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MYELOPROLIFERATIVE DISORDERS
Riadi Wirawan
Departemen Patologi Klinik FKUI-RSCM
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.2.
Diagrammatic representation of the BM pluripotent stem cell and the cell line that arise from it.
MYELOPROLIFERATIVE DISORDERS (MPD)
JAK2 MUTATION
Polycythemia Vera (PV)
Essential thrombocythemia (ET)
Myelofibrosis (MF
BCR-ABL FUSION GENE
Chronic myeloid leukemia (CML)
MYELOPROLIFERATIVE DISORDERS (MPD)
MPD : a group of conditions characterized by clonal
proliferation of one or more hematopoietic
components in the BM and in many cases the liver
and spleen
Disorders are include :
Polycythemia vera (PV)
Essential thrombocythemia (ET)
Myelofibrosis
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.230.
Relationship between the three myeloproliferative diseases. They may all arise by somatic mutation in the pluripotential stem and progenitor cells. Many transitional cases occur showing features of two conditions and, in other cases, the disease transforms during its course from one of these diseases to another or to acute myeloid leukaemia. The three diseases, polycythaemia rubra vera, essential thrombocythaemia and myelofibrosis, are characterised by JAK2 mutation in a varying proportion of cases.
This disorders are closely related to each other
Transitional form occur
A single acquired mutation of the cytoplasmic
tyrosine kinase Janus-associated kinase 2 (JAK-
2)(Val617Phe) occurs in the marrow and blood of
almost all patients with PV, 50% with ET and
myelofibrosis
The role of JAK2 mutation in the generation of myeloproliferative diseases. (a) (i) Most haemopoietic growth factor receptors do not have intrinsic kinase activity but associate with a protein kinase such as JAK2 in the cytoplasm. (ii) When the receptor binds a growth factor the cytoplasmic domains move closer together and the JAK2 molecules can activate each other by phosphorylation. (iii) The V617F JAK2 mutation allows the JAK protein to become activated even when no growth factor is bound.
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.231.
The role of JAK2 mutation in the generation of myeloproliferative diseases. (c) JAK2 activation leads to cell survival and proliferation through activation of three major pathways; the STAT transcription factors, the PI3K pathway acting through Akt and Ras activation which subsequently activate ERK and MAPK. The net result is production of a diverse range of proteins that promote cell survival and proliferation.
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.231.
Normal Primary or secondary
polycythaemia
Relative
polycythaemia
Total red cell volume
(51Cr)
♂ 25-35 mL/kg
♀ 22-32 mL/kg
N
Total plasma volume
(125I-albumin)
40-50 mL/kg N
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.232.
Total red cell volume and total plasma volume
POLYCYTHEMIA
Is define as an increased in the Hb
concentration above the upper limit of normal
for the patient age and sex
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.232.
Causes of polycythemia
Primary• Polycythemia (rubra) vera
• Familial (congenital) polycythemia
Secondary• Caused by compensatory erythropoietin increase in:
high altitudes pulmonary disease and alveolar hypoventilation (sleep apnoe) cardiovascular disease, especially congenital with cyanosis increased affinity haemoglobin (familial polycythemia heavy cigarette smoking
• Caused by inappropriate erythropoietin increased in:
renal diseases (e.g. hydronephrosis, vascular impairment, cysts, carcinoma) tumours such as uterine leiomyoma, hypernephroma, hepatocellular carcinoma, cerebellar haemangioblastomaRelative
• Stress or pseudopolycythemia
• Cigarette smoking
• Dehydration: water deprivation, vomiting
• Plasma loss: burns, enteropathy
POLYCYTHEMIA VERA
Polycythemia vera (PV)
Increased in red cell volume caused by a clonal malignancy of the marrow stem cell
The disease result from somatic mutation of a single hematopoietic stem cell (JAK-2 mutation is present in almost 100 % of patients)
Increased in red cells volume is the diagnostic finding and an overproduction of granulocyte and platelet
Chromosome abnormality : del 9p, del 20q
Clinical features
Common in older subjects, with an equal sex incidence Hyperviscosity :
Headache, dispnoe, blurr vision Phletoric appearance : ruddy cyanosis Bleeding : GI, uterine, cerebral Thrombosis : arterial (cardiac, cerebral, peripheral)
venous (leg veins, cerebral, portal, hepatic) Hypervolemia : retinal venous engorgement, hypertension Hypermetabolism
Night sweat Pruritus Gout Peptic ulcers
Splenomegali : 75% patients
Hoffbrand AV, Pettit JE. Color atlas of clinical hematology. 2nd ed. London : Mosby-Wolfe; 1998.p.198.
Gouty tophi on the index and middle fingers.
