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CHRONIC MYELOPROLIFERATIVE

DISORDERS
Hawwa Najiza
Rithika Sriram
Saloni Sawarthia
Introduction

Neoplastic
Proliferation
of white cells

Histiocytic or
Myeloid Lymphoid
Dendritic cell
Neoplasms Neoplasms
neoplasm
MYELOID
NEOPLASM
• Myeloproliferative disorders - clonal haematopoietic stem cell disorders

characterised by proliferation of one or more myeloid lineages (erythroid,

granulocytic, megakaryocytic and mast cells)

• Chronic : Usually increased production of terminally differentiated myeloid

elements
WHO Classification of MPNs:
o Chronic myeloid leukemia, bcr-abl positive
o Chronic neutrophilic leukemia
o Chronic eosinophilic leukemia, not otherwise specified
o Polycythemia vera
o Primary myelofibrosis
o Essential thrombocytosis
o Mastocytosis
o Myeloproliferative neoplasms, unclassified
o Myelodysplastic syndromes
Chronic Myeloid Leukemia
• Commonest leukemia
• 30-80 years of age, Males

• Proliferation of all hematopoietic lineages but predominantly granulocytic

• Presence of Chimeric fusion BCR-ABL gene and Philadelphia chromosome


• Etiology : Unknown, Radiation?
Molecular Pathogenesis:Balanced Reciprocal Translocation

Constitutive
(+) of tyrosine
kinase
BCR-ABL
Oncoproteins Increased cell
(p210) proliferation
Inhibition of
apoptosis
Natural History
• Chronic / Stable / Indolent phase (3-5 years) : Blast cells <10%

• Accelerated phase : Blast cells -10-19%

• Blast phase/ crisis : Blast cells >20% (AML or ALL) Cause of death
Clinical Features
Symptoms :
• Fever, weight loss,anorexia, sweating and heat intolerance -Hypermetabolic state

• Fatigue, weakness - Anemia

• Post-prandial fullness, reflux oesophagitis, dragging discomfort in left


hypochondrium- Massive splenomegaly

• Bleeding tendencies - low platelet count

• Sternal pain/ bone pain, priapism - leukostasis

• Dyspnoea, drowsiness, loss of coordination - leukostasis


•Signs :
Investigations and Treatment
Chronic Phase :
• Hb: <11gm%

• Peripheral smear :
1. Normocytic Normochromic anemia,
2. WBCs: >20,000/µL.
3. Shift to left – predominant cells - neutrophils and myelocytes.
4. Basophils , eosinophils present.
5. Blasts <10%. NAP/LAP score decreased
6. Platelet : increased
• Bone Marrow
1. Hypercellular. M:E ratio- 20:1
2. Myelopoiesis. Blasts <10%
3. Dwarf megakaryocytes
4. Sea Blue histiocytes
5. Fibrosis , reticulum stain

• FISH

• Biochemical :
1. Uric acid increased
2. LDH, ALP Vit B12 increased
• Accelerated Phase :
PS and Bone Marrow :
1. Increasing anemia
2. Blasts : 10-19%
3. Striking basophila (20%)
4. Thrombocytopenia

• Blast Phase :
1. Blasts >20%
2. Basophils >20%
3. Thrombocytopenia
4. Bone marrow fibrosis
Goal of treatment

• Eradication of any residual cells containing the BCR/ABL transcript.

• Complete molecular remission and cure


• Haematological remission
• Cytological remission
Treatment
• Tyrosine kinase inhibitors
• Imatinib
• Nilotinib
• Dasatinib
• Ponatinib
• Allogenic Stem Cell Transplantation
• Cytotoxic drugs
• Hydroxyurea
• Interferon α
Normal Bcr-Abl Signaling

ADP = adenosine diphosphate


ATP = adenosine triphosphate Bcr-Abl
P = phosphate

ADP P
P P P
ATP
P P P
SIGNALING
Imatinib Mesylate:
MOA

ADP = adenosine diphosphate Bcr-Abl


ATP = adenosine triphosphate
P = phosphate
P
ATP
P P P
Imatinib
mesylate SIGNALING

Savage and Antman. N Engl J Med. 2002;346:683.


