Chronic leukemia

ILOs
At the end of lecture, you should be able to:

❑ Define chronic myeloid and lymphoid leukemia.

❑ Mention Clinical presentation of chronic Leukemia

❑ How to diagnose chronic leukemias.

❑ Compare between chronic myeloid and lymphoid leukemia as regard

diagnosis and treatment.

❑ Know how we treat newly diagnosed patients with chronic leukemia.

Introduction
Blood cell development

AML ALL

CML
CLL
 Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION

Adapted and modified from U Va website

 Classification of leukemias

Acute Chronic

Myeloid Acute Myeloid Chronic Myeloid Leukemia

Leukemia (AML) (CML)
Origin

Lymphoid Acute Lymphoblastic Chronic Lymphocytic Leukemia

Leukemia (ALL) (CLL)
Origin
 Definitions;

• CML: dysregulated production and uncontrolled proliferation

of maturing granulocytes with fairly normal differentiation.

• CLL: progressive accumulation of functionally incompetent

mature lymphocytes, which are monoclonal in origin
 Epidemiology;

CML CLL
Incidence in adult; 15-20% Most common in
Western
Median age of 50 70
diagnosis in adults:

Male : Female Slightly more More frequently in

frequently in males males
 Risk factors;

CML CLL

Environmental factors Exposure to ionizing No clearly discernible

radiation is the only occupational or
known risk factor. environmental risk
factors that predispose
to CLL.

Genetic abnormalities Occur with higher than

expected frequency
among first-degree
family members
Clinical Features
 Clinical features:

❑ Bone marrow:
• Overcrowding by abnormal cells
• Inadequate production of normal
marrow elements
• Anemia, thrombocytopenia, ↓ number
and function of WBCs
❑ Peripheral tissues:
Infiltration by malignant cells
 Clinical features:

Anaemia Infiltration or Auto-immune →

Fatigue
Neutropenia (OR immuno- Recurrent infections
deficiency disorder)

Thrombocytopenia Infiltration or Auto-immune →

Bleeding episodes.

Bone pain Acute gouty arthritis (Sometimes

seen)
B-symptoms May present.
 Clinical features, Cont.;

Hepatomegaly, Left upper quadrant pain, and

splenomegaly early satiety.
lymphadenopathy Firm, rounded, discrete, non-
tender, and freely mobile upon
palpation. More in CLL

Central nervous system Neurological manifestation

Skin Most commonly involved non-

lymphoid organ in CLL.
CLL
CML
Diagnosis
18

Chronic Myeloid Leukemia

 Diagnosis

◼ Blood count
◼ Leukocytosis with a white count reaching upto 100,000/microL (range 12
to 1000/microL).
◼ Absolute basophilia is a universal finding in the blood smears from CML patients, and
absolute eosinophilia is seen in about 90 percent of cases.
◼ The platelet count can be normal or elevated
◼ Blood film:
◼ Shows virtually all cells of the neutrophilic series, from myeloblasts to mature
neutrophils with peaks in the percent myelocytes and segmented neutrophils.
◼ Blasts typically account for less than 2 percent.
◼ The presence of a greater percent of myelocytes than the more mature
metamyelocytes ("leukemic hiatus" or "myelocyte bulge") is one of the classic
findings in CML.
◼ Bone marrow aspirate & trephine:
◼ Hypercellular,
◼ Granulocytic hyperplasia with a maturation pattern that reflects that
seen in the peripheral smear.
◼ Other non-specific bone marrow findings include an increase in
reticulin fibrosis and vascularity.
◼ Hyperuricemia and hyperuricosuria
◼ Serum vitamin B12-binding proteine and serum vitamin B12
levels are increased
◼ Cytogenetic test- presence of the Ph chromosome
◼ Molecular test – presence of the BCR-ABL fusion gene
The Philadelphia (Ph) chromosome
Features of Patients with Newly Diagnosed
Philadelphia Chromosome–Positive Chronic
Myelogenous Leukemia in Chronic Phase
 Accelerated phase of CML

❑ Most patients eventually became resistant to therapy and the

disease enters a more agressive phase
❑ Criteria of accelerated phase
✓ Blasts in blood or bone marrow-10-19%
✓ Basophilia ≥ 20%
✓ Thrombocytopenia <100G/l unrelated to ttt
✓ Thrombocytaemia >1000G/l unresponsive to ttt
✓ Additional chromosomal aberrations
✓ refractory splenomegaly or refractory leucocytosis
 Blast phase (blast crisis) of CML

