AML, ALL, CML, CLL

1. LEUKAEMIAleukos "white”; haima "blood"
Dr. Samriddhi Karki
1st Year Resident
Department of Pathology

2. DEFINITION
• Leukaemia is a progressive, neoplastic
disease of the hematopoietic system
characterized by unregulated proliferation of
uncommitted or partially committed stem
cells.

3. TYPES
• Acute leukaemia:
▫ Rapid onset.
▫ Aggressive course.
▫ Poorly differentiated cells with many blasts.
• Chronic leukaemia:
▫ Gradual onset.
▫ Less aggressive.
▫ Mature cells.

4. Hematopoietic
stem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor
Lymphoid
progenitor
B-lymphocytes
T-lymphocytes
Plasma
cells
naïve
ALL
AML
Both leukaemia are further classified into LYMPHOID or
MYELOID according to the origin of leukaemic stem cell
clone.

5. If the prominent cell
line is of the myeloid
series it is a myeloid
leukemia .

6. Myeloid maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATION
Adapted and modified from U Va website

7. If the
prominent cell
line is of the
lymphoid
series it is a
lymphocytic
leukemia

8. • Therefore, there are four basic types of leukemia
▫ Acute myelocytic leukemia – AML
 Includes myeloblastic, promyelocytic, monocytic,
myelomonocytic, erythrocytic, and megakaryocytic
▫ Acute lymphocytic leukemia – ALL
 Includes T cell, B cell, and Null cell)
▫ Chronic myelocytic leukemia – CML
 Includes myelocytic and myelomonocytic)
▫ Chronic lymphocytic leukemia- CLL –
 Includes plasmocytic {multiple myeloma}, Hairy cell,
prolymphocytic, large granular cell lymphocytic, Sezary’s
syndrome, and circulating lymphoma)

9. EPIDEMIOLOGY
• Worldwide, the overall incidence of acute leukaemia is
4/100,000 population per year. ( 70% being AML)
• Age:
▫ Acute leukemias can occur in all age groups
 ALL is more common in children
 AML is more common in adults
▫ Chronic leukemias are usually a disease of adults
 CLL is extremely rare in children and unusual before the age of 40
 CML has a peak age of 30-50
• Sex:
▫ Acute leukemias are common in males.
• Race:
▫ More prevalant in whites.

10. PREDISPOSING FACTORS
• Inherited conditions
▫ Down syndrome, Fanconi anaemia, Bloom syndrome,
Wiskott-Aldrich syndrome, Neurofibromatosis.
• Acquired diseases:
▫ Aplastic anaemia, Myeloma, Polycythemia vera, CML,
PNH, Myelofibrosis.
• Environmental factors:
▫ Exposure to ionizing radiation
▫ Exposure to mutagenic chemicals and drugs
▫ Smoking

11. ACUTE MYELOID
LEUKAEMIA

12. • Neoplasms composed of immature
myeloid cells , predominantly
MYELOBLASTS.
• Occurs at all ages , incidence peaks after
the age of 60.
• M>F

13. MOLECULAR PATHOGENESIS

14. •GENETIC ALTERATIONS
• Inhibition of terminal myeloid differentiation 
proliferation of relatively undifferentiated
MYELOBLAST.
CBF1α
NPM
CBF1β
FLT3
RARα
PML
cKIT

15.  CHROMOSOMAL ABNORMALITIES:
 t(8;21) , inv(16) , t(15;17)
 t(8;21) , inv(16)
• Disrupt genes encoding for factors needed for
NORMAL MYELOID DIFFERENTIATION
 t(15;17)
• produce a fusion gene RARa and PML
• point mutation in FLT3

16. • Disrupts
▫ CBF1 α
▫ CBF1 β
• These genes are
required for normal
hematopoeisis .

17. PML + RAR α + Activated FLT3  potent inducer of AML
• Creates a fusion of a gene
encoding retinoic acid receptor α
(RAR α) and a portion of protein
called PML.
(RAR α + PML : interacts with transcriptional
repressors  inhibition of granulocytic
maturation)
• Activates mutations in FLT3
(FLT3 is a tyrosine kinase receptor that
transmits signals which increase cellular
proliferation and survival).

