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

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