Myeloproliferative disorders

Introduction Hemopoietic stem cell disorder

Clonal Characterized by proliferation

Granulocytic Erythroid Megakaryocytic

Interrelationship between Polycythaemia Essential thrombocythaemia myelofibrosis

Introduction / haemopoiesis

Introduction Normal maturation (effective)

Increased number of Red cells Granulocytes Platelets

(Note: myeloproliferation in myelodysplastic syndrome is ineffective) Frequent overlap of the clinical, laboratory &

morphologic findings Leucocytosis, thrombocytosis, increased

megakaeryocytes, fibrosis & organomegaly blurs the boundaries

Hepatosplenomegaly Sequestration of excess blood Extramedullary haematopoiesis Leukaemic infiltration

Rationale for classification

Classification is based on the lineage of the predominant proliferation

Level of marrow fibrosis

Clinical and laboratory data (FBP, BM, cytogenetic & molecular genetic)

Differential diagnosisFeatures distinguishing MPD from MDS, MDS/MPD & AML

Disease cellularity BM

% marrow blasts

Maturation Morphology Haemato-poiesis

Blood counts

Large organs

MPD Increased

Normal or

< 10%

Present Normal Effective

One or more

myeloid increase

d

Common

MDS Usually increase

d

Normal or < 20%

Present Abnormal

In-effective

Low one or more cytopeni

a

Un-common

MDS/MPD

Usually increase

d

Normal or <20%

Present Abnormal

Effective or in-

effective

Variable Common

AML Usually increase

d

Increased >20%

Minimal Dysplasia can be present

In-effective

Variable Un-common

Clonal evolutionClonal evolution & stepwise progression to fibrosis, marrow failure or

acute blast phase

Incidence and epidemiology

Disease of adult

Peak incidence in 7th decade

6-9/100,000

Pathogenesis

Dysregulated proliferation No specific genetic abnormality

CML (Ph chromosome t(9;22) BCR/ABL) Growth-factor independent proliferation

PV, hypersensitiviy to IGF-1

Bone marrow fibrosis in all MPD Fibrosis is secondary phenomena

Fibroblasts are not from malignant clone TGF-β & Platelet like growth factor

Prognosis

Depends on the proper diagnosis and early treatment Role of

IFN BMT Tyrosine kinase inhibitors

Myeloproliferative disorders

Clonal haematopoeitic disorders Proliferation of one of myeloid lineages

Granulocytic Erythroid Megakaryocytic

Relatively normal maturation

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

Myeloproliferative disorders

MPD•PRV•ET•MF

AML

MDS•RA•RARS•RAEB I•RAEB II

CMML

CML

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

Bone marrow stem cellClonal

abnormality

Granulocyte precursors

Red cell precursors

Megakaryocytes Reactive fibrosis

Essentialthrombocytosis

(ET)

Polycythaemia rubra vera

(PRV)

Myelofibrosis

AML

Chronic myeloid leukemia

70%10% 10%

30%

Epidemiology of CML

Median age range at presentation: 45 to 55 years

Incidence increases with age 12% - 30% of patients are >60 years old

At presentation 50% diagnosed by routine laboratory tests 85% diagnosed during chronic phase

Ionizing radiation Latent Period

Atomic bomb survivors 11 years ( 2-25)

Ankylosing spondylitis pts 3.6 years (1-6)

No evidence of other genetic factorsChemical have not been associated with CML

Incidence 1-1.5/100,000 populationMale predominance

Epidemiology of CML

Presentation

Insidious onset

Anorexia and weight loss

Symptoms of anaemia

Splenomegaly –may be massive

Pt . maybe asymptomatic

The Philadelphia Chromosome

2 3 4 51

7 8 9 10 11 126

13 14 15 16 17 18

20 21 22 X Y19

The Philadelphia Chromosome: t(9;22) Translocation

bcr-abl

Fusion proteinwith tyrosine

kinase activity

22

bcr

abl

Ph

9 9+

Philadelphia chromosome

Clinical Course: Phases of CML

Chronic phase

Median 4–6 yearsstabilization

Accelerated phase

Median durationup to 1 year

Blastic phase (blast crisis)

Median survival3–6 months

Terminal phase

Advanced phases

Treatment of Chronic Myeloid leukemia

Arsenic Lissauer, 1865Radiotherapy Pusey, 1902Busulfan Galton, 1953Hydroxyurea Fishbein et al, 1964Autografting Buckner et al, 1974Allogeneic BMT (SD) Doney et al, 1978Interferon Talpaz et al, 1983Allogeneic BMT (UD) Beatty et al, 1989Donor Leukocytes Kolb et al, 1990Imatinib Druker et al, 1998Imatinib/Combination therapy O’Brien et al, 200……

CML Treatment

•Chemotherapy to reduce WCC - Hydroxyurea

•Interferon based treatment

•Allogeneic bone marrow transplant

•Molecular therapy - Imatinib

CML- CP survival post BMT (IBMTR 1994-1999)

Years

Prob

abili

ty %

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

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

Mechanism of Action of Imatinib

Goldman JM. Lancet. 2000;355:1031-1032.