18. CLASSIFICATION

19. 1. French American British (FAB) classification
▫ Based on morphology and cytochemistry
2. WHO classification
▫ Based on molecular, morphologic, and clinical
features

20. FAB classification
M0: Minimally differentiated leukaemia
M1: AML without maturation
M2: AML with maturation
M3: Promyelocytic leukaemia
M4: Myelomonocytic leukaemia
M5: Monocytic leukaemia
M6: Erythroleukaemia
M7: Megakaryoblastic leukaemia

21. WHO Classification
1. AML with recurrent genetic abnormalities.
2. AML with multilineage dysplasia.
3. AML and myelodysplastic syndromes, therapy
related.
4. AML, not otherwise categorised.
5. Acute leukaemia of ambiguous lineage.
a. AML with t(8;21)(q22;q22)
• CBFa/ETO fusion gene
b. AML with abnormal bone marrow eosinophils
• inv(16)(p13;q22) or t(16;16)(p13;q22)
• CBFb/MYH11 fusion gene
c. Acute promyelocytic leukaemia
• AML with t(15;17)(q22;11-12)
• RARa/PML fusion gene
d. AML with 11q23 (MLL) abnormalities.
a. AML, minimally differentiated
b. AML without maturation
c. AML with maturation
d. AML with myelomonocytic maturation
e. AML with monocytic and monoblastic maturation
f. AML with erythroid maturation
g. AML with megakaryoblastic maturation
h. Acute basophilic leukaemia
i. Acute panmyelosis with myelofibrosis
j. Myeloid sarcomaa. Undifferentiated acute leukaemia
b. Bilineal acute leukaemia
c. Biphenotypic acute leukaemia

22. Acute myeloid leukaemia with recurrent
genetic abnormalities
a. AML with t(8;21)(q22;q22)
• CBFa/ETO fusion gene
b. AML with abnormal bone marrow eosinophils
• inv(16)(p13;q22) or t(16;16)(p13;q22)
• CBFb/MYH11 fusion gene
c. Acute promyelocytic leukaeima
• AML with t(15;17)(q22;11-12)
• RARa/PML fusion gene
d. AML with 11q23 (MLL) abnormalities.

23. AML with t(8;21)(q22;q22)
• Commonest translocation in
AML.
• Shows maturation in the
neutrophil lineage.
• Morphology
▫ Large blasts, heavily granulated
▫ Frequent Auer rods
• Immunophenotype
▫ CD13+ CD33+

24. AML with inv(16)(p13q22) or t(16;16)(p13;q22)
• Shows monocytic and
granulocytic differentiation.
• Abnormal eosinophils with
coarse basophilic granules
• Immunophenotype
▫ Granulocytic and monocytic
markers
▫ CD2 +

25. Acute promyelocytic leukaemia
• 5-10% of AML.
• Abnormal promyelocytes
predominate.
• Associated with disseminated
intravascular coagulation
• MPO , Sudan black : strongly
positive
• Chromosomal aberrations:
t(15;17)

26. AML with 11q23 abnormalities
• Associated with
monocytic features.
• Rare (more in infants)
• Associated with MLL
rearrangement.

27. Acute myeloid leukaemia with
multilineage dysplasia
• D.efined as acute leukaemia
with
▫ More than 20% blasts
▫ Dysplasia in 2 or more
myeloid cell lines, generally
including megakaryocytes.
• May occur de-novo or
following MDS.

28. AML and MDS, therapy related
• Following chemotherapy
or radiotherapy.
▫ Alkylating agent related
▫ Topoisomerase type II
inhibitor related

29. Acute myeloid leukaemia not otherwise
categorized
• Equivalent to FAB classification
a. AML, minimally differentiated
b. AML without maturation
c. AML with maturation
d. AML with myelomonocytic maturation
e. AML with monocytic and monoblastic maturation
f. AML with erythroid maturation
g. AML with megakaryoblastic maturation
h. Acute basophilic leukaemia
i. Acute panmyelosis with myelofibrosis
j. Myeloid sarcoma

30. AML , minimally differentiated
• Shows minimal myeloid
differentiation.
• Diagnosis cannot be made
on the basis of morphology
alone but requires
immunophenotyping.

