Apiluck Pituknoppakul

Clonal haematopoeitic disorders Proliferation of one of myeloid lineages

Granulocytic Erythroid Megakaryocytic

Normal maturation (effective) Hepatosplenomegaly

Sequestration of excess blood Extramedullary haematopoiesis Leukaemic infiltration

 a predilection to extramedullary

hematopoiesis, myelobrosis, and transformation at varying rates to acute leukemia transforming into each other.

PV , IMF , ET also appear capable of

Bone marrow stem cell

Clonal abnormality

Granulocyte precursors

Red cell precursors

Megakaryocytes

Reactive brosis

Chronic myeloid leukemia

Polycythaemia rubra vera (PRV)

Essential thrombocytosis (ET)

Myelobrosis

10% 70%

10% 30%

AML

 1. Chronic myelogenous leukemia, [Ph chromosome t(9;22)(q34;11), BCR/ABL-positive] 2. Chronic neutrophilic leukemia 3. Chronic eosinophilic leukemia (and the hypereosinophilic syndrome) 4. Polycythemia vera 5. Chronic idiopathic myelobrosis (with extramedullary hematopoiesis) 6. Essential thrombocythemia 7. Chronic myeloproliferative disease, unclassiable

 This phenotypic heterogeneity has a genetic

basis CML : t(9;22)(q34;11) CNL : t(15:19) translocation CEL : deletion or balanced translocations involving the PDGFR gene

 PV, IMF, and ET : expression of a JAK2

mutation, V617F

causes constitutive activation of this tyrosine

kinase that is essential for the function of the erythropoietin and thrombopoietin receptors but not the granulocyte colony stimulating factor receptor

 CML, CNL, and CEL, usually measured in

years, and high rate of transformation into acute leukemia decades, and transformation to acute leukemia is uncommon in the absence of exposure to mutagenic agents

PV, IMF, and ET : usually measured in

 most common of the chronic

myeloproliferative disorders

clonal disorder involving a multipotent

hematopoietic progenitor cell in which phenotypically normal red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus

 Incidence 2-3 / 100,000 Median age at presentation: 55-60 yrs M/F: 0.8:1.2

Familial transmission occurs but is infrequent

 Mens

Hb 18.5 g/dl Hct 60%

Womens
Hb 16.5 g/dl Hct 55%

12

 Unknown mutation in the autoinhibitory,

pseudokinase domain of the tyrosine kinase JAK2 which replaces valine with phenylalanine (V617F), causing constitutive activation of the kinaseappears to have a central role in the pathogenesis of PV

1.incidental discovery of a high hemoglobin or hematocrit 2.Splenomegaly 3.aquagenic pruritus 4.hyperviscosity, leading to neurologic symptoms such as vertigo, tinnitus, headache, visual disturbances, and transient ischemic attacks (TIAs)

5.Systolic hypertension 6.venous or arterial thrombosis (cerebral, cardiac, or mesenteric vessels are most commonly involved ) 7.Intraabdominal venous thrombosis : particularly common in young women 8. vascular stasis or thrombocytosis : digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage

9.erythromelalgia : Erythema, burning, and pain in the extremities 10.hyperuricemia with secondary gout, uric acid stones

True / Absolute Primary Polycythemia Secondary Polycythemia Apparent / Relative Reduction in plasma volume

 elevated plasma erythropoietin level

suggests either a hypoxic cause for erythrocytosis or autonomous erythropoietin production

assessment of pulmonary function and an

abdominal CT scan to evaluate renal and hepatic anatomy

 Absolute erythrocytosis Hypoxia

Renal disease

Carbon monoxide intoxication High anity hemoglobin High altitude Pulmonary disease Right-to-left shunts Sleep-apnea syndrome Neurologic disease

Renal artery stenosis Focal sclerosing or membranous glomerulonephritis Renal transplantation

 Tumors Hypernephroma Hepatoma Cerebellar hemangioblastoma Uterine bromyoma Adrenal tumors Meningioma Pheochromocytoma

