myeloproliferative diseases by dr. kamal e. higgy consultant haematologist
TRANSCRIPT
MYELOPROLIFERATIVE DISEASES
By
DR. KAMAL E. HIGGY
CONSULTANT HAEMATOLOGIST
Myeloid Disorders Usual Features at Diagnosis
DiseaseBM
cellularity
% Marrow Blasts
Maturation Morphology Haemato-poiesis
Blood count (s)
Organo-megaly
Myeloproliferatie disorder
Usually increased
Normal or slightly increased (<10%)
Present Relatively normal
Effective One or more myeloid cell lines increased
Common
Myelodysplastic syndromes
Usually increased, occasionally decreased
Normal or increased (<20%)
Present Dysplasia of one or more myeloid lineage
Ineffective Cytopenia (S) Uncommon
Myelodysplastic/ myeloproliferative disease
Usually increased
Normal or increased (<20%)
Present Dysplasia of one or more myeloid lineages frequent
Effective or ineffective; may vary among involved lineages
Variable Common
Acute myeloid leukaemia
Usually increased, occasionally decreased
Increased (≥ 20%)
Varies, frequently minimal
May or may not be associated with dysplasia in one or more myeloid lines
Ineffective or effective
Variable uncommon
WHO Classification Chronic Myeloproliferative Disease
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• Chronic Myelogenous Leukaemia [Ph chromosome, t(9;22)(q34;q11) , BCR/ABL- positive ]
• Chronic Neutrophilic Leukaemia• Chronic Eosinophilic Leukaemia
(and the hypereosinophilic syndrome)• Polycythaemia Vera• Chronic Idiopathic Myelofibrosis
(with extramedullary haematopoiesis)• Essential Thrombocythaemia• Chronic Myeloproliferative Disease, Unclassifiable
WHO Classification Myelodysplastic / Myeloproliferative Diseases
----------------------------------------------------------------- • Chronic Myelomonocytic Leukaemia
• Atypical Chronic Myeloid Leukaemia
• Juvenile Myelomonocytic Leukaemia
• Myelodysplastic/Myeloproliferative Disease, Unclassifiable
Myeloproliferative Disease
Recurring Genetic Abnormalities and Their Frequency (%)
at diagnosisDisease Specific abnormalities (%) Recurring, nonspecific
cytogenetic/genetic abnormalities(%)
CML, CP t(9;22)(q34;q11), BCR/ABL 100
CML, AP/BP
t(9;22)(q34;q11), BCR/ABL 100 +8, +9Ph,+19,i(17q), t(3;21)(q26;q22)(EVI1/AML1) 80
CNL None +8, +9, del(20q), del(11q14) ~10
CEL None +8, t(5;12)(q33;p13)(TEL/PDGFβR), dic(1;7), 8p11 (FGFR1)
?
PV JAK2 74 – 97 +8, +9, del(20q), del(13q), del(1p11) ~15
CIMF JAK2 33 – 57 +8, del(20q), -7/del(7q), del(11q), del(13q) ~35
ET JAK2 35 – 50 +8, del (13q) ~5
CML, CP = Chronic myelogenous leukaemia, chronic phase; CML, AP/BP= Chronic myelogenous leukaemia, accelerated or blast phase;
CNL = Chronic neutrophilic leukaemia; CEL = Chronic eosinophilic leukaemia; PV = Polycythaemia Vera;
EVI-1 = ecotropic viral integration site 1 JAK2 = Janus Kinase – 2 Gene
CIMF = Chronic idiopathic myelofibrosis; ET = Essential thrombocythaemia ? = Insufficient data available
Polycythaemia Vera
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- Hb : Males >17.5 gm/dl Females > 15.5 gm/dl
- RBC : Males > 6.0 X 1012/L
Females > 5.5X1012/L - PCV : Males > 51%
Females > 48%- TRCV : Males > 36 ml/kg (25-35)
Females > 32 ml/kg (22-32)- TPV : 40 – 50 ml/kg
Classification of Erythrocytosis
Raised PCV (female >0.48; male>0.51)
RCM
(Interpreted using ICSH reference values)
Increased RCM Normal RCMAbsolute erythrocytosis Apparent erythrocytosis
Abbreviations: PCV = Packed Cell Volume; RCM = red cell mass;
ICSH = International Council for Standardization in Haematology;
Primary ErythrocytosisCongenital #
Truncation of the EPO receptor*
Acquired
Polycythaemia Vera*
Secondary ErythrocytosisCongenital #
e.g., high oxygen affinity Hb,
autonomous high EPO production
Acquired
e.g., hypoxemia, renal disease
# Sometimes familial
* The only condition to be defined in this category at present
EPO = erythropoietin
Polycythaemia VeraCauses
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• Primary : Polycythaemia Vera• Secondary:
1. Erythropoietin Compensatory Increase:
High Altitude
C.V. disease
Pulmonary disease
High Affinity Hb
Heavy smoking
Methaemoglobinaemia
2. Abnormal Erythropoietin Production:
Renal diseases.
