Myelo-proliferative neoplasms (Chronic myeloid leukemia (Management…
When MPN should be suspected:
HCT > 50% (>55%)
Plt > 450G/L (>600G/l)
Enlargement of spleen in physical examination
Polycythemia Vera (JAK + ca.100% )
Essential Thrombocythemia (JAK + ca. 50%) + CALR
Myelofibrosis (JAK + ca. 50%) + CALR
Mastocytosis (kit mutation)
Chronic myeloid leukemia ( BCR/ABL w 100%)
Chronic eosinophilic leukemia ( FIP1L1 –PDGFRA)
Chronic neutrophilic leukemia
Mutation of hematopoetic stem cells
Hypercellular bone marrow
Dominance of the abnormal clone over normal clones
Presence of typical mutation (BCR/ABL, JAK2, MPL, CALR)
Transformation to acute leukemia
Growth factor-independent colony formation
Chronic myeloid leukemia
50% asymptomatic at diagnosis.
50%: fatique, weight loss, sweats, pain in abdomen, loss of apetite, splenic infarction, Headache or priapism (painful erection) (due to hyperleucocytosis)
Pallor, Splenomegaly often massive, lymphadenopathy (rare), Retinal haemorrhage due to leucostasis, Extramedullary soft tissue leukaemic deposit ‘chloroma’ (= blast crisis)
accounts for about 14% of all leukemias
a disease of adults with the peak of presentation being between 40 and 60 years.
defined by the presence of the Philadelphia chromosome
transformation to acute leukaemia (75% myeloid, 25% lymphoid) or myelofibrosis
CML follows an indolent (chronic) course, The end point is an acute phase (or blast crisis)
anemia–normocytic, in the late phase of disease.
Increased WBC - to 500 G/L ; median 100 G/L
thrombocythemia-in 50% of cases
Increased number of basophils
Decreased leukocyte alkaline phosphatase activity
”left shift”–blood smear reveals all maturation stages of granulocytic lineage to blasts
Bone marrow: Cytogenetics reveals t(9; 22) translocation (the Philadelphia chromosome), Increased cellularity, increased myeloid precursors.
Tyrosine kinase inhibitors BCR/ABL: Imatynib, Dazatynib, Nilotynib, Bozutynib, Ponatynib
In case of resistance to all TKI -alloSCT
Type of Response to TKI: Hematologic, Cytogenetic, Molecular (< .1%).
Resistance to TKI
Amplifiaction of BCR/ABL
Mutaiotionin the region of connectionTKI to BCR/ABL protein
Side-effects of imatinib include nausea, headache, rashes and cytopenia.
Allogeneic haemopoietic stem cell transplantation can cure approximately 70% of chronic phase CML patients.
Differentiating benign leukemoid reaction from CMl
no splenomegaly, Increased leukocyte alkaline phosphatase, History of a precipitating event (e.g., infection)
CMl—opposite to the below findings
Polycythaemia (or erythrocytosis)
Primary polycythaemia: Polycythemia vera
High viscosity: Headache,dizziness, erytromelalgia
Pruritis (itchy skin (after shower) – degranulation of mastocytes
thrombosis and thrombophlebitis
Fatique, loss weight
Splenomegaly, hepatomegaly, Plethora (redness and fullness of the face)
CBC: 1.Increased numer of RBC, Hb, Hct
3.increased numer of WBC
Low ESR, Increased uric acid, Low Fe level, Increased B12 vitamin, Low Epo in serum
2 major + 1 minor or first major and 2 minor
Hemoglobin >18,5 G% in men , 16,5 g% in women
JAK 617F mutation or mutation in exon 12
BM biopsy –hypercelluarity, triliniage growth
EPO below range
Endogenous erythroid colony formation in vitro
phlebotomy to keep the hematocrit level below 45%
cytoreductive chemotherapy: hydroxyurea (initial dosage of 500 mg twice a day) or busulfan (initial dosage of 4 mg/d).
IFN-α (initial dosage of 3 million U subcutaneously 3 times a week)
low-dose aspirin ( up to 100 mg/day) to prevent thrombosis
clonal stem cell disorder in which there is an alteration in the pluripotent progenitor cell leading to excessive prolif- eration of erythroid, myeloid and megakaryocytic progenitor cells.
PV develops into myelofibrosis in 30% of cases and into acute myeloblastic leukaemia in 5% as part of the natural history of the disease.
an increase in haemoglobin, PCV and red cell count.