Drugs

Androgens Recombinant erythropoietin Familial (with normal hemoglobin function, Chuvash, erythropoietin receptor mutations) Polycythemia vera

Bone marrow in PV

Hb, HCT, and Red cell mass increased ( Not always) Increased neutrophils and platelets Hyperuricemia Hypercellular bone marrow
panmyelosis

Low or normal serum EPO

23

 A bone marrow aspirate and biopsy provide

no specic diagnostic information since these may be normal or indistinguishable from ET or IMF

JAK2 V617F mutation screen positive in

95% JAK2 exon 12 mutations : remainder of pts

 relate directly to the increase in blood

viscosity associated with red cell mass elevation indirectly to the increased turnover of red cells, leukocytes, and platelets with the attendant increase in uric acid and cytokine production

 sudden massive increase in spleen size can

be associated with splenic infarction or progressive cachexia Myelobrosis appears to be part of the natural history of the disease but is a reactive, reversible process development of leukemia : related to older age but not disease duration

 avoid thrombotic complications reduce hyperviscosity Low dose ASA : all pts

Hydroxyuria if high risk of thrombosis ( age

> 60 , prior thrombosis ) or symptomatic thrombocytosis ( plt > 1,500,000) Symptomatic treatment : gout , pruritus Allogeneic bone marrow transplantation may be curative in young patients

avoid thrombotic complications maintenance of the hemoglobin level 14 g/dL; hematocrit <45% in men 12 g/dL; hematocrit <42% in women reduce hyperviscosity Phlebotomy : bringing the red cell mass into the normal range Periodic phlebotomies : maintain the red cell mass within the normal range and to induce a state of iron deciency, which prevents an accelerated reexpansion of the red cell mass

 Asymptomatic hyperuricemia (<10 mg%)

requires no therapy

Generalized pruritus : hydroxyurea,

interferon and PUVA

Asymptomatic thrombocytosis no therapy unless the platelet count is suciently high to cause an acquired form of von Willebrand's disease due to proteolysis of high-molecular-weight vWF multimers Symptomatic splenomegaly treated with IFN- IFN- reduces JAK2 V617F expression in PV patients

reduce the platelet count Hydroxyurea , Anagrelide, a phosphodiesterase inhibitor massive splenomegaly unresponsive to reduction by hydroxyurea or IFN- therapy and associated with intractable weight loss will require splenectomy

 agnogenic myeloid metaplasia

myelobrosis with myeloid metaplasia

 least common chronic myeloproliferative

disorder

clonal disorder of a multipotent

hematopoietic progenitor cell of unknown etiology characterized by marrow brosis, extramedullary hematopoiesis, and splenomegaly.

 CYTOKINE FIBROBLAST FIBROSIS Transforming growth factor beta PDGF Basic broblast growth factor

 absence of a specic clonal marker

1.3/100,00 people

Median age 60 (90% are >40)

Malignant Acute leukemia (lymphocytic, myelogenous, megakaryocytic) Chronic myelogenous leukemia Hairy cell leukemia Hodgkin disease Idiopathic myelobrosis Lymphoma Multiple myeloma Myelodysplasia Polycythemia vera Systemic mastocytosis

Nonmalignant HIV infection Hyperparathyroidism Renal osteodystrophy Systemic lupus erythematosus Tuberculosis Vitamin D deciency Thorium dioxide exposure Gray platelet syndrome

 unknown no cytogenetic abnormality specic to the

disease Nonrandom chromosome abnormalities such as 9p, 20q, 13q, trisomy 8 or 9, or partial trisomy 1q are common Fibrosis associated with overproduction of transforming growth factor and tissue inhibitors of metalloproteinases

 Osteosclerosis : associated with

overproduction of osteoprotegerin, an osteoclast inhibitor Marrow angiogenesis occurs due to increased production of vascular endothelial growth factor (VEGF) broblasts in chronic IMF are polyclonal and not part of the neoplastic clone

