Chronic leukemias have an insidious onset and are usually less aggressive than acute leukemias. The two main types are chronic myeloid leukemia, characterized by the Philadelphia chromosome, and chronic lymphocytic leukemia, which mainly affects B cells. These diseases involve increased numbers of mature but dysfunctional white blood cells and are diagnosed based on blood counts, bone marrow examination, and identification of genetic abnormalities.

1. CHRONIC
LEUKEMIAS
Dr Vijay Shankar S

2.  Chronic leukemias
 Types
 Chronic myeloid leukemia
 Philadelphia chromosome
 Chronic lymphocytic leukemia
 Lab diagnosis

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

5. Chronic Myeloid Leukemia
 Middle age 40-60y
 Philadelphia chromosome, t(9:22)
 Anemia, Fever & Bleeding
 Marked leucocytosis – >50,000 (abnormal)
 Marked splenomegaly, Hepatomegaly

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)

11. Translocation t(9;22)(q34;q11)

12. Translocation t(9;22)(q34;q11)

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

18. Blast phase (blast crisis) of CML
• Criteria of blast phase
1. Blasts ≥20%
2. extramedullary tumors
• Phenotype of blasts
1. Mieloblasts - 50%
2. Limphoblasts - 30%
3. Megakarioblasts – 10%
4. Acute myelofibrosis

19. Lab findings
 Blood picture
 Bone marrow examination
 Cytogenetics
 Cytochemistry ( NAP)

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

23. Chronic Myeloid Leukemia:

24. basophil blast
neutrophils
and
precursors promyelocyte
CML

25. Blood smear shows a preponderance of mature neutrophilic
granulocytes.Myelocyte at center, basophil at upper right

27. Blood smear showing a greater left shift. At center is a myeloblast

28. Two basophils in blood smear

29. Increased granulocytopoiesis in a bone marrow smear. Neutrophilic
granulocytes,two basophils, and four eosinophils

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

36. CLL with smudge cells

37. lymphocytes
‘smudge’ cells
CLL

38. CLL – Blood Film

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

43. SUMMARY
 Chronic leukemias
 Types
 Chronic myeloid leukemia
 Philadelphia chromosome
 Chronic lymphocytic leukemia
 Lab diagnosis