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