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Outline

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Outline Classification of malignant disease Myeloid vs lymphoid Acute vs chronic The leukemia vs lymphoma question Lymphoproliferative disorders Chronic ... – PowerPoint PPT presentation

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Title: Outline


1
Outline
  • Classification of malignant disease
  • Myeloid vs lymphoid
  • Acute vs chronic
  • The leukemia vs lymphoma question
  • Lymphoproliferative disorders
  • Chronic myeloproliferative disorders

2
Classification
  • Classification system for haematological
    malignancies is awkward
  • Names are relics from pre-molecular era when only
    microscopes mattered
  • Descriptive but not user-friendly
  • All sound the same
  • Considerable overlap and disease features

3
Classification
  • "high-modulus bead apex rubber with
  • spiral-wound, jointless edge and
  • capplies
  • ???
  • snow tires
  • Names are perfectly descriptive, but only if you
    know what it all means

4
Classification
  • Similar, poorly descriptive names
  • AND
  • Overlapping features
  • EQUALS
  • Some confusion

5
Myelo
  • one of the confusing things is the word part
    myelo
  • generally refers to bone marrow in general
  • precedes another descriptor examples
  • myelofibrosis marrow fibrosis
  • myelosuppression marrow suppression
  • myeloablation marrow ablation

6
MYELOID
  • similar to the word myelo
  • much more specific meaning
  • usually used in context
  • myeloid vs lymphoid

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Myeloid vs Lymphoid
  • lymphoid
  • B cells
  • T cells
  • myeloid everything else
  • RBC
  • Platelets
  • macrophages/monocytes
  • granulocytes
  • neutrophils
  • basophils
  • eosinophils

9
Myeloid vs Lymphoid
  • any disease that arises from the myeloid elements
    is a myeloid disease
  • AML, CML, PRV, ET, Myelofibrosis
  • any disease that arises from the lymphoid
    elements is a lymphoid disease
  • ALL, CLL, Hodgkins, Mycosis Fungoides

10
Acute vs. Chronic leukemia
  • Acute leukemias
  • young, immature, blast cells
  • more fulminant presentation
  • more aggressive course

11
Acute vs. Chronic leukemia
  • Chronic leukemias
  • accumulation of mature, differentiated cells
  • often subclinical or incidental presentation
  • in general, more indolent course
  • Frequently splenomegaly
  • accumulation of cells

12
Acute vs. Chronic leukemia
  • Acute leukemia blasts in marrow and often
    blood
  • Chronic leukemia mature appearing cells in
    marrow and blood

13
Acute vs. Chronic leukemia
  • leukemias are classified according to cell of
    origin
  • lymphoid cells
  • ALL - lymphoblasts
  • CLL mature appearing lymphocytes
  • myeloid cells
  • AML myeloblasts
  • CML mature appearing neutrophils

14
leukemia vs lymphoma
  • Reasonably straightforward
  • leukemia increased WBC in blood and marrow
  • leukemias can be myeloid or lymphoid
  • lymphocytosis, neutrophilia, blasts of either
    origin
  • lymphoma is always of a lymphoid origin
  • B cell lymphoma (85)
  • T and NK cell lymphoma (15)

15
leukemia vs Lymphoma
  • lymphoma of two general types
  • Hodgkins lymphoma
  • B cell origin
  • Reed-Sternberg cells
  • Non-Hodgkins lymphoma
  • all others
  • B, T and NK

16
leukemia vs Lymphoma
  • leukemia presents in blood and marrow
  • lymphoma most often presents primarily with
    lymphadenopathy
  • however one caveat

17
leukemia vs Lymphoma
  • A few specific entities can present as either
  • lymphoblastic lymphoma
  • and
  • acute lymphoblastic leukemia
  • are the same disease, but named depending on
    mode of presentation
  • nodal or leukemic

18
leukemia vs Lymphoma
  • other common example
  • chronic lymphocytic leukemia
  • and
  • small lymphocytic lymphoma
  • the two best examples
  • called leukemia vs lymphoma depending on mode
    of presentation