Imatinib Mesylate:
Side Effects
• Fluid retention
• Weight gain
• Nausea
• Skin rashes
• Periorbital edema
• Bone/ muscle aches
• fatigue
Agent Approved indications Dose schedule toxicities
Imatinib mesylate All phases 400mg daily
300mg daily

Dasatinib All phases Firstline:100mg daily Myelosuppression


Salvage:140mg daily Pulmonary HTN
Lowest: 20mg daily Pleural & pericardial effusion

Nilotinib All phases except blastic Firstline:300mg twice Diabetes


phase Salvage:400mg twice Vasooclusive disease
Lowest: 200mg twice Pancreatitis

Bosutinib All phases except 500mg daily Diarrhoea


frontline Lowest: 300mg daily

Ponatinib All phases except 45mg daily Skin rashes


frontline Lowest: 15mg daily Pancreatitis
Vasoocclusive disease
Monitoring

• Till cytogenetic response :


oBonemarrow biopsy (6 month-intervals)

• Once cytogenetic response achieved:


oQuantitative RT-PCR from peripheral blood (3-month intervals)
Failure

• No haematological response at 3 months

• Incomplete haematological response at 6 months

• No cytological response at 6 months

• Incomplete cytological response at 12 months ( Ph chromosome +


>35%)
Allogenic Stem Cell Transplantation:
Factors affecting outcome
• Patient’s age

• Duration of chronic phase

• Relationship with the donor

• Degree of matching

• Preparative regimen
Allogenic Stem Cell Transplantation:
Preparative regimens
• Cyclophosphamide plus total-body irradiation

• Cyclophosphamide plus Busulphan

• Reduced-intensity transplants: preparative regimen aimed at


eliminating host lymphocytes
Allogenic Stem Cell Transplantation:
Complications
• GVHD
• Organ dysfunction
• Development of 2° cancers
• Infertility
• Chronic immune mediated complications
• Cataract
• Hip necrosis
Interferon α
• Dose: 3-9MU/day im or sc
• Actions:
oDecrease in BM cellularity
oReduction in no. of Ph+ cells in 20% cases
oElimination of Ph chromosome in 5% cases
oReduction in platelet count
• Side effects:
oFlu-like syndrome
oWt loss
oFatigue
oNausea, vomiting, headache
Splenectomy

• Massive splenomegaly

• Repeated splenic infarcts


Variants Of CML

• Juvenile myelomonocytic leukemia


Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

• Chronic eosinophilic leukemia

• Granulocytic sarcoma

• Chronic neutrophilic leukemia


Chronic Eosinophilic Leukemia

• ↑TLC

• ↑ Eosinophilic count

• Eosinophilic precursors in blood & BM

• Clonal cytogenetic abnormalities


o Del[4q12]
Chronic Neutrophilic Leukemia
• Leukocytosis
• Predominently mature neutrophils
• Metamyelocytes
• Myelocytes
• ↑ NAP score
• ↑ S. uric acid
• ↑ S. Vitamin B12
• BM: Hyperplasia of myeloid cells
• Ph’ chromosome –ve
POLYCYTHEMIA RUBRA VERA
• Rare disease
• Age group: 40 years
• Increased red cell mass
• Increased viscosity (Hyperviscosity syndrome)
• Due to mutation in kinase-JAK2 (>90%)
SYMPTOMS
• Lassitude
• Loss of concentration
• Headaches
• Dizziness and blackouts
• Aquagenic pruritis (worsens after a hot bath)
• Epistaxis
• Diaphoresis
• Weight loss
SIGNS
• Splenomegaly
• Hepatomegaly
• Skin plethora
• Conjunctival plethora
• Systolic hypertension
REVISED WHO CRITERIA FOR PCV
• Major
–Hgb >18.5 g/dl in men, 16.5 g/dL in women or evidence of increased
red cell volume.
–Presence of JAK2 V617F mutation
• Minor
–Hypercellular bone marrow biopsy with prominent erythroid,
granulocytic, and megakaryocytic hyperplasia.
–Serum erythropoietin level below normal reference range.
–Endogenous erythroid colony formation in vitro
• Using vitro culture techniques, there is formation of erythroid
colonies in absence of added erythropoietin

