3. Leukemias are classified into 2 major groups
Acute Onset is usually rapid,
The disease is very aggressive,
The cells involved are usually poorly
differentiated with many blasts.
Chronic Onset is insidious,
The disease is usually less aggressive,
The cells involved are usually more mature
cells
4. Comparison of acute and chronic
leukemias:
Acute Chronic
Age all ages usually adults
Clinical onset sudden insidious
Course (untreated) 6 mo. or less 2-6 years
Leukemic cells immature >20% blasts more mature
` cells
Anemia prominent mild
Thrombocytopenia prominent mild
WBC count variable increased
Lymphadenopathy mild present;often
prominent
Splenomegaly mild present;often
prominent
6. CML results from a somatic mutation in a
pluripotential lymphohematopoietic cell
CML is a MPD characterized by increased
granulocytic cell line, associated with erythroid
and platelet hyperplasia
The disease usually envolves into an
accelerated phase that often terminates in
acute phase
chronic phase 3-5 years
accelerated phase
blastic phase 3-6 months
7. Etiology
Exposure to high- dose ionizing radiation
Chemical agents have not been established as a cause
8. Epidemiology
CML accounts for approximately 15 percent of all
cases of leukemia and approximately 3 percent of
childhood leukemias
The median age of onset is 53 years
9. Pathogenesis
Hematopoietic abnormality
Expansion of granulocytic progenitors and a decreased
sensitivity of the progenitors to regulation – increased white cell
count
Megakaryocytopoiesis is often expanded
Erythropoiesis is usually deficient
Function of the neutrophils and platelet is nearly normal
10. Pathogenesis
Genetic abnormality
CML is the result of an acquired genetic abnormality
A translocation between chromosome 9 and 22 [t(9;22)] –
the Philadelphia chromosome
The oncogene BCR-ABL encodes an enzyme – tyrosine
phosphokinase (usually p210)
14. Philadelphia Chromosome
• More than 95% of patients with CML has Philadelphia (Ph)
chromosome
A subset of patients with CML lack a detectable Ph
chromosome but have the fusion product for the bcr/abl
translocation detectable by reverse transcriptase- polymerase
chain reaction (RT-PCR)
15. The bcr/abl fusion protein
Uncontrolled kinase activity
that results in
Increased granulocyte-colony stimulating factor
Increased platlet derived growth factor
Suppression of apoptosis in hematopoietic cells
16. Clinical features
30 percent of patient are asymptomatic at the time of
diagnosis
Symptoms are gradual in onset:
easy fatigability, malaise, anorexia, abdominal discomfort,
weight loss, excessive sweating
● Less frequent symptoms:
Night sweats, heat intolerance- mimicking
hyperthyroidism, gouty arthitis, symptoms of leukostasis
(tinnitus, stupor), splenic infartion (left upper-quadrant
and left shoulder pain), urticaria (result of histamine
release)
● Physical signs:
Pallor, splenomegaly, sternal pain
17. Accelerated phase of CML
Most patients eventually became resistant to therapy
and the disease enters a more agressive phase
Criteria of accelerated phase
1. Blasts in blood or bone marrow-10-19%
2. Basophilia ≥ 20%
3. Thrombocytopenia
4. Thrombocytaemia
5. Additional chromosomal aberrations
6. refractory splenomegaly or refractory leucocytosis
20. CML vs Leukemoid Reaction
Characteristic
feature
CML Leukemoid
Reaction
Age >40 yrs Any age
Leukocytosis >100,000 30,000 – 50,000
Absolute Basophilia Present May not
Splenomegaly Prominent May not
Philadelphia
Chromosome
Present Absent
LAP / NAP Very low / Absent High
Transformation to
Acute leukemia
Yes No
21. Laboratory features
The hemoglobin concentration is decreased
Nucleated red cells in blood film
The leukocyte count above 25000/μl (often above
100000/μl), granulocytes at all stages of development
The basophil count is increased
The platelet count is normal or increased
Neutrophils alkaline phosphatase activity is low or absent
(90%)
22. Laboratory features (2)
The marrow is hypercellular (granulocytic hyperplasia)
Reticulin fibrosis
Cytogenetic test- presence of the Ph chromosome
Molecular test – presence of the BCR-ABL fusion gene
31. Chronic Lymphocytic
Leukemia
Elderly age
Anemia, fever & bleeding – slow over years.
Lymphocytosis & Lymphadenopathy
Spleen, & liver enlargement
Common B cell (CD5 +ve)
32. Chronic leukemias
Chronic lymphocytic leukemia
This 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 abnormality
The lymphocytes appear normal, but are immunologically
incompetent. However, some functionally normal B cells
remain and there is a normal T cell pool
33. Chronic leukemias
Etiology
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.
34. Chronic leukemias
Signs and symptoms
Organomegaly and lymphadenopathy
Often discovered accidentally
Fatigue
Near the end – bruising, pallor, fever, and weight loss
35. Lab 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
39. Peripheral blood smears show predominantly mature lymphocytes, some
with a clumped chromatin pattern
40. Peripheral blood smears show predominantly mature lymphocytes,
some
with a clumped chromatin pattern
41. Bone marrow smear in B-CLL, with diffuse infiltration of
the bone marrow
42. 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) – GOOD
PROGNOSIS
Stage B – same as A, but > 3 areas of lymphoid
involvement – INTERMEDIATE PROGNOSIS
Stage C – lymphocytosis with anemia, thrombocytopenia,
or both – POOR PROGNOSIS