19
leukemia vs Lymphoma
  • most lymphoid diseases can enter a
  • leukemic phase if advanced
  • enough
  • high tumor burden, spills out into blood
  • BUT
  • myeloid diseases very rarely present in
  • lymph nodes

20
Lymphoma Classification
  • complicated, getting worse
  • now able to distinguish subtle differences in
    cells better than ever before
  • broadly,
  • Hodgkins vs non-Hodgkins

21
Lymphoma Classification
  • Old classification Working Formulation
  • Classified according to clinical behaviour
  • Low Grade
  • Intermediate Grade
  • High Grade

22
Lymphoma Classification
  • newer classification REAL, WHO
  • take into account
  • cell type (B vs. T)
  • disease biology
  • immunophenotype
  • Cytogenetics

23
Lymphoma Classification
24
  • For every stage of lymphocyte development,
  • there is a corresponding lymphoid neoplasm

25
B Cell Development
Bone Marrow
Periphery
Antigen-Independent
Antigen-Dependent
Stem Cell Pro-B Cell Pre-B Cell
Immature-B Cell Naïve-B Cell
Mature-B Cell
Surrogate Light Chain of Pre-BCR
Iga/Igß
IgM
IgM
IgM
Y
Y
II
II
Y
II
II
Y
Y
IgD
Y
II
II
II
II
II
II
µ
DHJH
VHDHJH
VLJL
Ig
Ig gene rearrangement -ive and ive selection
Pan B Cell Antigens CD19, CD20
CD38
CD22, CD23, CD40
Somatic Hypermutation
CLL, Myeloma, Waldenstroms
Burkitts
Precursor B-ALL
26
Acute Lymphoblastic leukemia
  • 11 of all leukemias
  • 85 of childhood leukemia
  • Commonest 2-10 years
  • 20 ? after 40 years

27
Aetiology
  • Chemicals/toxins
  • Radiation
  • Viruses
  • Genetics and congenital factors

28
Presentation
  • Acute leukemia is always serious and life
    threatening
  • Anemia Pallor, lethargy, dyspnoea
  • Leucopenia Infection - mouth, skin, perianal
    region
  • Thrombocytopenia bruising, menorrhagia, gum
    bleeding
  • Hepatosplenomegaly is common
  • Gum hypertrophy, skin infiltration

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35
Differential Diagnosis
Lymphadenopathy Infectious mono. or
other viral infections, Lymphoma,
Hepatosplenomegaly Myelo or
Lymphoproliferative disorders
Autoimmune, Metabolic, storage
disorders Pancytopenia Aplastic
anemia, Drug related, Hypersplenism,
Myelodysplasia
36
Investigations General
FBC Usually shows ? HB and platelets
(maybe lt20) WCC can vary lt1.0 - gt
200 x 109/l, Abnormal differential,
Film Blasts Coag. Screening Maybe
abnormal Chemistry LDH reflects tumor
burden, renal failure, hyperuricemia Others
Chest x-ray, USD, Virology, LP, Blood
C/S Initial evaluations are not only directed
towards diagnosis but to initiate supportive
measures for patients with advanced
disease (Large mediastinal mass, Renal Failure,
Very high WCC)
37
Investigations Specific
  • Morphology
  • Immunophenotype
  • Cytogenetics
  • Molecular genetics

38
FAB classification of ALL
L1 Small, monomorphic cells L2 Large,
heterogenous cells L3 Burkitt-cell type,
vacuolated
39
Immunophenotyping Flowcytometery
HLA-DR CD34
Stem cell compartment
TdT
CD7 CD3
CD19 CD22
CD13 CD33
T-ALL
B-ALL
AML
40
Abnormalities seen in at least 90 of
cases Karyotype is of major prognostic
significance Used in planning Treatment t(922)
, t(119), t(411), t(814)
41
Poor prognostic factors in ALL
Age Sex WCC _at_ DX. CNS disease
Immunophenotype Cytogenetics Remission
lt1 or gt10yrs Male gt 50x109/l Blasts in CSF B
or T, Diff Subtypes Ph (922) or
(411) Failure to remit with 1 course of chemo
42
Treatment
  • Supportive Care
  • Red cell transfusion for anaemia
  • Platelets transfusion for thrombocytopenia
  • Vigorous treatment of infection
  • Social and psychological support
  • Hydration and treatment for hyperuricemia