❑Criteria of blast phase

✓ Blasts in blood or bone marrow ≥20%
✓ extramedullary tumors
✓ Large foci or clusters of blasts in BMB
 Differential diagnosis

❑ leukemoid reaction:
syndrome with morphologic changes similar to leukemia in
peripheral blood usually 2ry to infections as T.B., pneumonia,
meningitis or metabolic causes. But:
✓ Eosinophils and bosophils are decreased (rather than
increased).
✓ WBCs are alkaline phosphatase stongly +ve (rather than -
ve).
✓ B.M. is only moderately hyperplastic

❑ Other myeloproliferative neoplasms

29

Chronic Lymphocytic Leukemia

❑ CBC:
WBC:.
Diff: lymphocytosis ,the absolute lymphocyte count is>5x109/l and
may be up to 300x109/l or more.
Anemia : normocytic normochromic anemia is present in later
stages,autoimmune haemolysis.
Platelets : thrombocytepenia may occur.
❑ Blood film:
70-99% of white cells mature lymphocyte.
Smudge or smear cells also present.
❑ Immunophenotyping:
Shows that the lymphocyte are B cells(CD19)expressing one form of
light chain( or only)cells are also CD5 & CD23 are both +ve.
❑ Bone marrow aspiration:
Lymphocytic replacement of normal marrow.

❑ Immunoglobulin electrophoresis:
of Ig more marker with advance disease.

❑ Cytogenetic :
The 4 most common abnormalities are; deletion
of13q14,trisomy 12,deletion of11q23&structural abnormality
of 17p involving the p53 gene.
33
Staging :

❑ Staging is very important for prognosis and

treatment.

❑ There are two staging system(Rai and Binet).

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A-Rai Classification:

Stage definition

0 Absolute lymphocytosis.

1 Stage 0+enlarged lymph nodes.

11 Stage 0+liver or/and spleen   adenopathy.

111 Stage 0+anemia organomegally or adenopathy.

1V Stage 0+thrombocytopenia organomegally or adenopathy.

 B-Binet Classification:

Stage . Organomegally Hb Platelet.

.
A < 3 areas 10 100

B >3 areas 10 100

C Not considered <10 and /or

<100
35
 Differential diagnosis

❑Other causes of:

▪ Lymphadenopathy

▪ Splenomegaly

▪ Hepatomegaly

▪ Immune anemia or thrombocytopenia

Management
38

Chronic Myeloid Leukemia

 Overview

❑Supportive ttt: hydration, uricosiric drugs….

❑Oral chemotherapeutic agents (hydroxyurea,

busulfan)

❑Interferon alfa

❑BCR-ABL tyrosine kinase inhibitors (TKIs), such

as imatinib , dasatinib , and nilotinib .

❑Allogeneic hematopoietic cell transplantation (HCT).

Tyrosine kinase inhibitors
 2. Stem cell transplantation;

◼ Allogeneic stem cell transplantation.

◼ Autologous stem cell transplantation.

42

Chronic Lymphocytic Leukemia

 Treatment :

❑ Not all patients will require active ttt

❑ Indication for treatment:

✓ Huge organomegaly or LN.
✓ Hemolytic episodes.
✓ Bone marrow suppression.
✓ Severe constitutinal symptoms
✓ Rapid lymphocyte doubling time
 A. Supportive care:

◼ Anemia – red cell transfusion

◼ Thrombocytopenia – platelet concentrates

◼ Infection – broad spectrum IV antibiotics + IVIG

◼ Hematopoietic growth factors : GM-CSF, G-CSF

◼ Metabolic problems:

◼ Monitoring hepatic / renal / hematologic function;

◼ Fluid & electrolyte balance, nutrition Hyperuricemia- hydration, Allopurinol

◼ Psychological support.
 Modality of Treatment:

1-Chemotherapy:
❑ Chlorambucil: 6mg/m2 daily for 10 days monthly for 2-4
month after which remission will be obtain.

❑ Fludarabine: more effective as single agent.

❑ Corticosteroid : indicated in autoimmune hemolytic anemia

and thrombocytopenia.

2-Radiotherapy:
Is useful in reducing the size of LN not responsive to chemo.

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 Cont:

3-Monoclonal antibody:
Both campath (anti CD52)and Rituximab(anti CD20)produce
response in proportion of patient.

4-Splenectomy :
For immune-mediated cytopenia or painful bulky splenomegally.

5-immunoglobulin replacement:
for patient with hypogammaglobulinemia and recurrent infection.

6- Stem cell transplant:

Useful in some patients

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Thank you