31. AML without maturation
• Most common in adults and in
infants.
• Auer rods are rarely found.
• MPO and Sudan black B stain
is positive in > 3% of blasts,
indicating granulocytic
differentiation.
• Chromosomal aberrations :
▫ Trisomy 8
▫ t(9;22)
▫ t(6;9)
▫ del(5q-)

32. AML with maturation
• Most common in adults (30%)
• Auer rods may be present.
• MPO and Sudan black B are
strongly positive.
• Chromosomal aberrations:
▫ t(8;21) (q22;q22)associted with
better prognosis.
▫ t(6;9) associated with basophilia
▫ (12p-) associated with basophilia

33. Acute myelomonocytic leukaemia
(Naegeli type)
• Characterized by proliferation of
both neutrophil and monocyte
precursor.
• Infiltrations of leukaemic cells in
extramedullary sites is more
frequent
• Serum / urine muramidase
levels are elevated due to
monocytic proliferation.

34. Acute monocytic leukaemia (Schilling
type)
• 80% or more of the
leukaemic cells are of
monocytic lineage .
• High frequency of
extramedullary infiltrations
of the lungs, colon ,
meninges, lymph nodes,
bladder, and larynx.

35. Acute erythroid leukaemias
(DiGuglielmo’s syndrome)
• Predominant erythroid cell
population.
• Adults>50 years

36. Acute Megakaryoblastic Leukaemia
• Here, >50% of the blasts
are of megakaryocyte
lineage

37. Acute basophilic leukaemia
• AML with primary
differentiation to
basophils.

38. Acute panmyelosis with myelofibrosis
• Acute panmyeloid
proliferation with
accompanying
fibrosis of the bone
marrow.

39. Myeloid sarcoma
• 5-15%
• Are the tumor mass of myeloblasts and
immature myeloid cells occuring in an
extramedullary sites ( skin, breast, cervix, bone,
orbit, paranasal sinus, pleura)
• Previously called as CHLOROMAS because
these turned green in dilute acid ( because of
large amount of MPO)

40. Acute leukaemia of ambiguous lineage
• Acute undifferentiated leukaemia:
▫ Here, the morphological, cytochemical and immuno-
phenotypical features of the proliferating blasts lack
sufficient evidence to classify as myeloid or lymphoid
origin.
• Bilineal leukaemia:
▫ Dual population of blasts
• Biphenotypic
▫ Two characteristics on same blast cell.

41. CLINICAL FEATURES

42. General:
• Fatigue : 50%
• Fever : 20%
• Bone pain : 15-20% , sternal tenderness (50%)
• Bleeding : 5% (APL)
• Splenomegaly: mild
• Hepatomegaly: mild
• Lymphadenopathy: extremely uncommon except
in AML-M5.

43. Systemic:
• SKIN:
▫ Non-specific lesions, leukaemia cutis , Granulocytic sarcoma of skin and
subcutis
• SENSORY ORGAN:
▫ Retinal, choroidal, iridial, and optic nerve infiltration can occur.
• GI Tract:
▫ Gingival hypertrophy, enterocolitis, fever, abdominal pain, bloody
diarrhoea, intestinal perforation, proctitis.
• RESPIRATORY TRACT:
▫ Laryngeal obstruction, alveolar infiltration
• HEART:
▫ Pericardial infiltrates, transmural ventricular infiltrates
• UROGENITAL SYSTEM
▫ Leukaemic cell infiltration in kidneys; haemorrhage in pelvis
• BONES:
▫ Bone pain, necrosis, arthritis with effusion
• CNS:
▫ Meningeal involvent is important in the treatment of AML –M5

44. INVESTIGATIONS

45. Peripheral Blood Smear
• Haemoglobin:
▫ Decreased (5-9 gm/dl)
▫ Normocytic normochromic anaemia.
• WBC:
▫ Increased ( 20,000/cumm to 100,000/cumm)
▫ SUBLEUKAEMIC leukaemia:
 TLC <4000/cumm with few blasts in PBS
▫ ALEUKAEMIC leukaemia:
 TLC < 4000/cumm with no blasts in PBS
▫ BLAST cells > 20%, presence of AUER RODS in the cytoplasm of
blast cells.
▫ Neutropenia and monocytosis
• Platelets:
• Moderate to severe thrombocytopenia

