Heri Fadjari 2007

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

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

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

CML

AML

CMML MDS RA RARS RAEB I RAEB II

Bone marrow stem cell Clonal abnormality

Granulocyte precursors

Red cell precursors

Megakaryocytes

Reactive fibrosis

Chronic myeloid leukemia

Polycythaemia rubra vera

Essential thrombocytosis

Myelofibrosis 10%

70%

10%

AML
30%

Polycythemia
True / Absolute
Primary Polycythemia Secondary Polycythemia

Epo dependent Hypoxia dependent Hypoxia independent Epo independent Apparent / Relative Reduction in plasma volume

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

Polycythemia rubra verae

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

JAK2 Mutation JAK/STAT: cellular proliferation and cell survival 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 Deficiency in mice at embryonic stage is lethal due to the absence of definitive erythropoiesis

Clinical findings
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

Clinical features
Hypertention
Stroke Gout

Leukaemic transformation
Myelofibrosis

Diagnostic Criteria
A1 A2 A3 A4 B1 B2 B3 B4 Raised red cell mass Normal O2 sats and EPO Palpable spleen No BCR-ABL fusion Thrombocytosis >400 x 109/L Neutrophilia >10 x 109/L Radiological splenomegaly 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

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 (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%)

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

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

Low risk Cytoreductive therapy Aspirin therapy No Optional High risk Yes Yes Intermediate risk + CVS risk factors: No + Extreme Th-cytosis: Yes + CVS risk factors: Yes + Extreme Th-cytosis: No

Low risk: Age<60 years and no history of thrombosis, platelet count>1.500.000/mm3, or cardiovascular risk factors (smoking, dislipidemia) High risk: Age>60 years or a history of thrombosis

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

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

Clinical Manifestations
Complaints

- 60% Weakness, Fatigue (anemia) - 32% Weight Loss - 24% Physical Findings Pallor - Most common Hepatomegaly, Splenomegaly, - Uncommon Lymphadenopathy -

Bone pain (back or chest)

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

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

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

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 sx

of hyperviscosity are present UA and UPEP Metastatic bone Survey Bone Marrow Biopsy

Rouleaux formation

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

International Staging System

Stage I
Stage II Stage III

2M <3.5 mg/L and serum albumin 3.5 g/dL neither stage I nor Stage III 2M 5.5 mg/L

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

Bone Marrow Biopsy

Prognostic Factors
Performance status 3 0r 4
Serum albumin < 3 g/dL Serum Cr 2.0 mg/dL Platelet Count <150,000 Age 70 years Beta-2-microglobulin >4 mg/L Serum Calcium 11 mg/dL

Hemoglobin <10 g/dL

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 CR

and 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 that has not responded to chemo

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

MGUS
Monoclonal protein is Present Serum M Protein <3 gm/dL

Bone Marrow Plasma Cells <10%

Absence of Anemia, Renal failure,

Hypercalcemia, Lytic Bone Lesions 16% of pts will progress to MM Managed with Observation Only

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