Chronicmyeloproliferative neoplasm ,cll

1. Neoplastic White Cell Disorders
Chronic Myeloid
leukemia

2. Chronic Myeloproliferative
disorders(CMPD) /
Myeloproliferative
Neoplasm(MPN)

3. Lesson Plan (objectives)
• Defination of CMPDs/MPN
• Classification ( including recent WHO)
• Chronic myeloid Leukemia (CML) :
Clinical features
• Pathogenesis of CML (Ph chromosome)
• Clinical Phases of CML with PBS/BM findings
• other MPNs

4. • Chronic Lymphocytic Leukemia:
• Classification
• Clinical features
• Lab findings (PBS/BM)
• Binet /Rai staging
• Variants of CLL

5. Chronic Myeloproliferative
disorders(CMPD)
• Group of stem cell disorders charcterized by
overproduction of mature white cell, red cells
or platelets
• Maturation of the neoplastic cell line is
relative normal.
• Variable degree of myeloid, erythroid and
megakaryocytic hyperplasia with
predominance of one series
• Progressive & exibit transition one disorder to
another over a period-marrow failure or

6. Chronic Myeloproliferative
disorders
• CML
• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis

7. WHO classification 2008
Myeloproferative Neoplasms(clonal
neoplastic nature)
• CML –Ph chromosome positive t(9:22)
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia-
NOS/hypereosinophilic syndrome
• Primary myelofibrosis
• Polycythemia vera
• Essential thrombocythemia
• Mastocytosis
• MPN-unclassified

8. Chronic Myeloid Leukaemia
1. A clonal disorder of
pluripotent stem cell
with mature
granulocytes and
their precursors
accumulating in
excess in the
marrow and blood.
2. 15% of all
leukaemias

9. CML
1. Adults between the ages of 25 & 60 are
affected; mean age at presentation is 45 yrs;
2. It may occur in children & neonates
3. M:F = 1.4:1
4. Increased incidence has been observed in
atomic bomb survivors
5. Philadelphia chromosome is characteristically
present in typical CML

10. CML
1. Insidious onset
2. Mild to moderate anaemia (pallor dyspnoea,
tachycardia, fatigue, weakness)
3. Hypermetabolism (anorexia, lassitude, weight
loss, night sweats)
4. dragging sensation in abdomen (Massive
splenomegaly); left upper quadrant pain
(splenic infarction)
5. Bruising, epistaxis, menorrhagia & bleeding
due to platelet dysfunction
6. Rarely gout (hyperuricemia), priapism, visual
disturbances,

11. CML – Clinical findings - Summary
Symptoms % Physical Findings %
Fatigue 80 Splenomegaly 95
Weight loss 60 Hepatomegaly 50
Abdominal fullness 40 Sternal tenderness 80
Easy bruising 35 Purpura 25
haemorrhage 35 Retinal Haemorrage 20
Abdominal pain
(Splenic infarct)
30
hypermetabolic
State, fever
10

12. CML – Philadelphia (Ph) Chromosome
Reciprocal
t(9;22)(q34;q11) in
which the c-ABL
gene from 9 is
juxtaposed with the
BCR sequence on
22 forming a fusion
gene (BCR-ABL); the
product is a 210kD
tyrosine kinase
The abnormal chromosome 22
is Philadelphia chromosome

13. CML – BCR-ABL Fusion Gene
• In a minority of patients (5-
10%), BCR-ABL
rearrangement with fusion
gene is present in the
absence of visible
karyotypic abnormality.
• It is demonstrated by FISH
or PCR
• Fusion gene product
increases cell division &
inhibits apoptosis

14. CML – Clinical Phases
1. The initial phase of CML is stable or indolent
(usually lasting 2-4 years),
2. It is followed in about 50% of patients by an
accelerated stage (6-12 months)
3. Finally an acute phase or blast crisis (2-4
months) similar to acute leukemia.
4. Death is usually secondary to blast crisis,
marrow failure or marrow fibrosis.

15. FAB classification of CML
• Chronic granulocytic leukemia(CGL)-Ph +ve
• Atypical CML (aCML)-monocytosis,dysplasia
in erythroid/megakaryocyte or
• Chronic myelomonocytic leukemia- Ph–ve,
monocytosis

16. Phases of CML
• Chronic phase
• Accelerated phase
• Blastic phase

17. CML – Chronic phase
Peripheral Smear
• Anaemia-NCNC
• WBCis elevated
(2,00,000/cummm )
• Blast if present <5%
• Segmented neutrophils,
metamyelocytes
myelocytes predominate,
but eosinophilia &
basophilia are
characteristic
• Platelet numbers may be
normal or elevated (50%)
in most patients.
• NAP is abnormally

19. CML – Bone Marrow
• The bone marrow is
hypercellular (100%) with a
great increase in the M:E
ratio; a left shifted myeloid
series, and increased
eosinophils.
• Megakaryocytes may be
normal or elevated and are
often smaller than normal.