43
Principles of therapy in ALL
  • Remission induction
  • Consolidation
  • CNS prophylaxis
  • Allogeneic BMT for high risk groups
  • Maintenance

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Treatment Outcome
  • The most important factor to influence treatment
    outcome is AGE
  • Continuous decline in CR from 95 in children to
    40-60 in pts older than 60
  • Cytogenetics
  • Overall CR in adults 75 (63-86)
  • leukemia Free Survival 31 (13-44)

49
Childhood ALL
50
Chronic Lymphocytic leukemia
  • Commonest leukemia in the western world
  • Clonal proliferation of the B-Lymphocytes
  • Disease of the elderly
  • Younger patients now seen
  • MF ratio, 21
  • CLL is highly variable disorder
  • 75 cases, diagnosis by chance on a routine blood
    test

51
Aetiology
  • Cause unknown
  • Not associated with radiation or exposure to
    occupational hazards
  • Among the leukemias, CLL has the strongest
    tendency for familial incidence

52
Clinical Findings
  • Asymptomatic incidental finding
  • Anaemia thrombocytopenia
  • Infections
  • Weight loss, Night sweats, Fever (B Symptoms)
  • Lymphadenopathy
  • Splenomegaly
  • AIHA (Auto immune haemolytic anaemia)

53
Binet system
  • A lt3 lymphoid sites involved, Hbgt10, Pltsgt 100
  • B gt3 lymphoid sites, Hbgt10, Pltsgt100
  • C Hblt 10, Plts lt100, independent of lymph site
    involvement

54
Prognosis
  • Late stage patients have usually progressive
    disease
  • Highly Variable for early stage patients
  • Significant subset of early stage eventually
    progress
  • Refractory to treatment
  • Infectious Complications
  • Autoimmune complications

55
Prognosis
  • RAI / BINET Stage
  • LDH
  • ?2m
  • Lymphocyte Doubling Time
  • FISH
  • CD38 (B-Cell marker)
  • ZAP-70 (T-Cell marker aberrantly expressed on
    B-Cells)
  • Somatic Hypermutation

56
Treatment
  • Watchful waiting First do no harm
  • Single agents
  • Alkylators Chlorambucil, Cyclophosphamide
  • Purine analogues Fludarabine
  • Monoclonal antibodies
  • Rituximab (Anti CD20 antibody)
  • Campath (Anti CD52 antibody)
  • Combination Chemoimmunotherapy
  • FCR
  • Stem Cell Transplant

57
Myeloproliferative disorders
  • Clonal haematopoeitic disorders
  • Proliferation of one of myeloid lineages
  • Granulocytic
  • Erythroid
  • Megakaryocytic
  • Relatively normal maturation

58
Myeloproliferative disorders
  • WHO Classification of CMPD
  • Ch Myeloid leukemia
  • Ch Neutrophillic leukemia
  • Ch Eosinophillic leukemia / Hyper Eo Synd
  • Polycythemia Vera
  • Essential Thrombocythemia
  • Myelofibrosis
  • CMPD unclassifiable

59
Myeloproliferative disorders
60
Myeloproliferative disorders
  • Ch Myeloid leukemia (BCR-ABL positive)
  • Polycythemia Vera
  • Essential Thrombocythemia
  • Myelofibrosis
  • Specific clincopathologic criteria for diagnosis
    and distinct diseases, have common features
  • Increased number of one or more myeloid cells
  • Hepatosplenomegaly
  • Hypercatabolism
  • Clonal marrow hyperplasia without dysplasia
  • Predisposition to evolve