Bcr-Abl

ATP

Substrate

Imatinib

Y = TyrosineP = Phosphate

Bcr-Abl

Substrate

PPP

P

Imatinib compared with interferon and low doseCytarabine for newly diagnosed chronic-phase

Chronic Myeloid leukemia

S.G. O’Brien et al

New England Journal of MedicineVol. 348 March 2003

Imatinib vs Interferon in newly diagnosed CP Chronic Myeloid leukemia (18 months)

CHR 96% 67%

MCR 83% 20%

CCR 68% 7%

Intolerance 0.7% 23%

Progressive 1.5% 7%disease

Imatinib 400mg Interferon and Ara-C

Evolution of treatment goals

HR MCR CCR PCR -

HU

IFN

Imatinib

BMT

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

CML

Diagnosis

Young with a well-matched donor

Start Imatinib at400mg/day

Cosider for Allograft

Allo SCT

Poor response or Initial response

Followed byLoss of response

Add or substituteOther agents

Allo-SCTAuto

Good response maintained

Continue Imatinib indefinitely

Polycythemia

True / Absolute Primary Polycythemia Secondary Polycythemia

Epo dependent Hypoxia dependent Hypoxia independent

Epo independent Apparent / Relative

Reduction in plasma volume

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: 0.8:1.2

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

Polycythaemia vera(Polycythaemia rubra vera)

Definition of polycythemia Raised packed cell volume (PCV / HCT) Male > 0.51 (50%) Female > 0.48 (48%)

Classification Absolute

Primary proliferative polycythaemia (polycythaemia vera)

Secondary polycythaemia Idiopathic erythrocytosis

Apparent Plasma volume or red cell mass changes

Polycythaemia vera(Polycythaemia rubra vera)

Polycythaemia vera is a clonal stem cell disorder characterised by increased red cell production

Abnormal clones behave autonomous Same abnormal stem cell give rise to granulocytes and

platelets

Disease phase Proliferative phase “Spent” post-polycythaemic phase Rarely transformed into acute leukemia

Polycythaemia vera(Polycythaemia rubra vera)

Clinical features Age

55-60 years May occur in young adults and rare in childhood

Majority patients present due to vascular complications

Thrombosis (including portal and splenic vein) DVT Hypertension Headache, poor vision and dizziness Skin complications (pruritus, erythromelalgia) Haemorrhage (GIT) due to platelet defect

Polycythaemia vera(Polycythaemia rubra vera)

Hepatosplenomegaly

Erythromelalgia

Increased skin temp Burning sensation Redness

Liver40%

Spleen70%

Erythromelalgia

Polycythaemia vera(Polycythaemia rubra vera)

Laboratory features and morphology

Hb, PCV (HCT), and Red cell mass increased

Increased neutrophils and platelets

Normal NAP Plasma urate high Circulation erythroid

precursors Hypercellular bone

marrow Low serum erythropoietin

Bone marrow in PV

Polycythaemia vera(Polycythaemia rubra vera)

Treatment To decrease PVC (HCT)

Venesection Chemotherapy

Treatment of complications

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)

Clinical features

Hypertention Gout Leukaemic transformation Myelofibrosis

Diagnostic Criteria

A1 Raised red cell massA2 Normal O2 sats and EPOA3 Palpable spleenA4 No BCR-ABL fusionB1 Thrombocytosis >400 x 109/LB2 Neutrophilia >10 x 109/LB3 Radiological splenomegalyB4 Endogenous erythroid colonies

A1+A2+either another A or two B establishes PV

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 >1,500,000/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

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

Causes of secondary polycythemia

EPO RECEPTOR–MEDIATED Activating mutation of the erythropoietin

receptor DRUG-ASSOCIATED

EPO Doping Treatment with Androgen Preparations

Secondary polycythaemia

Polycythaemia due to known causes

Compensatory increased in EPO High altitude Hulmonary diseases Heart dzs eg- cyanotic heart disease Abnormal hemoglobin- High affinity Hb Heavy cigarette smoker

Inappropriate EPO production Renal disease-carcinoma, hydronephrosis Tumors-fibromyoma and liver carcinoma

Secondary polycythaemia

Arterial blood gas Hb electrophoresis Oxygen dissociation curve EPO level Ultrasound abdomen Chest X ray Total red cell volume(51Cr) Total plasma volume(125 I-

albumin)

Relative polycythaemia

Apparent polycythaemia or pseudopolycythaemia due to plasma volume contraction

Causes Stress Cigarette smoker or alcohol intake Dehydration Plasma loss- burn injury