Massive uterine fibromatosis
Hepatocellular Carcinoma
Cerebellar Haemangioblastoma• Relative: Stress, Dehydration, Plasma Loss.
Polycythaemia VeraClinical Features
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• Headache, Lethargy, Dyspnea• Weight Loss, Night Sweats• Generalized pruritis (Increase after hot bath)• Plethoric Appearance• Haemorrhage & Thrombosis• Hypertension (In about 1/3rd of the patients)• Gout (Increased Uric Acid)• Peptic Ulcers (In 5 – 10% of the patients)• Splenomegaly (In 2/3rd of patients)• Accidental Discovery (On Routine exam)
Polycythaemia VeraLaboratory Investigations
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- C.B.C- Neutrophil Alkaline Phosphatase (N.A.P.) - Serum B12 & B12 binding capacity
- Bone Marrow - Blood Viscosity- Uric Acid Level - Hb Electrophoresis- Arterial Oxygen Tension - T.R.C.V.- I.V. Pyelography, CT & US - JAK2: 74 – 97 % (PV)
- Erythropoietin Assay 33 – 57 % (ET)
35 – 50 % (MF)
Polycythaemia Vera Classic Polycythaemia Vera Study Group
Diagnostic Criteria --------------------------------------------------------------------------------------------------------------------------------------------------------------------------
A1 ↑ Red Cell Mass B1 Thrombocytosis
Male ≥36 ml/kg Platelet count >400,000/µl
Female ≥32ml/kg B2 Leukocytosis >12,000/µl
(No fever or infection)
A2 Normal Arterial B3 ↑ Leukocyte Alkaline
O2 Saturation ≥92% Phosphatase score >100
(No fever or infection)
A3 Splenomegaly ↑ Serum B12 (>900pg/ml)
or
↑ Unbound B12 binding
capacity (>2200pg/ml)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
• Diagnosis is acceptable if the following combinations are present: A1 + A2 + A3 or A1 + A2 + any two from Category B.
Polycythaemia Vera Proposed diagnostic criteria
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A1 Raised red cell mass B1 Thrombocytosis
(>25% above mean normal Platelet count>400X109/1
predicted value)
A2 Absence of a cause of B2 Neutrophil leukocytosis
Secondary Polycythaemia neutrophil count >10X109/1
A3 Palpable splenomegaly B3 Splenomegaly demonstrated
by isotope/ultrasound scanning
A4 Clonality marker B4 Characteristic BFU-E growth
e.g. - abnormal marrow karyotype or reduced serum erythropoietin
- JAK2------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
A1 + A2 + A3 or A4 establishes PV
A1 + A2 + Two of B establishes PV
Polycythaemia Vera
Treatment -------------------------------------------------------------
-
• Venesecton• Radioactive Phosphorus (P32)• Chemotherapy:
e.g. Hydroxyurea
Chronic Idiopathic Myelofibrosis Prefibrotic Stage
Clinical findings Morphological findings
Spleen and liver:No or mild splenomegaly or hepatomegaly
Blood:• No or mild leukoerythroblastosis• No or minimal red blood cell poikilocytosis; few if any dacrocytes
Splenomegaly:Haematologic parameters variable, but often:• Mild anaemia• Mild to moderate leukocytosis• Mild to marked thrombocytosis
Bone marrow: Hypercellularity Neutrophilic proliferation Megakaryocytic proliferation and atypia (Clustering of megakaryocytes, abnormally lobulated megakaryocytic nuclei, naked megakaryocytic nuclei) Minimal or absent reticulin fibrosis
Chronic Idiopathic Myelofibrosis Fibrotic Stage
Clinical findings Morphological findingsSpleen and liver:Moderate to marked splenomegaly and hepatomegaly
Blood: Leukoerythroblastosis Prominent red blood cell poikilocytosis with dacrocytes
Haematology:• Moderate to marked anaemia• Low, normal or elevated WBC• Platelet count decreased, normal or elevated
