Myeloproliferative Diseases 2007

7/27/2019 Myeloproliferative Diseases 2007

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Heri Fadjari 2007


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Stem cell disorders characterized by an abnormal

proliferation in one or more cell line derived from a

common stem cell

The individual feature of these diseases result from a:

disturbed haemopoietic microenvironment

clonal abnormality

disturbance in haemopoietic regulation.

relatively normal maturation


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Classification

CML (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


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WHO Classification of CMPD

Ch Myeloid leukemia

Ch Neutrophillic leukemia

Ch Eosinophillic leukemia / Hyper Eo Synd Polycythemia Vera

Essential Thrombocythemia

Myelofibrosis

CMPD unclassifiable


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Myeloproliferative disorders

MPD

PRV

ET

MF AML

MDS RA

RARS

RAEB I

RAEB II

CMML

CML


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Bone marrow stem cell

Clonal abnormality

Granulocyte

precursors

Red cell

precursors

Megakaryocytes Reactive

fibrosis

Essential

thrombocytosis

Polycythaemia

rubra vera

Myelofibrosis

AML

Chronic myeloid

leukemia

70% 10%

10%

30%


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Polycythemia

True / Absolute

Primary Polycythemia

Secondary Polycythemia

Epo dependent Hypoxia dependent

Hypoxia independent

Epo independent

Apparent / Relative

Reduction in plasma volume


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Causes of secondary polycythemia

ERYTHROPOIETIN (EPO)-MEDIATED Hypoxia-Driven

COPD

Right-to-left cardiopulmonary vascular shunts

High-altitude habitat

Chronic carbon monoxide exposure (e.g., smoking)

Hypoventilation syndromes including sleep apnea Hypoxia-Independent (Pathologic EPO Production)

Malignant tumors : HCC, RCC, Cerebellar hemangioblastoma

Nonmalignant conditions

Uterine leiomyomas, Renal cysts, Postrenal transplantation

Adrenal tumors

EPO RECEPTORMEDIATED Activating mutation of the erythropoietin receptor

DRUG-ASSOCIATED EPO Doping

Treatment with Androgen Preparations


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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 rubra verae


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JAK2 Mutation

JAK/STAT: cellular proliferation and cell survival

Abnormal signaling in PV through JAK2 was first

proposed in 2004A single nucleotide JAK2 somatic mutation (JAK2V617F

mutation) in the majority of PV patients

Deficiency in mice at embryonic stage is lethal due tothe absence of definitive erythropoiesis

Polycythemia rubra verae


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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 findings


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Clinical findings


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Hypertention

Stroke

Gout

Leukaemic transformation

Myelofibrosis

Clinical features


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Diagnostic Criteria

A1 Raised red cell mass

A2 Normal O2 sats and EPO

A3 Palpable spleen

A4 No BCR-ABL fusionB1 Thrombocytosis >400 x 109/L

B2 Neutrophilia >10 x 109/L

B3 Radiological splenomegaly

B4 Endogenous erythroid colonies

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


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Treatment

The mainstay of therapy in PV remains phlebotomy to keep thehematocrit below 45 percent in men and 42 percent in women

Additional hydroxyurea in high-risk pts for thrombosis (age over70, prior thrombosis, platelet count >1,500,000/microL, presenceof cardiovascular risk factors)

Aspirin (75-100 mg/d) if no CI

IFNa (3mu three times per week) in patients with refractorypruritus, pregnancy

Anagrelide (0.5 mg qds/d) is used mainly to managethrombocytosis in patients refractory to other treatments.

Allopurinol


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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


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Clinical Features

Vasomotor (40%)

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 (25%) and Haemorrhage (20%)

Transformation (10%)


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Investigations

ET is a diagnosis of exclusion

Rule out other causes of elevated platelet count

- Infection

- Rebound thrombocytosis

- Tissue damage (surgery)

- Chronic inflammation

- Malignancy

- Renal diseases

- Hemolytic anemia

- Post splenectomy

- Chronic blood loss


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Diagnostic criteria for ET

Platelet count >600 x 109/L for at least 2 months

Megakaryocytic hyperplasia on bone marrow aspirationand biopsy

No cause for reactive thrombocytosis

Absence of the Philadelphia chromosome Normal red blood cell (RBC) mass or a HCT


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Therapy of ET based on the risk of thrombosis