Laboratory findings
Increased hemoglobin concentration, hematocrit, RBC, total red cell volume (TRCV), blood viscosity and low serum erythropoietin
Leucocyte : Neutrophil leucocytosis Basophilia Increased Neutrophil Alkaline Phosphatase
(NAP) score Increased vit B12 and vit B12 binding capacity Increased uric acid serum and normal LDH
Thrombocyte count raise in about 50 % patients
Bone marrow
Hypercellular
Prominent megakaryocyte
Laboratory findings
Criteria for diagnosis of polycythemia (rubra) vera
A1 Total red cell mass male > 35 mL/kg female > 32 mL/kg
A2 Arterial oxygen saturation normal (> 92%)
A3 Splenomegaly
A4 JAK2 mutation
B1 Platelets > 400 x 109/L
B2 White cells > 12 x 109/L
B3 Increased NAP score (n : 10-100)
B4 Raised serum vitamin B12 levelA1 + A2 + A3 or A1 + A2 + A4 orA1 + A2 + another two BNAP = neutrophil alkaline phosphatase.
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.232.
Treatment
Maintain a normal blood count, Ht should be maintain at 45 % and platelet count < 400.000/uL
Venesection : To reduce hematocrit < 45% Rapid reduction of red cell volume Resulting IDA, does not control the platelet count
Cytotoxic myelosuppression Poor tolerance of venesection, symptomatic, progressive
splenomegaly, weight loss, night sweat Hydroxyurea for controlling the blood count, side effects
myelosuppression, skin toxicity and nausea
Treatment
Phosphorus32 therapy
Use for older patients with severe disease
Late development of leukemic
Interferon alpha
Suppress excess proliferation in the marrow
Low dose aspirin : reduce thrombotic complication
Course and prognosis
Prognosis is good, median survival 10-16
years
Major clinical problems : thrombosis and
hemorrhage
Transformation PV to :
Myelofibrosis ( 30 %)
Acute leukemia (5 %)
ESSENTIAL THROMBOCYTHEMIA
Essential thrombocythemia
Megakaryocyte proliferation
Increased platelet count
Overproduction of platelet
Normal hematocrite
Philadelphia chromosome or BCR-ABL fusion gene
are absent
No collagen fibrosis in the marrow
Persisting platelet count > 400.000/uL,
exclude thrombocytosis by other causes
before diagnosis can be made
JAK-2 mutation in 50 % cases
Essential thrombocythemia
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.237.
Causes of a raised platelet count
Reactive
• Haemorrhage, trauma, postoperative
• Chronic iron deficiency
• Malignancy
• Chronic infections
• Connective tissue disease (e.g. rheumatoid arthritis)
• Post-splenectomy
Endogenous
• Essential thrombocythaemia (JAK2 mutation + or -)
• In some cases of polycythaemia vera, myelofibrosis
and chronic myeloid leukaemia
Clinical features
Thrombosis : Venous Arterial
Hemorrhage : Result of abnormal platelet function May cause chronic or acute bleeding
Erythromelalgia : burning sensation felt in the hands or feet and reliaved by aspirin
Splenomegaly or splenic atrophy (infarction)
Hoffbrand AV, Pettit JE, Moss PAH. Essential haematology .4th ed. Oxford : Blackwell Science; 2001.p.230.
Gangrene of the left fourth toe in thrombocythaemia essential.
Laboratory findings
Peripheral blood Thrombocytosis with abnormal large platelet Megakaryocyte fragment may be seen in PB Abnormal platelet aggregation with
adrenaline
Bone marrow : excess of abnormal megakaryocyte
Cytogenetics : negative BCR-ABL fusion gene
Essential thrombocythaemia : peripheral blood film showing a gross increase in platelet numbers.
Treatment
To control platelet count so as to reduce the risk of thrombosis (risk > 60 years, thrombocyte > 1.000.000/uL, with previous episode of thrombosis or hemorrhage, smoking history and hypertension)
Keep the platelet count below 600.000/uL Hydroxyurea most widely use Alpha interferon valuable in younger patient Anagrelide for reducing the platelet count Plateletpheresis helpful in short term management Aspirin to reduce thrombotic risk
Course
Stationery 10 – 20 years Transform to myelofibrosis or acute leukemia
MYELOFIBROSIS
Myelofibrosis
Myelofibrosis is a clonal stem cell disease, in
some patient there is osteosclerosis
Progressive generalized reactive fibrosis of
the bone marrow in association with the
development of hemopoiesis in the spleen
and liver (myeloid metaplasia)
JAK mutation occurs in ± 50 % cases
No specific cytogenetic abnormalities
1/3 patients have a previous history of PV
Clinical feature
Insidious onset in older people as usual with
anemia
Massive splenomegaly
Hypermetabolic symptom : loss of weight,
anorexia, fever and night sweat
Bleeding problem, bone pain or gout
Laboratory findings
Anemia but normal or increase hemoglobin
level may be found
Leucocytosis and thrombocytosis are
frequent at the time of presentation, later
leucopenia and thrombocytopenia are
common
Leucoerythroblastic blood film : immature
granulocyte with NRBC
Tear drop cells
Bone marrow : unobtainable by aspiration,
trephine biopsy showed fibrotic hypercellular
marrow, increase megakaryocyte, increase
bone formation
Increased NAP score
High serum urate and LDH level increase
turn over cell
JAK-2 mutation in 50 % cases
Laboratory findings
Peripheral blood film in essential thrombocythaemia showing increased numbers of platelets and a nucleated megakaryocytic fragment.