20. CML – Accelerated Phase
1. Blast <20%, 10-19%
2. Increasing spleen size unresponsive to
therapy
3. Basophilia >20%
4. Persistant or increasing WBc>10x10 9
5. Persistant thrombocytopenia(<1lac)/thrombocytosis (>10lac/cumm)
6. ~50% patients with CML enter into
accelerated phase after about 3 years
7. There is increasing anaemia, basophilia,
eosinophilia, thrombocytopaenia;
8. There is increase in BM blast cells;
9. Additional cytogenetic abnormalities appear
(trisomy 8, isochromosome 17, duplication of

21. Clinical Features
1. Starts insidiously, usually in late middle age
(~40 -60 years)
2. Plethoric & cyanotic;
3. Head ache, dizziness, hypertension (33%),
blurred vision, and hematemesis
4. Increased risk of peptic ulceration (5-10%),
hyper uricemia, gout;
5. Bleeding and thrombotic episodes, pruritus
after hot bath.
6. Splenomegaly (75%)

22. CML – Blast Crisis
1. Blast cells increase to >20% (PS/BM)with
anaemia,thrombocytopenia
2. ~In 50% of patients, blast crisis follows
accelerated phase
3. In the rest, blast crisis develops abruptly
4. In 70% of case, blasts are myeloid character;
in most of the rest, ALL with B cell markers
occurs ; rarely T cell blasts are seen;
5. ALL blast crisis is treated like ALL and has
better prognosis
6. New tyrosine kinase inhibitors (dasatinib,
nilotinib) are being tried

23. CML – Treatment
1. Drugs that inhibit ABL-BCR kinase (imatinib,
Gleevec) have been used to induce
remissions in >90% of patients
2. But relapses and resistance to drug occur
3. Allogeneic bone marrow transplantation is
the favoured treatment in younger patients

24. Ph Negative CML
1. 5% of patients with CML
2. Usually have features of myelodysplasia
3. Prognosis is worse than Ph positive CML
Juvenile CML
1. Rare; Affects young children
2. Manifests with skin rashes, lymphadenopathy,
hepatosplenomegaly & recurrent infections
3. High Hb F, monocytosis, normal LAP
4. Ph chromosome is negative; Prognosis is poor
5. Stem cell transfer is the treatment of choice

25. Eosinophilic & Chronic Neutrophilic Leukaemia
1. Eosinophilic Leukaemia: Some cases of
idiopathic hypereosiniphilia have an
interstitial deletion of chromosome 4 with
FIP1L1-PDGFRA fusion gene; these patients
often respond to imatinib
2. Patients with Chronic Neutrophilic Leukaemia
usual have mild splenomegaly with good
prognosis

26. Polycythemia vera
• Polycythemia vera is a chronic
myeloproliferative disorder characterized by
increased red blood cell mass (RCM), or
erythrocytosis
• The resultant hyperviscosity of the blood
predisposes such patients to thrombosis

27. • Increased RCM is accompanied by increased
white blood cell (myeloid) and platelet
(megakaryocytic) production, which is due to
an abnormal clone of the hematopoietic stem
cells with increased sensitivity to the different
growth factors for maturation.

28. Essential thrombocythemia
• Clonal myeloproliferative neoplasm
• Marked megakaryocytic hyperplasia and
thrombocytosis of more than 4.5 lac/cumm
• JAk2 MUTATION
• Thrombohemorrhagic Manifestation-Loss of
PGD2 receptors-thrombosis
• Storage pool defects in the platelets promote
bleeding tendency

29. Primary myelofibrosis/Idiopathic
myelofibrosis(IMF)
• Progressive MPN arising from a pluripotent
hemopoitic progenetor cell characterized by
granulocytic and megakaryocyticproliferation
asso. With marrow fibrosis which is not clonal
• Reaction to clonal MPNs.
• Fibroblast are polyclonal –secret collage in
response to cytokines secreted by
megakaryoctes.
• TGF-B & PDGF are mediators of collagen
deposition in marrow

30. CLL
White Cell Disorders
Chronic Lymphoid leukemia

31. DEFINITION
• characterized by accumulation in the blood of
mature neoplastic lymphocytes of either B- or
T-cell types.

32. Clinical features
• occurs in older subjects with only 15% of cases
before 50 years of age.
• M:F ratio 2 : 1.
• Symmetricalcal enlargement of cervical, axillary or
inguinal lymph nodes is the most frequent clinical
sign
• Nodes are usually discrete and non-tender.
• Tonsillar enlargement may be a feature.
• Features of anaemia may be present.
• Patients with thrombocytopenia may show
bruising or purpura.

33. • Splenomegaly and, less commonly,
hepatomegaly are Comnon in later stages.
• immunosuppression resulting from
hypogammaglobulinaemia and cellular
immune dysfunction.