• Diagnosis requires presence of both major criteria and 1 minor or first major and 2
minor criteria
MANAGEMENT
• Aspirin: Reduces risk of thrombosis
• Venesection: Prompt relief of hyperviscosity symptoms (repeated
every 5-7 days until hematocrit is reduced to below 45%)
• Hydroxycarbamide or interferon-alfa: Reduces risk of vascular
occlusion, controls spleen size and reduces transformation to
myelofibrosis
• Radioactive phosphorus: Reserved for older patients
PROGNOSIS
• Median survival after diagnosis in treated patients: >10years
• Complications:
Increased risk of arterial thrombosis, particularly stroke and venous
thromboembolism
May convert to another myeloproliferative disorder or acute leukaemia
or myelofibrosis
MYELOFIBROSIS
ETIOLOGY
Marrow: Hypercellular (excess of abnormal megakaryocytes)

Release growth factors, eg: platelet derived growth factor

Reactive proliferation of fibroblasts

Fibrosis of marrow
• Age group: >50 years
• Signs and symptoms:
Lassitude
Weight loss
Night sweats
Massive splenomegaly due to extramedullary hematopoiesis
BLOOD PICTURE
• Leukoerythroblastic anemia with circulating immature RBCs
(increased reticulocytes and nucleated RBCS) and granulated
precursors (myelocytes)
• RBCs shaped like teardrops (teardrop poikilocytes)
• Giant platelets
DIAGNOSIS
• Biopsy shows excess of megakaryocytes, increased reticulin and fibrous
tissue replacement
• Presence of a JAK-2 mutation supports the diagnosis
• WBC counts: low to moderately high
• Platelet count: high, normal, or low
• Urate levels: may be high due to increased breakdown
• Folate deficiency
MANAGEMENT
• Red cell transfusions for anemia
• Folic acid to prevent deficiency
• Hydroxycarbamide: To control spleen size, WBC count or systemic
symptoms
• Splenectomy for a grossly enlarged spleen
• Ruxolitinib: Inhibitor of JAK-2 recently being used
ESSENTIAL THROMBOCYTOSIS
• Increased proliferation of megakaryocytes Raised level of circulating
platelets that are dysfunctional
• Age group: 60 years
• Presents with vascular occlusion or bleeding or with an asymptomatic
isolated raised platelet count
• May progress to myelofibrosis or acute luekaemia
SYMPTOMS
• Asymptomatic
• Digital ischemia from microvascular thrombi
• Pruritis
• Erythromelalgia
• Hemorrhage
DIAGNOSIS
• Important to rule out other reactive causes of thrombocytosis
• High platelet count
• May have splenomegaly
• Presence of JAK-2 mutation supports the diagnosis
MANAGEMENT
• Low dose aspirin
• Oral hydroxycarbamide
• Anagrelide, an inhibitor of megakaryocyte maturation: For those with
platelet count >1000*109/L, and risk factors for thrombosis like
hypertension or diabetes
• Intravenous radioactive phosphorus useful in old age
MYELODYSPLASTIC SYNDROMES
• Heterogenous group of acquired clonal stem cell disorders
• Progressive cytopenias, dysplasia in one or more cell lines, ineffective
hematopoiesis
• Risk of development of AML
• Can be primary or secondary
• Produce several structural abnormalities during maturation and
premature cell destruction
THANK YOU

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