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CHRONIC MYELOPROLIFERATIVE DISORDERS
Hawwa Najiza
Rithika Sriram
Saloni Sawarthia
Introduction
Neoplastic Proliferation of white cells
Myeloid Neoplasms
Lymphoid Neoplasms
Histiocytic or Dendritic cell
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:
oChronic myeloid leukemia, bcr-abl positive
oChronic neutrophilic leukemia
oChronic eosinophilic leukemia, not otherwise specified
o Polycythemia vera
o Primary myelofibrosis
o Essential thrombocytosis
oMastocytosis
oMyeloproliferative neoplasms, unclassified
oMyelodysplastic 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
BCR-ABL Oncoproteins(p210)
Constitutive (+) of tyrosine kinase
Inhibition of apoptosis
Increased cell proliferation
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
PP P
ADP P
P
PP P
ATP
SIGNALING
Bcr-Abl
ADP = adenosine diphosphate
ATP = adenosine triphosphateP = phosphate
Imatinib Mesylate:MOA
P
PP P
ATP
SIGNALING
Imatinibmesylate
Bcr-Abl
Savage and Antman. N Engl J Med. 2002;346:683.
ADP = adenosine diphosphate
ATP = adenosine triphosphateP = phosphate
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 daily300mg daily
Dasatinib All phases Firstline:100mg dailySalvage:140mg dailyLowest: 20mg daily
MyelosuppressionPulmonary HTNPleural & pericardial effusion
Nilotinib All phases except blasticphase
Firstline:300mg twice Salvage:400mg twiceLowest: 200mg twice
DiabetesVasooclusive diseasePancreatitis
Bosutinib All phases exceptfrontline
500mg dailyLowest: 300mg daily
Diarrhoea
Ponatinib All phases except frontline
45mg dailyLowest: 15mg daily
Skin rashesPancreatitisVasoocclusive 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% casesoElimination 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
• Chronic myelomonocytic leukemia
• Chronic eosinophilic leukemia
• Granulocytic sarcoma
• Chronic neutrophilic leukemia
Myelodysplastic syndromes
Chronic Eosinophilic Leukemia
• ↑TLC
• ↑ Eosinophilic count
• Eosinophilic precursors in blood & BM
• Clonal cytogenetic abnormalities
oDel[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 erythroidcolonies 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 leukaemiaor myelofibrosis
MYELOFIBROSIS
ETIOLOGY
Fibrosis of marrow
Reactive proliferation of fibroblasts
Release growth factors, eg: platelet derived growth factor
Marrow: Hypercellular (excess of abnormal megakaryocytes)
• 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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