46. Bone Marrow
• Hypercellular marrow.
• Blast cell >20%
• Marked depletion of cells of
▫ Erythroid series
▫ Maturing cells of myeloid series like, myelocytes,
metamyelocytes, neutrophils and megakaryocytes
 Dysmegakaryopoisis :- monolobate and hyperlobate forms

47. PROGNOSIS

48. Good prognostic factors
• Age < 40 yrs.
• Leukemia without MDS
• TLC < 25 х 10⁹/L
• t(15; 17) in M3
• t(8; 21) in M2
• inv(16) in M4E0
• trisomy 21

49. Poor prognostic factors
• Del (7q)
• Del (5q)
• 11q 23 abnormalities
• High TLC > 100 x 10⁹/l
• AML associated with myelodysplastic
changes
• Extremes of age < 2 yrs. & > 55 yrs.

50. ACUTE LYMPHOID
LEUKAEMIA

51. • Neoplasms composed of immature
lymhoid cells, predominantly
LYMPHOBLASTS.
• Peak incidence : 2-5 year
(Second peak : 30-40 year)
• M>F

52. MOLECULAR PATHOGENESIS

53. Genetic aberrations
• 90% have structural or numerical chromosomal
changes.
• Hyperploidy  commonest
• Hypoploidy
• Gain of function mutation in NOTCH1 gene
• Loss of function mutation in PAX5, E2A, EBF
• Balanced translocation t(12;21).

54. CLASSIFICATION

55. Classification
FAB classification
•Three subtypes
•L1
•L2
•L3
WHO classification

56. L1 ALL
• Best prognosis.
• Most common type of ALL in
children.
• Lymphoblasts are
predominantly small.
• Nuclear shape is regular with
occasional cleft.
• Nucleoli are not prominent.
• Cytoplasm is scant .

57. L2 ALL
• Most frequent ALL found in
adults.
• Cells are large with variation
in size.
• Nucleus is irregular, with
clefting.
• Nucleoli are always present
but vary in size and number.
• Cytoplasm is abundant with
variable basophilia.

58. L3 ALL
• Rare form.
• Can occur in both children and adults.
• Cells are large with abundant, intensely basophilic
cytoplasm.
• Prominent cytoplasmic vacuolization.
• Prominent nucleoli (1-2)

59. Scoring system for FAB criteria in ALL
• Because of the difficulty in distinguishing L1 and L2 .
• Total score range from -4 to +2
• If total score is 0 to +2 L1
• If total score is -1 to -4  L2
CRITERIA SCORE
High N/C ratio >75% of cells +
Low N/C ratio > 25% of cells -
Nucleoli: 0 to 1(small) > 75% of cells +
Nucleoli: 1 or more (prominent) > 25% of cells -
Irregular nuclear membrane > 25% of cells -
Large cells > 50% of cells -

60. WHO classification
Precursor B-cell acute
lymphoblastic leukemia / lymphoma
Precursor T-cell acute lymphoblastic
leukemia / lymphoma

61. CLINICAL FEATURES

62. • Fatigue
• Pallor
• Infections
• Hemorrhages
• Bone pain
• Lymphoadenopathy : 75%
• Hepatosplenomegaly
• Mediastinal mass
• CNS involvement

63. INVESTIGATIONS

64. Peripheral Blood Smear
• Haemoglobin:
▫ Decreased.
▫ Normocytic normochromic anaemia.
• WBC:
▫ Increased ( 20,000/cumm to 200,000/cumm)
▫ SUBLEUKAEMIC leukaemia:
▫ ALEUKAEMIC leukaemia:
▫ BLAST cells > 20%.
▫ Hyperleukocytosis
▫ Neutropenia .
• Platelets:
• Decreased (occasionally increased)

65. Bone marrow
• Hyper cellular
• Blast cells 20-100%
• Reduction in erythroid and myeloid precursors
• Megakaryocytic – decreased

66. • Serum LDH: elevated
• Serum uric acid : elevated
• Serum immunoglobulin (IgA and IgM) : slightly
decreased in 1/3rd of children with ALL
• Urinalysis:
▫ Microscopic hematuria and presence of uric acid
crystals
• Chest Xray:
▫ Enlargement of thymus or mediastinal nodes, with or
without pleural effusion
• CSF examination:
▫ Leukaemic blasts can be identified in 1/3rd of childhood
ALL.