Bone Marrow: Reticulin and/or collagen fibrosis Decreased cellularity Dilated marrow sinuses with intraluminal haematopoiesis Prominent megakaryocytic proliferation and atypia (clustering of megakaryocytes, abnormally lobulated megakaryocytic nuclei, naked nuclei) New bone formation (osteosclerosis)
Essential ThrombocythaemiaDiagnostic Criteria
Positive Criteria1. Sustained platelet count ≥600X109/L
2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes
Criteria of exclusion3. No evidence of polycythaemia vera (PV)
- Normal red cell mass or Hb <18.5g/dl in men, 16.5g/dl in women
- Stainable iron in marrow, normal serum ferritin or normal MCV
- If the former condition is not met, failure of iron trial to increase red cell
mass or Hgb levels to the PV range
2. No evidence of CML
- No Philadelphia chromosome and no BCR/ABL fusion gene
Essential Thrombocythaemia Diagnostic criteria (Continued)
3. No evidence of chronic idiopathic myelofibrosis- Collagen fibrosis absent
- Reticulin fibrosis minimal or absent
4. No evidence of myelodysplastic syndrome- No del(5q), t(3;3)q21;q26), inv(3)(q21q26)
- No significant granulocytic dysplasia, few if any
micromegakaryocytes
5. No evidence that thrombocytosis is reactive due to:- Underlying inflammation or infection
- Underlying neoplasm
- Prior splenectomy
Giant Plat
Megakaryocytes in Clusters
Chronic Myelogenous Leukaemia Presenting Manifestations
Common Anaemia
Splenomegaly
Less CommonSymptoms due to the raised metabolic rate
Haemorrhagic Manifestations, especially bruising
Chronic Myelogenous Leukaemia Presenting Manifestations (Cont…)
Occasional
• Acute abdominal pain• Bone or joint pains• Menstrual disturbances• Neurological symptoms• Priapism• Gout• Skin disorder• Disturbances of vision or hearing• Accidental discovery on routine blood examination
Chronic Myelogenous LeukaemiaEvolution of the disease
Chronic Phase
Accelerated Phase
Blastic Transformation
(AML) (ALL)
Chronic Myelogenous LeukaemiaLaboratory Investigations
• CBC
Chronic Myelogenous LeukaemiaLaboratory Investigations (Cont…)
• Neutrophil Alkaline Phosphatase• Bone Marrow Examination.• Serum B12 & B12 binding capacity
• Cytogenetic Studies
(Ph1) chromosome [ t ( 9 : 22 ) ]• DNA restriction enzyme analysis
BCR-ABL (Breakpoint Cluster Region)
Chronic Myelogenous Leukaemia
Accelerated Phase
• Blasts 10% to 19% of peripheral blood white cells or bone marrow cells
• Peripheral blood basophils at least 20%• Persistent thrombocytopenia (<100X109/L)
unrelated to therapy or persistent thrombocytosis (> 1000X109L) unresponsive to therapy
• Increasing spleen size and increase WBC count unresponsive to therapy
Chronic Myelogenous Leukaemia
Accelerated Phase (Cont…)
• Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML)
• Megakaryocytic proliferation in sizable sheets and clusters, associated with marked reticulin or collagen fibrosis, and/or severe granulocytic dysplasia, should be considered as suggestive of CML-AP
These findings have not yet been analyzed in large clinical studies, however, so it is not clear if they are independent criteria for accelerated phase. They often occur simultaneously with one or more of the other features listed
Chronic Myelogenous Leukaemia
Blastic Phase (BP)
Diagnosis is established if one or more of following is present:
• Blasts 20% or more of peripheral blood white cells or bone marrow cells
• Extramedullary blast proliferation
• Large foci or clusters of blasts in bone marrow biopsy
Chronic Myelogenous Leukaemia
Chronic Phase (BP) Treatment
Hydroxyurea (HU):
WBC/ul HU (mg/kg BW/DAY)
>50,000 50
15-50,000 30 – 40
<15,000 25 Busulphan Alpha – Interferon:
5 MU/DAY
7.5 MU/DAY if WBC > 10,000/mcl
10 MU/DAY if WBC > 20,000/mcl
3 MU/DAY if cytopenia develops BMT, ABMT & STEM CELL HARVEST Gleevec