 No signs or symptoms are specic for chronic

IMF asymptomatic at presentation usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination A blood smear shows the characteristic features of extramedullary hematopoiesis

 Bone marrow brosis Hypercatabolic syndromes (Fatigue, fevers,

weight loss, night sweats) Evolution to acute leukemia

 Suggested by peripheral blood smear normocytic anemia increased or decreased number of granulocytes

and platelets myelophthisis

conrmed by bone marrow biopsy Usually dry tap

Tear drop RBCs Leukoerythroblastic blood picture (nucleated RBCs and granulocyte precursors)

DDX : PV , CML , Other disorder that cause myelobrosis Marrow is usually not aspirable due to increased marrow reticulin marrow biopsy will reveal a hypercellular marrow with trilineage hyperplasia in particular, increased numbers of megakaryocytes in clusters and with large, dysplastic nuclei no characteristic morphologic abnormalities that distinguish IMF from the other chronic myeloproliferative disorders

 Splenomegaly : extramedullary

hematopoiesis may be suciently massive to cause portal hypertension and variceal formation. occurrence of autoimmune abnormalities such as immune complexes, antinuclear antibodies, rheumatoid factor, or a positive Coombs' test

Cytogenetic analysis useful both to exclude CML and for prognostic purposes, because complex karyotype abnormalities portend a poor prognosis in chronic IMF number of circulating CD34+ cells is markedly increased in chronic IMF (>15,000/ L) compared to the other chronic myeloproliferative disorders,

 approximately 45% of chronic IMF patients :

express the JAK2 V617F mutation

 Survival in chronic IMF varies according to

specic clinical features shorter than in patients with PV or ET natural history of chronic IMF is one of increasing marrow failure with transfusion- dependent anemia and increasing organomegaly due to extramedullary hematopoiesis

 chronic phase accelerated phase :

constitutional symptoms and increasing marrow failure 10% of patients aggressive form of acute leukemia for which therapy is usually ineective

Important prognostic factors for disease acceleration Anemia Leukocytosis Thrombocytopenia presence of circulating myeloblasts older age ( > 60 yrs ) presence of complex cytogenetic abnormalities constitutional symptoms

 No specic therapy exists for chronic IMF

ANEMIA Neither recombinant erythropoietin nor androgens, such as Danazol, have proved consistently eective as therapy for anemia SPLENOMEGALY Splenectomy may also be necessary if splenomegaly impairs alimentation

 Allopurinol : control signicant

hyperuricemia hydroxyurea has proved useful for controlling organomegaly in some patients , for signicant leukocytosis or thrombocytosis Glucocorticoids : control constitutional symptoms and autoimmune complications , alone or in combination with low dose thalidomide (50100 mg/d)

 Allogeneic bone marrow

transplantation :only curative treatment should be considered in younger patients

 clonal disorder of unknown etiology involving

a multipotent hematopoietic progenitor cell platelets without a denable cause

manifested clinically by overproduction of

clonal marker is available to consistently

distinguish ET from the more common nonclonal, reactive forms of thrombocytosis

 The 2.5

best prognosis in MPD : Male = 2:1 age at diagnosis: 60 yrs

cases/100,000

Female Median Life

expectancy : 5-10 yrs

Malignancy Infection Myeloproliferative disorders Myelodysplastic disorders Postsplenectomy or hyposplenism Hemorrhage Iron deciency anemia Surgery Rebound: Correction of vitamin B12 or folate deciency, post-ethanol abuse Hemolysis

Asymptomatic / Splenomegaly 25 48% Vasomotor symptom

Headache Syncope Atypical chest pain Livedo reticularis Erythromelalgia (burning pain of the hands or feet associated with erythema
and warmth)

Thrombosis and Haemorrhage Transformation : Myelofibrosis, PV, AML

Transient visual disturbances (eg, amaurosis fugax,, ocular migraine)

 thrombotic tendencies : microvascular

occlusions , erythromelalgia, ocular migraine, or TIAs mild splenomegaly Massive splenomegaly is more indicative of another myeloproliferative disorder

Thrombosis : arterial and venous site

risk factor : age > 60, smoking, dyslipidemia Antiphospholipid antibody

Hemorrhage :
risk factor : plt > 1,000,000 / ul ASA > 325 mg/d or NSAIDS use

 PBS : increase number of platelet , giant plt. LAP score : normal or elevated abnormalities of platelet function :

prolonged bleeding time and impaired platelet aggregation can be present marrow biopsy usually reveals megakaryocyte hyperplasia and hypertrophy as well as an overall increase in marrow cellularity.