Differentiation of PV, Secondary PV and Relative Erythrocytosis

Features PV 2ndaryPV

Rel.Erythro

organo-megaly

present absent absent

O2 Sat Normal Dec. NormalRBC mass Inc Inc NormalEPO Dec Inc NormalWBC Inc Normal Normal

Essential Thrombocytosis

Clonal stem cell disorder characterized by marked thrombocytosis and abnormal platelet function

Plt count 600-2500 X 109/L Abnormal plt aggregation studies

Essential Thrombocythaemia (ET)

Clonal MPD Persistent elevation of Plt>600 x109/l Poorly understood Lack of positive diagnostic criteria 2.5 cases/100000 M:F 2:1 Median age at diagnosis: 60, however 20% cases <40yrs

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

Investigations

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

Diagnostic criteria for ET

Platelet count >600 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 <0.48 Presence of stainable iron in a bone marrow

aspiration No evidence of myelofibrosis No evidence of MDS

Therapy of ET based on the risk of thrombosis

Essential thrombocythaemiaPrimary thrombocytosis / idiopathic thrombocytosis

Clonal myeloproliferative disease of megakaryocytic lineage

Sustained thrombocytosis Increase megakaeryocytes Thrombotic or/and haemorrhage episodes

Positive criteria Platelet count >600 x 109/L Bone marrow biopsy; large and increased megas.

Essential thrombocythaemiaPrimary thrombocytosis / idiopathic thrombocytosis

Criteria of exclusion No evidence of Polycythaemia vera No evidence of CML No evidence of myelofibrosis (CIMF) No evidence of myelodysplastic syndrome No evidence of reactive thrombocytosis

Bleeding Trauma Post operation Chronic iron def Malignancy Chronic infection Connective tissue disorders Post splenectomy

Essential thrombocythaemiaPrimary thrombocytosis / idiopathic thrombocytosis

Clinical features

Haemorrhage Microvascular occlusion

TIA, gangrene Splenic or hepatic vein

thrombosis Hepatosplenomegaly

Essential thrombocythaemiaPrimary thrombocytosis / idiopathic thrombocytosis

Treatment Anticoagulant Chemotherapy Role of aspirin

Disease course and prognosis 25 % develops myelofibrosis Acute leukemia transformation Death due to cardiovascular complication

Agnogenic Myeloid Metaplasia

Stem cell mutation causes hematopoietic abnormalities

Extramedullary hematopoiesis BM fibrosis:uncontrolled production of

fibroblasts from degenerating platelets result in dense thread-like scar tissue: dry BM tap

Differences from CML LAP inc., Ph neg, nRBC, splenomegaly, tear

drop cell

Myelofibrosis

Myelofibrosis Myeloproliferative disorder (monoclonal stem cell

disorder) in which increased marrow fibrosis is dominant feature

Rare 50-70 yrs Clinical: fatigue, weakness, malaise, fever/night

sweats, abdominal pain, anorexia/wt loss, nasuea/vomiting

May be primary or secondary (breast cancer, prostate cancer, Hodgkin's disease, non-Hodgkin's lymphoma, autoimmune diseases)

Hematopoietic stem cells grow out of control, producing both immature blood cells and excess fibrous tissue—replacing normal marrow

Myelofibrosis Extramedullary hematopoeisis—hepatic and

splenic enlargement, thoracic paravertebral masses

Bones Uniform or heterogeneous increased density Spine (“sandwich sign” or diffuse density),

pelvis, skull, ribs, proximal femur/humerus Cortical thickening in long bones Decreased T1 and T2 marrow signal

Bone marrow bx needed to confirm dz Progressive bone marrow failure = severe

anemia / thrombocytopenia/leukopenia risk of bleeding/infection

Slowly progressive dz leading to death No available tx to effectively reverse progression;

possible cure with bone marrow or stem cell transplantation (significant risks)

MyelofibrosisChronic idiopathic myelofibrosis

Progressive fibrosis of the marrow & increase connective tissue element

Agnogenic myeloid metaplasia Extramedullary erythropoiesis

Spleen Liver

Abnormal megakaryocytes Platelet derived growth factor (PDGF) Platelet factor 4 (PF-4)

MyelofibrosisChronic idiopathic myelofibrosis

Insidious onset in older people

Splenomegaly- massive Hypermetabolic symptoms

Loss of weight, fever and night sweats MyelofibrosisChronic idiopathic myelofibrosisc

Bleeding problems Bone pain Gout Can transform to acute

leukaemia in 10-20% of cases

MyelofibrosisChronic idiopathic myelofibrosis

Anaemia High WBC at presentation Later leucopenia and

thrombocytopenia Leucoerythroblastic blood

film Tear drops red cells Bone marrow aspiration-

Failed due to fibrosis Trephine biopsy- fibrotic

hypercellular marrow Increase in NAP score