there is a normal T cell pool

CHRONIC LEUKEMIASEtiology

Genetic factors are important since it runs in families

Clinical course The pace of the disease varies and is dependent on

the rate of accumulation of abnormal lymphocytes Median survival is 3-4 years, but 10-15% survive >

10years There is no tendency for blast transformation, but

complications of advanced disease result from progressive accumulation of long-lived, poorly functional lymphocytes.

Signs and symptoms Organomegaly and lymphadenopathy Often discovered accidentally Fatigue

CHRONIC LEUKEMIAS Near the end – bruising, pallor, fever, and weight

lossLab features

Absolute lymphocytosis of 10-150 x 109/L Lymphocytes usually appear normal, but they are

markedly fragile and smudge cells are seen on the peripheral smear

It is not necessary to do a bone marrow biopsy for diagnosis.

Anemia occurs late in the disease and may be due to decreased production secondary to marrow infiltration, hypersplenism, or autoimmune hemolytic anemia: the same things may cause neutropenia or thrombocytopenia

Hypogammaglobulinemia as the disease progresses

CLL WITH SMUDGE CELLS

Smudge cell

CHRONIC LEUKEMIAS

Prognosis is related to the extent and distribution of the disease – also called the stage:Stage A – lymphocytosis without anemia or thrombocytopenia and < 3 areas of lymphoid involvement (lymph nodes, spleen, liver)

Stage B – same as A, but > 3 areas of lymphoid involvement

Stage C – lymphocytosis with anemia, thrombocytopenia, or both

CHRONIC LEUKEMIAS

TreatmentStage A – observe onlyStage B with no symptoms – same as AStage B with symptoms - therapeutic intervention to relieve signs and symptoms

Stage C - therapeutic intervention to relieve signs and symptoms

The goal of therapy is simply to relieve signs and symptoms

A new monoclonal antibody, CAMPATH, that targets the mature B cells in B cell CLL is now being used.

CHRONIC LEUKEMIAS

Differential diagnosisMust distinguish between CLL and

prolymphocytic leukemia, hairy cell leukemia, large, granular lymphocyte leukemia, Sezary’s syndrome, and circulating lymphoma cellsProlymphocyte leukemia

This is an aggressive leukemic disorder of mature B or T cells

> 55% of the lymphocytes are prolymphocytes which are large with moderate amounts of pale basophilic cytoplasm, mature condensed chromatin, and a single prominent nucleolus

PROLYMPHOCYTIC LEUKEMIA

CHRONIC LEUKEMIAS

Hairy cell leukemia This is mainly a disease of elderly men Patients present with marked splenomegaly,

but not lymphadenopathy Patients have fatigue and malaise Pancytopenia The peripheral smear shows atypical

mononuclear lymphocytoid cells with hairy projections on their surfaces

The bone marrow yields a dry tap because the malignant cells are often surrounded by fibrosis

Splenectomy and interferon as well as new chemotherapeutic drugs are successful in promoting long lasting remissions

HAIRY CELL LEUKEMIA

CHRONIC LEUKEMIAS

Large, granular lymphocyte leukemia T cell or NK cell in origin Is characterized by a moderate lymphocytosis

composed of cells with abundant pale-staining cytoplasm and nuclei with mature, clumped chromatin

Anemia is common, but neutropenia is rare Most patients survive > 10 years

Sezary’s syndrome Occurs in patients with cutaneous T cell

lymphoma The lymphocytes seen in the peripheral smear

have a very large, convoluted nuclear outline and finely distributed chromatin

LARGE, GRANULAR LYMPHOCYTE LEUKEMIA

SEZARY’S SYNDROME

CHRONIC LEUKEMIAS

Circulating lymphoma cells Patients with non-Hodgkins lymphoma may

develop peripheral blood involvement