67. PROGNOSTIC FACTORS

68. Factor Good prognosis Bad prognosis
Race White Black
Age 2-8 yrs <1yr.,adult, >10 yrs
Sex Female Male
Meningeal
involvement
- +
LN, liver, spleen - Massively enlarged
Mediastinal mass - +
TLC <20x109 /L >50 x109 /L
Type of ALL L1 L2,L3
Cytogenetics Hyperploidy t (4;11),t (9;22),
BCR-ABL fusion m RNA,
MLL-AF4 fusion mRNA.

70. THANK YOU
QUESTIONS ?

71. CHRONIC MYELOID LEUKAEMIA

72. • It is a myeloproliferative neoplasm
characterized by increased proliferation of
predominantly granulocytic cell line without the loss of
their capacity to differentiate.
• Originate in a single abnormal haemopoietic
stem cell involving all haematopoietic cell lines.
• M>F
• Peak incidence : 50-60 yr

73. WHO classification of myeloproliferative
neoplasms
1. Chronic myeloid leukaemia
2. Chronic neutrophilic leukaemia
3. Polycythaemia vera
4. Primary myelofibrosis
5. Essential thrombocytopenia
6. Chronic eosinophilic leukaemia, NOS
7. Mastocytosis
8. Myeloproliferative neoplasm, unclassified.

74. MOLECULAR PATHOGENESIS

75. • Hematopoietic stem cells of CML contain a
t(9;22) (q34;q11) resulting in Philadelphia
chromosome.
• Philadelphia chromosome refers to shortened
chromosome 22.

76. • This translocation result in the fusion of the
▫ ABL ( Abelson leukaemia virus) gene on chromosome 9
With
▫ BCR ( Breakpoint cluster region) gene on chromosome
22
• The site of breakpoint in BCR gene is variable , thus
the size of BCR/ABL protein varies from 185kDa to
230kDa.
• Most patient with typical CML have 210 kDa fusion
protein .

77. BCR-ABL fusion gene
encodes for
Tyrosine kinase activity
(Tyrosine kinase normally function in signal transduction pathways that
regulate cell growth)
causing
Activation of cytoplasmic and nuclear signal transduction
pathways affecting cell growth and proliferation.
• Uncontrolled tyrosine kinase activity results in:
▫ Deregulation of cellular proliferation (preferentially
granulocytic and megakaryocytic)
▫ Decreased apoptosis
▫ Poor adherence of leukaemic cells to bone marrow stroma .

78. CLINICAL FEATURES

79. • Asymptomatic – 40%
• Generalized weakness
• Loss of weight , sweating due to anaemia,
• Anorexia hypermetabolism
• Dragging sensation in the abdomen
• Left upper quadrant pain
• Splenomegaly: 80-90%
• Hepatomegaly
• Sternal tenderness
• Priapism, visual disturbances, venous thrombosis

80. INVESTIGATIONS

81. HAEMATOLOGICAL FINDINGS:
• Hemoglobin
▫ Decreased : 7-11 gm/dl
▫ Normocytic normochromic anaemia
• WBC:
▫ TLC : 100,000/cumm – 50,000/cumm
▫ Directly proportional to the size of spleen, basophil count,
percentage of blast cells and degree of anaemia.
▫ All stages of maturation (myeloblast to segmented neutrophils )are
present with peaks of myelocytes and segmented neutrophils.
▫ Basophils and eosinophils are increased.
• Platelets:
▫ Slightly increased .
• Decreased neutrophil alkaline phosphate score.

82. BONE MARROW
• Markedly hypercellular.
• Myeloid:erythroid ratio is increased ( 10:1 to 50:1)
• Blasts < 10%
• Basophils, monocytes, eosinophils increased.
• Megakaryocytes are increased in number with smaller
size and hypolobated nuclei.
• Peudo-Gaucher cells and sea blue histiocytes may
be present.
• Bone marrow biopsy might show marrow fibrosis.