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Platelet count >600,000 /ul 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 Presence of stainable iron in a bone marrow aspiration No evidence of myelofibrosis No evidence of MDS

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50% of ET patients express the JAK2 V617F mutation. When JAK2 V617F is absent, cytogenetic evaluation is mandatory to determine Massive splenomegaly should suggest the presence of another myeloproliferative disorder Importantly, what appears to be ET can evolve into PV or IMF after a period of many years

 intravascular stasis and thrombosis hemorrhage due to acquired von Willebrand

disease

70

 Hydroxyurea

: the most effective to reduce thrombosis Leukemogenesis 3.5% at median follow up 8 yrs. Busulphan, 32p : high Leukemogenesis Anagrelide : response rate 80 %, Leukemogenesis : no report , now

 Incidence 1-1.5/100,000 population

Median age at presentation: 45 to 55 years Male predominance

At presentation
50% diagnosed by routine laboratory tests 85% diagnosed during chronic phase

 Neoplastic transformation of pluripotent

stem cells increase myeloid series

Etiology : unknown Associated with RADIATION

 Abnormal : Philadelphia chromosome 90-95% pts.translocation Balanced reciprocal translocation t(9;22)

(q34;11)

10

11

12

13

14

15

16

17

18

c-abl

bcr

Bcr-abl Tyrosine kinase Signal transduction pathway

 Abl stands for "Abelson", the name of a

leukemia virus which carries a similar protein

BCR ("breakpoint cluster region")

 5-10% : Philadelphia chromosome negative Higher age , monocytes Less basophils, thrombocytosis,

splenomegaly

50% of Ph-negative : CMMoL , MDS/MPD

Clinical Course: Phases of CML

Advanced phases Chronic phase Accelerated phase Median 46 years stabilization Median duration up to 1 year Blastic phase (blast crisis) Median survival 36 months Terminal phase

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Chronic phase
peripheral blasts < 10% Common Symptoms/signs

Fatigue, Weight loss/anorexia, Abdominal fullness Palpable splenomegaly Common Laboratory Findings Abnormal dierential, leukocytosis, Basophilia Thrombocytosis (<1 million) Anemia Low LAP score, high LDH, hyperuricemia BMA : hypercellular, M:E, megakaryocyte

Accelerated phase peripheral blasts 10%

Unexplained fever Progressive splenomegaly Platelet < 100,000 /l basophils + eosinophils eosinophils > 20% peripheral blasts > 20% , blast +promyelocyte > 30% marrow blasts > 30%, blast +promyelocyte > 50% Bleeding, infection, prominent constitutional symptom Tissue manifestation of extramedullary disease
Lymphadenopathy Chloroma : hyperpigmented skin

Blastic phase

 Allogeneic stem cell transplantation

(SCT) Imatinib (Glivec) , Dasatinib , Nilotinib IFN-based treatments Chemotherapy with hydroxyurea or busulfan Leukapheresis and plateletpheresis

Diagnosis

Young with a well-matched donor

Start Imatinib at 400mg/day

Cosider for Allograft

Poor response or Initial response Followed by Loss of response Add or substitute Other agents Allo-SCT Auto

Good response maintained

Allo SCT

Continue Imatinib indenitely

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 No treatment (3 yrs) Hydroxyurea (4 yrs) Imatinib mesylate median not reached (at

least 5 yrs and probably much more) Transplant cure but signicant mortality and morbidity