PCV is a more reliable indicator of polycythaemia than is Hb
divided into absolute erythrocytosis where there is a true increase in red cell volume, or relative erythrocytosis where the red cell volume is normal but there is a decrease in the plasma volume
Absolute erythrocytosis is due to primary polycythaemia (PV) or secondary polycythaemia.
A congenital autosomal reces- sive disorder (Chuvasch polycythaemia) is due to a defect in the oxygen-sensing erythropoietin production pathway caused by a mutation of the von Hippel–Lindau (VHL) gene, resulting in an increased production of erythropoietin.
Due to an appropriate (hypoxic) increase in erythropoietin:
High altitude, Chronic lung disease, Cardiovascular disease
(right-to-left shunt), Sleep apnoea, Morbid obesity, Heavy smoking (commonest)
Due to an inappropriate increase in erythropoietin:
Renal disease–renal cell carcinoma, Wilms’ tumour, Hepatocellular carcinoma Adrenal tumours
thrombosis: Parestesis, disturbanceof vision, paresis, thrombophlebitis
Bleeding due to disturbance of function of platelets
Increased platelets count
Disturbance of aggregation of platelets
Mutation: V617F gene JAK-2, CALR 30%, MPL 5%
Cytgenetic tests not performer routinely
Bone marrow hypercellular with increased megakariopoeisis.
Increased uric acid
Increased B12 witamin
Low TPO in serum
all 4 criteria
PLt > 450G/L
BM biopsy proliferation mainly megacariocytic lineage
No criteria for PRV, MF, CML, MDS , myeloid neoplasm
JAK 2 + if negative no eidence of reactive thrombosytosis
Thrombotic risk factors:
History of pulmonary embolism or thrombosis or thrombophlebitis
Cardiac risk factors +PLT>1000G/L+ AGE 40-60
bleeding risk factor (Acquired VON WILLEBRANDT syndrome, TROMBOFILIA) + PLT>1000G/L + AGE <40
Plt<1500G/L no risk factor - ASA 50-100 MG/d
PLT<1500G/L + risk factors – Cytoreductive treatment + ASA
PLT>1500G/L - Cytoreductive treatment+ ASA
ERYTHROMELALGIA - ASA 50-100 MG/D + Cytoreductive treatment
Antiplatelets: aspirin, ticlopidin.
cytostatic: Hydroxycarbamide, anagrelide
Other: Interferon alfa
characterizedby anemia, bone marrow fibrosis, extramedullary hematopoiesis, leukoerythroblastosis, teardrop - shaped RBCs in peripheral blood, and hepatosplenomegaly.
median age at diagnosisis 65 years.
main causes of death are infection, hemorrhage, cardiac failure, postsplenectomy complications, and transformation to acute leukemia
Leukemic transformation occurs in 20% of patients within the first10 years
Increased/normal/ decreased WBC
Increased/ normal/ decreased platelets count
Erytroblasts in blood smear
Threphaine biopsy: fibrosis reticular and fibrotic
Molecular tests: 1.Mutaion V617F gen JAK-2/ CALR/ MPL
Philadelphia chromosome is absent; this helps to distinguish myelofibrosis from most cases of CML.
Increased uric acid
increased number of CD34+ cells
3 major criteria and 2 minor criteria
presense of megakaryocyte proliferation accompanied by collagens/ reticulin fibrosis
not meeting criteria for PRV, ET, CML, MDS , myeloid neoplasm
JAK2 V617V + if negative no fibrosis sec to infection/ metasatic neoplasm /HCl/
Ruxolitinib – inhibitor JAK2
Treatment of symptoms: Prednison, Hydroxycarbamide, Erytropoetin
Increased proliferation of pathologic mastocytes
Constant activation of the kit receptor causes proliferation of mastocytes
Clinical picture of the disease:
Mediators –general symptoms -(histamin, prostaglandyns, leukotriens)
Infiltration of mastocytes in tissue
diagnostic criteria *
Skin – erythema , Darrier’s syndrome.
dyspnea, itching, fever, diarrhea, low blood pressure, shock
due to infiltration of mast cel in organs: enlarged spleen , liver, osteolysis , bone fracture
BM –presence of mastocytes
Molecular –mutation kit
Increased level of tryptase in serum
Skin mastocytosis-topical steroids, anti histaminic therapy
Aggressive SM– Dasatinib/Imatinib
uncontrolled clonal proliferation of one or more of the cell lines in the bone marrow, namely erythroid, myeloid and megakaryocyte lines