83. Cytogenetic analysis
• To confirm the diagnosis.
• Has prognostic importance.
• Philadelphia chromosome : in majority of
cases.
• Other chromosomal changes : duplication of
Ph` chromosome, +8, +19.

84. Biochemical abnormalities:
• Serum uric acid: elevated
• Serum vitamin B12 : increased
• Serum LDH: elevated

85. STAGES OF CML
1. CHRONIC PHASE:
▫ Initial phase in majority of cases.
▫ Lasts for 3-5 years.
1. ACCELERATED PHASE:
▫ Follows chronic phase in majority of cases.
2. ACUTE BLASTIC CRISIS

86. CHRONIC PHASE
PBS:
• Leukocytosis with peaks of
myelocytes and segmented
neutrophils.
• Blasts usually <2 % .
• Basophilia and eosinophilia
• Platelet count : N or increased

87. Bone marrow:
• Hypercellular
• Blasts <5% of marrow
cells.
• Increased M:E ratio.
• Megakaryocytes: small
in size, hypolobated
nuclei.
• Pseudo-gaucher cell and
sea blue histiocytes :
30%

88. ACCELERATED PHASE
When one or more of the followings are present
• Blasts 10% or more in PBS and in bone marrow.
• PBS: Basophilia >20%
• Persistent thrombocytopenia not due to therapy or
persistent thrombocytosis not responding to therapy.
• Increasing WBC count and splenomegaly not
responding to therapy.
• Cytogenetic evolution:
▫ Additional Ph` chromosome, +8

89. BLASTIC PHASE:
• Resembles acute leukaemia.
• Diagnosis can be made in the presence of one or
more of the following:
▫ Blasts > 20% in PBS and Bone marrow smear.
▫ Extramedullary proliferation of the blasts.
▫ Large aggregates and clusters of blasts in the bone
marrow biopsy specimen.
• BLAST CRISIS can be :
▫ Myeloid crisis: 70%
▫ Lymphoid crisis: 30%

90. DIFFERENTIAL DIAGNOSIS

91. 1. Leukaemoid reaction
Features CML Leukaemoid
reaction
Nature of disease Myeloproliferative Reactive
WBC count Usually
>1,00,000/cumm
Usually
<50,000/cumm
Myelocyte and neutrophil peaks + -
Basophilia,Eosinophilia + _
Toxic granules - +
NAP score Low N/ High
Bone marrow Trilineage hyperplasia Myeloid
hyperplasia
Splenomegaly + -
Genetic analysis Ph` chromosome Normal

92. 2. Other myeloproliferative disorders
• Polycythaemia vera / Myelofibrosis/ Essential
thromnocythaemia:
▫ Moderately increased WBC count
▫ NAP score is normal or increaased
▫ Absence of Ph` chromosome
• Polycythemia vera:
▫ PCV markedly increased .
• Myelofibrosis:
▫ Marked anisopoikilocytosis, nucleated RBCs, tear drop cells
• Essential thrombocythaemia:
▫ Normal Hb; numerous , large, hyperlobated megaryocytes.

93. 3. Chronic myelomonocytic leukaemia
• Moderate leukocytosis
• Increased neutrophils and band forms
• Monocytosis
• Absence of Ph` chromosome or BCR/ABL gene
rearrangement.

94. 4. Acute leukaemia
• Mild splenomegaly
• No basophilia
NOTE :
• Ph` chromosome can occur in few cases on ALL

95. CHRONIC LYMPHOCYTIC
LEUKAEMIA

96. Chronic lymphoid leukaemia
B-Cell type T cell type
• Chronic lymphocytic leukaemia
• B cell prolymphocytic leukaemia
• Waldenstrom macroglobulinaemia
• Hairy cell leukaemia
• Plasma cell leukaemia
• Leukaemic phase of non-Hodgkins
lymphoma
• T cell prolymphocytic leukaemia
• T cell granular lymphocytic
leukaemia
• Adult T cell leukaemia /lymphoma
• Sezary syndrome

97. • Neoplastic disorder characterised by
monoclonal proliferation mature appearing
lymphocytes in the peripheral blood, bone
marrow and lymph nodes.
• In most cases, the cells are monoclonal B
lymphocytes that are CD5+
• Median age at presentation: 65yr
• M>F

98. MOLECULAR PATHOGENESIS
• Deletions of 13q14.3  most common
• Trisomy 12 (10-30%)
• Deletions of 11q, 17p
• Rarely associated with chromosomal
translocations ; t(11;14) , t(14;18), t(14;19)

99. Deletion of 13q14.3
• 13q14.3 contains a tumor suppressor gene ,
called as
▫ DBM ( disrupted in B-cell malignancies),
▫ LEU1, LEU2, LEU5.