Low risk High risk Intermediate risk

Cytoreductive

therapy

No Yes + CVS risk factors: No

+ Extreme Th-cytosis: Yes

Aspirin therapy Optional Yes + CVS risk factors: Yes

+ Extreme Th-cytosis: No

Low risk: Age1.500.000/mm3, or cardiovascular risk factors

(smoking, dislipidemia)

High risk: Age>60 years or a history of thrombosis


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Introduction

Neoplastic proliferation of a single clone of plasma

cells producing a monoclonal immunoglobulin

The clone proliferates in the bone marrow

Skeletal destruction with osteolytic lesions,

osteopenia, and fractures


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Epidemiology

1% of all malignant Disease

>10% of all hematologic malignancies

Annual incidence of 4/100,000

Slightly more frequent in men than women

Median age at Diagnosis is 66 yrs.

5, 10, and 20 year survivals: 31, 10, and 4%

respectively


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Clinical Manifestations

Complaints

Bone pain (back or chest) - 60%

Weakness, Fatigue (anemia) - 32%

Weight Loss - 24%

Physical Findings

Pallor - Most common

Hepatomegaly, -

Splenomegaly, - Uncommon

Lymphadenopathy -


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Complications

Radiculopathy

Spinal Cord Compression

2 to Vertebral Fx or Plasmacytoma

Infection

Suppression of normal plasma cell function

Strep Pneumoniae and Gram Negative

Amyloidosis More common in Light Chain MM


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Bone Disease

Lytic Lesions 60%

Osteoporosis, Fracture, Compression Fx 20%

Myeloma Cells Produce Cytokines that:

Stimulate Osteoclastic Activity

Inhibit Osteoblastic Activity

Can be Detected by Plain Xray


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Renal Disease (myeloma kidney)

Serum Cr Elevated in 50% and >2 in 20% at

diagnosis

Cast Nephropathy

Large, Waxy casts in distal tubules composed

of precipitated light chains

Not detected on Dipstick

Hypercalcemia

Amyloidosis


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Initial Work-up CBC w/diff peripheral smear

Normocytic, Normochromic Anemia most common

Rouleaux Formation >50% of patients

Chemistry (ca, alb, cr, LD, CRP, B2M)

SPEP Monoclonal Protein

Serum Viscosity (if M-protein conc. Is high, >5g/dL) or sxof hyperviscosity are present

UA and UPEP

Metastatic bone Survey

Bone Marrow Biopsy


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Rouleaux formation


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Diagnostic Criteria

Presence of an M-Protein in serum and/or urine

Presence of clonal bone marrow plasma cells or

plasmacytoma

Presence of Related Organ/Tissue involvement

Hypercalcemia, renal insufficiency, anemia,

lytic bone lesions


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International Staging System

Stage I 2M


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Bone Marrow Aspirate

Usually >10% plasma Cells, but can be from 5-100%

50% involvement worse prognosis

Immunoperoxidase staining detects either kappa or

lambda light chains, NOT both (confirming

proliferation is monoclonal)

Immunophenotyping Malignant Plasma Cells stain

positive for CD38, CD56, and CD138


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Bone Marrow Biopsy


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Treatment

Melphalan and Prednisone (Oral) Preferred Tx in pts NOT going for BMT

7 day course repeated q 6weeks (x 3)

Objective response in 50-60%, MS of 2-3 yrs

Melphalan, prednisone, and Thalidomide

RR of 93% with 26% CR

When compared to above regimen, had better CRand RR; however, more toxicity

Thalidomide with or w/o Dexamethasone

Preferred in Candidates for BMT

For pts with Relapsed or Resistent Disease

VAD (Vincristine, Dexamethasone, and Adriamycin)

Radiation Reserved for pts with focal process thathas not responded to chemo


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Treatment Outcomes

Cure Not yet been Achieved

Molecular Complete Response

No evidence of Disease

Complete Response

No detectable M protein AND nml % of Plasma cells in

Bone Marrow

Progressive Disease >25% increase in M Protein, new bony lesions, or a

new plasmacytoma


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MGUS

Monoclonal protein is Present

Serum M Protein


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Asymptomatic Multiple Myeloma

Smoldering Multiple Myeloma

M protein > 3gm/dl, BM Plasma Cells 10%

Absence of Complications (anemia, renal failure, etc)

Observation until Disease Progression

Indolent Multiple Myeloma

Stable serum/urine M protein

Bone marrow plasmacytosis Mild anemia, or few lytic lesions

Observation until Disease Progression

Myeloproliferative Diseases 2007

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