61
Bone marrow stem cell
Clonal abnormality
Essential thrombocytosis (ET)
Polycythaemia rubra vera (PRV)
Myelofibrosis
Chronic myeloid leukemia
10
10
70
AML
30
62
Epidemiology of CML
  • Median age range at presentation 45 to 55 years
  • Incidence increases with age
  • 12 - 30 of patients are gt60 years old
  • At presentation
  • 50 diagnosed by routine laboratory tests
  • 85 diagnosed during chronic phase

63
Epidemiology of CML
Ionizing radiation Latent Period Atomic bomb
survivors 11 years ( 2-25) Ankylosing
spondylitis pts 3.6 years (1-6) No evidence
of other genetic factors Chemical have not been
associated with CML
Incidence 1-1.5/100,000 population Male
predominance
64
Presentation
Insidious onset Anorexia and weight
loss Symptoms of anaemia Splenomegaly maybe
massive Pt . maybe asymptomatic
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The Philadelphia Chromosome
67
The Philadelphia Chromosome t(922)
Translocation
9
9
Philadelphia chromosome
22
Ph
bcr
bcr-abl
Fusion protein with tyrosine kinase activity
abl
68
Clinical Course Phases of CML
Advanced phases
Chronic phase Median 46 years stabilization
Accelerated phase Median duration up to 1 year
Blastic phase (blast crisis) Median survival 36
months Terminal phase
69
Treatment of Chronic Myeloid leukemia
Arsenic Lissauer, 1865 Radiotherapy Pusey,
1902 Busulfan Galton, 1953 Hydroxyurea Fishb
ein et al, 1964 Autografting Buckner et al,
1974 Allogeneic BMT (SD) Doney et al,
1978 Interferon Talpaz et al, 1983 Allogeneic
BMT (UD) Beatty et al, 1989 Donor Leukocytes
Kolb et al, 1990 Imatinib Druker et al,
1998 Imatinib/Combination therapy OBrien et al,
200
70
CML Treatment
  • Chemotherapy to reduce WCC - Hydroxyurea
  • Interferon based treatment
  • Allogeneic bone marrow transplant
  • Molecular therapy - Imatinib

71
CML- CP survival post BMT (IBMTR 1994-1999)
Probability
Years
72
Issues related to BMT
  • 70 long term cure rate
  • Donor Availability
  • Age of patient
  • Length/stage of disease
  • Treatment related mortality
  • Long term sequalae infertility, cGVHD

73
The Ideal Target for Molecular Therapy
  • Present in the majority of patients with a
    specific disease
  • Determined to be the causative abnormality
  • Has unique activity that is
  • - Required for disease induction
  • - Dispensable for normal cellular function

74
Mechanism of Action of Imatinib
Goldman JM. Lancet. 20003551031-1032.
75
Imatinib compared with interferon and low
dose Cytarabine for newly diagnosed
chronic-phase Chronic Myeloid leukemia S.G.
OBrien et al New England Journal of
Medicine Vol. 348 March 2003
76
Imatinib vs Interferon in newly diagnosed CP
Chronic Myeloid leukemia (18 months)
Imatinib 400mg Interferon and Ara-C
CHR 96 67 MCR 83 20 CCR 68
7 Intolerance 0.7 23 Progressive 1.
5 7 disease
77
Evolution of treatment goals
HR MCR CCR PCR -
HU IFN Imatinib BMT
78
Issues related to Imatinib
  • Very few molecular responses (5-10)
  • Resistance in some patients
  • Lack of response in some patients
  • Expensive
  • Long term toxicity/side effects unknown

79
CML
80
Polycythemia
  • True / Absolute
  • Primary Polycythemia
  • Secondary Polycythemia
  • Epo dependent
  • Hypoxia dependent
  • Hypoxia independent
  • Epo independent
  • Apparent / Relative
  • Reduction in plasma volume