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.237.
Course
Transformation to acute myeloid leukemia (AML) 10 – 20 % cases
Median survival 3,5 years Cause of death : heart failure, infection and
leukemic transformation Poor prognosis if :
Hb < 10 g/dL WBC < 4000/uL Thrombocyte < 30.000/ul Presence of abnormal chromosome
CHRONIC MYELOID LEUKEMIA (CML)
Clonal disorders of a pluripotent stem cell
15% of leukemia & and may occur at any age
CML characteristic present of Philadelphia (Ph)
chromosome, t(9;22) (q34;q11) resulting
BCR-ABL fusion gene codes for a fusion
protein of size p210
CML
The Philadelphia chromosome. (a) There is translocation of part of the long arm of chromosome 22 to the long arm of chromosome 9 and reciprocal translocation of part of the long arms of chromosome 9 to chromosome 22 (the Philadelphia chromosome). This reciprocal translocation brings most of the ABL gene into the BCR region on chromosome 22 (and part of the BCR gene into juxtaposition with the remaining portion of ABL on chromosome 9). (b) The breakpoint in ABL is between exons 1 and 2. The breakpoint in BCR is at one of the two points in the major breakpoint cluster region (M-BCR) in CML or in some cases of Ph+ ALL. (c) This results in a 210-kDa fusion protein product derived from the BCR-ABL fusion gene. In other cases of Ph+ ALL, the breakpoint in BCR is at a minor breakpoint cluster region (m-BCR) resulting in a smaller BCR-ABL fusion gene and a 190-kDa protein.
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.175.
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.176.
(d) Karyotype showing the t(9;22) (q34;q11) translocation. The Ph chromosome is arrowed. (e) Visualization of the Philadelphia chromosome on: (i) dividing (metaphase); and (ii) quiscent (interphase) cells by fluorescence in situ hybridization (FISH) analysis (ABL probe in red and BCR probe in green) with fusion signals (red/green) on the Ph and der(9) chromosomes.
(e)
Occur in either sex (male : female ratio = 1,4 : 1)
Most frequency between age 40-60 yo
Hypermetabolism : weight loss, anorexia or night
sweats, gout
Splenomegaly
Anemia : pallor, dyspnoe & tachycardia
Leukostasis : visual disturbances and priapism
Abnormal platelet function : bruising, epistaxis,
menorrhagia or haemorhage
Clinical features
Hoffbrand AV, Pettit JE. Color atlas of clinical hematology. 2nd ed. London : Mosby-Wolfe; 1998.p.198.
CML: ocular fundus in the hyperviscosity syndrome shows distended retinal veins and deep retinal haemorrhages at the macular. Hb: 14 g/dL; WBC: 590 x 109/L; platelets: 1050 x 109/L
CML: acute inflammation and swelling of the fourth finger due to uric acid deposition. Hb: 8.6 g/dL; WBC: 540 x 109/L; platelets: 850 x 109/L; serum uric acid: 0.85 mmol/L.
Normochromic normocytic anemia
Leukocytosis 50.000 - > 500.000/uL with complete
spectrum of myeloid cell, dominate neutrophils and
myelocytes, basophilia
Thrombocyte : ↑/N/↓
Neutrophil alkaline phosphatase score low. Raised
in MPD and infection
Hyperuricemia
BM hypercellular with granulopoietic predominant
Ph chromosome (+)
Laboratory findings
Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology .5th ed. Oxford : Blackwell Publishing; 2006.p.177.
Chronic myeloid leukaemia: peripheral blood showing a vast increase in buffy coat. The white cell count was 532 x 109/L.
Chronic myeloid leukaemia: peripheral blood film showing various stages of granulopoiesis including promyelocytes, myelocytes, metamyelocytes and band and segmented neutrophils.
CML chronic phase
CML accelerated phase
CML blastic phase : Acute myeloid leukemia (AML)
Acute lymphoid leukemia (ALL)
Bilineage acute leukemia
Biphenotype acute leukemia
Course
The diagnosis of CML-AP may be made when one or more of the following are present : Blast 10-19% of WBC in PB and or nucleated BM cells Basophilia ≥ 20% Persistent thrombocytopenia (< 100.000/uL) unrelated to
therapy or persistent thrombocytosis (> 1.000.000/uL) unresponsive to therapy
Increasing spleen size and increasing WBC count unresponsive to therapy
Cytogenetic evidence of clonal evolution
Chronic myelogenous leukaemia, accelerated phase
Blast phase may be diagnose if ≥ 1 more is present : Blast 20% of WBC in PB and or nucleated BM cells Extramedullary blasts proliferation Large foci or cluster of blast in BM biopsy
Chronic myelogenous leukaemia, blastic phase
Prognosis
Death occur from : blast phase or intercurrent hemorrhage or infection
Prognostic according : age spleen size platelet count PB and BM blast cell on presentation