34. Laboratory findings
• Lymphocytosis.
• The absolute lymphocyte Count is >5 x 109/L
and may be up to 300 X 109/L or more.
• Between 70 and 99% of white cells in the
blood film appear as small lymphocytes
• Smudge or smear cells are also present

35. Chronic lymphocytic leukaemia
Small lymphocytic lymphoma
• Chronic Lymphocytic Leukaemia (CLL)/Small
lymphocytic lymphoma (SLL) are
morphologically indistinguishable but differ only
in their clinical presentation;
• CLL is the most common leukaemia of adults in
west; (lymphocyte count >4000/mm3);
(2.7/100,000 incidence) representing about 30%
of all leukemia.
• SLL forms 4% of NHL

36. Chronic lymphocytic leukaemia
Small lymphocytic lymphoma
• Lymphocytes are 6 to 12µ,
with slightly irregular nuclei,
condensed chromatin &
scanty cytoplasm;
• In SLL, lymphnode structure is
effaced by these cells
admixed with larger pro-
lymphocytes (proliferation
centres)
SLL

37. Chronic lymphocytic leukaemia
Small lymphocytic lymphoma
• In CLL, mature appearing,
but functionally
incompetent lymphocytes
flood BM, peripheral blood,
and various organs with PB
lymphocytosis (>5.0 x109/L,
but usually >15.0 x109/L and
sometimes > 100.0 x109/L).
• PB also shows smudge cells
(arrow)

40. CLL/SLL Clinical Features
• Occurs after 50 years; median age 60;
• M:F = 2:1;
• Usually asymptomatic; 50% show fatigability,
weight loss, anorexia;
• Generalised lymphadenopathy &
hepatosplenomegaly in 50 – 60%;
• Hypogammaglobulinaemia is common;
• Autoantibodies with haemolytic anaemia &
thrombocytopaenia in 10-15%

41. CLL/SLL Course
• Median survival 4 – 6 years; those with low
tumour burden, ≥ 10 years
• Common chromosomal abnormalities: del(11q),
del(13q12-14), del(17p), trisomy 12q
• Del(11q), Del(17p) carry poor outlook;
• Transformations to more aggressive forms may
occur:
• prolymphocytic transformation in 15 – 30%
• large B cell lymphoma (Richter syndrome) in
10%

42. CLL/SLL Course
Rai staging of CLL:
• 0: lymphocytosis in blood (>5 x 109
/L) & marrow
• I: lymphocytosis and lymphadenopathy
• II: lymphocytosis and hepatomegaly or
splenomegaly
• III: lymphocytosis and anemia (Hb <100g/L)
• IV: lymphocytosis and thrombocytopenia (<100
x 109
/L)

43. CLL/SLL Course
Binet staging of CLL:
A: no anemia, no thrombocytopenia, fewer than 3
lymphoid areas enlarged (cervical, axillary and
inguinal lymphadenopathy, spleen, liver)
B: no anemia, no thrombocytopenia, 4 or more
lymphoid areas enlarged
C: anemia (hemoglobin < 10 g/dl) or platelet count
< 100 billion/L

44. VARIANTS OF CLL

45. Chronic Prolymphocytic Leukemia
• can be thought of as a variant of CLL. The
predominant cell is a prolymphocyte, larger
than the lymphocytes of CLL (10-15m),
resembles activated lymphocytes with almost
fine chromatin, a single large nucleolus, and
pale blue cytoplasm.
• Patients tend to be older (70 years) (CLL - 64
years) and have an aggressive clinical course.
• The median survival is 3 years (8 years for CLL)

46. Chronic Prolymphocytic Leukemia
• PWBC count is high (usually >100.0 x10 /L).
• Immunophenotype: similar to CLL (CD19+;
CD5+), but surface Ig is strongly expressed.
• Splenomegaly is common, but lymph-
adenopathy unusual.
• About 20% are of T cell origin. The prognosis is
poor, median survival is only 6 months.
• It frequently involves the skin causing a papular
nonpruritic nonscaling rash.

47. Hairy Cell Leukemia
Clinical Features
• 2% of all leukaemias; Middle aged Caucasian
males; 4:1 male to female predominance
• Splenomegaly, often massive, is most common;
less frequently, hepatomegaly &
pancytopaenia (<50%)
• Patients may present with symptoms of
pancytopenia (fatigue, infection, easy bruising)
or splenomegaly, but lymphadenopathy is rare.

48. Hairy Cell Leukemia
Clinical Features
• low grade B cell leukemia of moderately large
mononuclear cells having distinctive "hairy"
cytoplasmic projections.
• In bone marrow biopsy,- abundant cytoplasm
creates a "fried egg" appearance to each cell
producing a "honeycomb" appearance
• Bone marrow aspirates are usually "dry" because
of increased recticulin

49. Hairy Cell Leukemia
• Tumour cells are Positive for
tartrate resistant acid
phosphatase stain (TRAP
positive)
• Immuno-phenotypic pattern:
positivity for CD19+; CD20;
CD11c+; CD25+ (IL-2R), CD103,
SIgH & either ǩ or ʎ light chain