100. CLINICAL FEATURES

101. • Asymptomatic (25%)
• Weakness
• Fatigue
• Weight loss
• Repeated infections
• Bleeding
• Generalized lymphadenopathy: commonest
• Splenomegaly

102. INVESTIGATIONS

103. HAEMATOLOGICAL FINDINGS
• Haemoglobin:
▫ Decreased
▫ Normocytic normochromic anaemia
• WBC count:
▫ >50,000/cumm with >80%of cells being lymphocytes.
▫ Absolute lymphocyte count >5000/cumm
▫ Predominant cell is a small lymphocyte with clumped chromatin, round
nucleus.
▫ Smudge / basket cells + .
▫ Prolymphocytes ( larger cells with prominent nucleoli ) are <
2%.
• Platelets:
▫ Normal or decreased.

104. BONE MARROW EXAMINATION
• Hypercellular
• Lymphocytic infiltrate:
▫ >30%
▫ Patterns of infiltration :
1. Interstitial
2. Nodular  favourable prognosis
3. Diffuse  worst prognosis
4. Combination of above three

105. IMMUNOPHENOTYPING
• Provides definitve diagnosis
• Should be performed in all cases before
beginning treatment.
• CD5 and CD23 positivity are distinctive for
CLL. It also express CD19, CD20, and CD21.

106. Differential diagnosis
• Reactive lymphocytosis
▫ Absolute lymphocyte count < 5000/cumm
▫ Reactive lymphocytes are large cells with abundant
cytoplasm and dark blue edges.
• Other chronic lymphoid leukaemias
▫ Prolymphocytic leukaemia
 Prolymphocytes >55%
▫ Leukaemic phase of non-Hodgkin lymphoma:
 FOLLICULAR :
 Lymphocytes show deep nuclear clefts
 CD5-
 MANTLE CELL:
 Small cleaved lymphocytes
 CD23-
▫ Hairy-cell leukemia
 Lymphocytes have fine projections on cell surface

107. PROGNOSIS

108. • Prognosis depends on the stage of the disease
at diagnosis.
• TWO main staging systems :
▫ Rai ( 1975)
▫ Binet (1981)

109. RAI CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis
______________________________________________________________________________
_______
Low risk
• 0 Blood (> 5000/cumm monoclonal
lymphocytes)
and marrow (>30%) lymphocytosis
Intermediate risk
• I Lymphocytosis and lymphandenopathy
• II Lymphocytosis and enlarged spleen and/or liver
High risk
• III Lymphocytosis and anemia (Hb < 11g/dL)
• IV Lymphocytosis and thrombocytopenia (
Plt < 100,000/ul.)

110. BINET CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis
_____________________________________________________________________
________
• A Lymphocytosis with less than 3 areas
of palpable lymphoid-tissue enlargement
• B Lymphocytosis and 3 and more areas of
palpable lymphoid-tissue enlargement
• C Lymphocytosis with anemia (Hb <11g/dL;
women <10g/dL) or thrombocytopenia
Plt <100,000/uL)
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Lymphoid areas : lymph nodes ( cervical, axillary, inguinal) , spleen, liver

111. Markers of poor prognosis in CLL
• Advanced Rai or Binet stage
• Presence of deletion of 11q and 17p
• Expression of ZAP-70
• Peripheral lymphocyte doubling time <12 months
• Diffuse marrow infiltration
• Transformation to aggressive tumors:
▫ Prolymphocytic transformation
 Increasing splenomegaly, worsening cytopenias, appearance
of prolymphocytes(>10%)
▫ Diffuse large B cell lymphoma( Richter syndrome)
 Rapidly enlarging mass with a lymph node or the spleen
• Poor response to chemotherapy
• High 2- microglobulin level
• CD38+

112. THANK YOU
QUESTIONS ?