81
Causes of secondary polycythemia
  • ERYTHROPOIETIN (EPO)-MEDIATED
  • Hypoxia-Driven
  • Chronic lung disease
  • Right-to-left cardiopulmonary vascular shunts
  • High-altitude habitat
  • Chronic carbon monoxide exposure (e.g., smoking)
  • Hypoventilation syndromes including sleep apnea
  • Renal artery stenosis or an equivalent renal
    pathology
  • Hypoxia-Independent (Pathologic EPO Production)
  • Malignant tumors
  • Hepatocellular carcinoma
  • Renal cell cancer
  • Cerebellar hemangioblastoma
  • Nonmalignant conditions
  • Uterine leiomyomas
  • Renal cysts
  • Postrenal transplantation
  • Adrenal tumors
  • EPO RECEPTORMEDIATED

82
POLYCYTHEMIA VERA
  • Chronic, clonal myeloproliferative disorder
    characterized by an absolute increase in number
    of RBCs
  • 2-3 / 100000
  • Median age at presentation 55-60
  • M/F 0.81.2

83
POLYCYTHEMIA VERA
  • JAK2 Mutation
  • JAK/STAT cellular proliferation and cell
    survival
  • deficiency in mice at embryonic stage is lethal
    due to the absence of definitive erythropoiesis
  • Abnormal signaling in PV through JAK2 was first
    proposed in 2004
  • a single nucleotide JAK2 somatic mutation
    (JAK2V617F mutation) in the majority of PV
    patients

84
Clinical features
  • Plethora
  • Persistent leukocytosis
  • Persistent thrombocytosis
  • Microcytosis secondary to iron deficiency
  • Splenomegaly
  • Generalized pruritus (after bathing)
  • Unusual thrombosis (e.g., Budd-Chiari syndrome)
  • Erythromelalgia (acral dysesthesia and erythema)

85
Clinical features
  • Hypertention
  • Gout
  • Leukaemic transformation
  • Myelofibrosis

86
Diagnostic Criteria
  • A1 Raised red cell mass
  • A2 Normal O2 sats and EPO
  • A3 Palpable spleen
  • A4 No BCR-ABL fusion
  • B1 Thrombocytosis gt400 x 109/L
  • B2 Neutrophilia gt10 x 109/L
  • B3 Radiological splenomegaly
  • B4 Endogenous erythroid colonies
  • A1A2either another A or two B establishes PV

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Treatment
  • The mainstay of therapy in PV remains phlebotomy
    to keep the hematocrit below 45 percent in men
    and 42 percent in women
  • Additional hydroxyurea in high-risk pts for
    thrombosis (age over 70, prior thrombosis,
    platelet count gt1,500,000/microL, presence of
    cardiovascular risk factors)
  • Aspirin (75-100 mg/d) if no CI
  • IFNa (3mu three times per week) in patients with
    refractory pruritus, pregnancy
  • Anagrelide (0.5 mg qds/d) is used mainly to
    manage thrombocytosis in patients refractory to
    other treatments.
  • Allopurinol

89
Essential Thrombocythaemia (ET)
  • Clonal MPD
  • Persistent elevation of Pltgt600 x109/l
  • Poorly understood
  • Lack of positive diagnostic criteria
  • 2.5 cases/100000
  • MF 21
  • Median age at diagnosis 60, however 20 cases
    lt40yrs

90
Clinical Features
  • Vasomotor
  • Headache
  • Lightheadedness
  • Syncope
  • Erythromelalgia (burning pain of the hands or
    feet associated with erythema and warmth)
  • Transient visual disturbances (eg, amaurosis
    fujax, scintillating scotomata, ocular migraine)
  • Thrombosis and Haemorrhage
  • Transformation

91
Investigations
  • ET is a diagnosis of exclusion
  • Rule out other causes of elevated platelet count

92
Diagnostic criteria for ET
  • Platelet count gt600 x 109/L for at least 2 months
  • Megakaryocytic hyperplasia on bone marrow
    aspiration and biopsy
  • No cause for reactive thrombocytosis
  • Absence of the Philadelphia chromosome
  • Normal red blood cell (RBC) mass or a HCT lt0.48
  • Presence of stainable iron in a bone marrow
    aspiration
  • No evidence of myelofibrosis
  • No evidence of MDS

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Therapy of ET based on the risk of thrombosis
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