1、Chronic myelogenous leukemia,Classification of Myeloid Neoplasms According to the 2008 World Health Organization Classification Scheme,CML results from a somatic mutation in a pluripotential lymphohematopoietic cell CML is a MPD characterized by increased granulocytic cell line, associated with eryt
2、hroid and platelet hyperplasia The disease usually envolves into an accelerated phase that often terminates in acute phasechronic phase 3-5 yearsaccelerated phaseblastic phase 3-6 months,Epidemiology,CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 percent of ch
3、ildhood leukemias The median age of onset is 53 years Frequency 1/100 000 people from general population,Pathogenesis,Hematopoietic abnormalityExpansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation increased white cell countMegakaryocytopoiesis is often ex
4、pandedErythropoiesis is usually deficientFunction of the neutrophils and platelet is nearly normal,Pathogenesis,Genetic abnormalityCML is the result of an acquired genetic abnormalityA translocation between chromosome 9 and 22 t(9;22) the Philadelphia chromosomeThe oncogene BCR-ABL encodes an enzyme
5、 tyrosine phosphokinase (usually p210),Philadelphia Chromosome,More than 95% of patients with CML has Philadelphia (Ph) chromosome A subset of patients with CML lack a detectable Ph chromosome but have the fusion product for the BCR-ABL translocation detectable by reverse transcriptase- polymerase c
6、hain reaction (RT-PCR),The bcr/abl fusion protein,Uncontrolled kinase activity Deregulated cellular proliferation Decreased adherence of leukemia cells to the bone marrow stroma Leukemic cells are protected from normal programmed cell death (apoptosis),Clinical features,30 percent of patient are asy
7、mptomatic at the time of diagnosis Symptoms are gradual in onset: easy fatigability, malaise, anorexia, abdominal discomfort, weight loss, excessive sweating Less frequent symptoms: Night sweats, heat intolerance- mimicking hyperthyroidism, gouty arthitis, symptoms of leukostasis (tinnitus, stupor),
8、 splenic infartion (left upper-quadrant and left shoulder pain), urticaria (result of histamine release) Physical signs: Pallor, splenomegaly, sternal pain,Laboratory features,The hemoglobin concentration is decreased Nucleated red cells in blood film The leukocyte count above 25000/l (often above 1
9、00000/l), granulocytes at all stages of development Hypersegmentated neutrophils The basophiles count is increased The platelet count is normal or increased Neutrophils alkaline phosphatase activity is low or absent (90%),Laboratory features (2),The marrow is hypercellular (granulocytic hyperplasia)
10、 Reticulin fibrosis Hyperuricemia and hyperuricosuria Serum vitamin B12-binding proteine and serum vitamin B12 levels are increased Pseudohyperkalemia, and spurious hypoxemia and hypoglycemia Cytogenetic test- presence of the Ph chromosome Molecular test presence of the BCR-ABL fusion gene,Different
11、ial diagnosis,Polycythemia vera Myelofibrosis Essential thrombocytemia Extreme reactive leukocytosis,CML stages,In chronic phase, fewer than 10% of the cells in the blood and bone marrow are blast cells.Accelerated phase In accelerated phase CML, 10% to 19% of the cells in the blood and bone marrow
12、are blast cells.Blastic phase In blastic phase CML, 20% or more of the cells in the blood or bone marrow are blast cells. When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called blast crisis.,Treatment Prognostic factors,Sokal score = = (11x age + 35x spleen + 89x
13、blasts + 0,4x platelet 550)/1000Euro scale = = (0,666x age /0 when age / + 0,0420x spleen + 0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0 when basophils 3%/ + 1,0956x platelet /0 when platelet /) x 1000,EUTOS SCORE,The new EUTOS score predicts complete cytogenetic remission (CCgR) 18 m
14、onths after the start of therapy, which is an important predictor for the course of disease. Patients without CCgR at this point of treatment are less likely to achieve one later on and are at a high risk of progressing to blastic and accelerated phase diseaseThe strongest predictors for CCgR at 18
15、months are spleen size and percentage of basophils. Spleen size is measured in cm under the costal margin, basophils as their percent in peripheral blood. Both need to be assessed at baseline. Their relationship to CCgR is expressed by the formula: 7 * basophils + 4 * spleen size If the sum is great
16、er than 87, the patient is at high risk of not achieving a CCgR at 18 months, while a sum less than or equal to 87 indicates a low risk,Treatment,IKT (imatinib, nilotinib, dasatinib) Allo- SCT,Treatment Hydroxyurea,Often used initially for white cell count reduction Dose: 1-6g/d orally, depending on
17、 the hight of the white cell count The dose should be decreased to 1-2g/d when the leukocyte count reaches 20000/l Drug should be stopped if the white count falls to 5000/l Side effects: suppression of hematopoiesis, often with megaloblastic erythropoiesis,Treatment Interferon-alfa,In CML patients d
18、uring preganancy Patients with low risk (Sokal/Euro score) and high TRM, patient not eligible for alloSCT (treatment initiated before imatynib era) Dose: 3million units/m subcutaneously 3 days per week, and after 1 week 5 million u/m. Maximal dose: 5 million u/m per day. After maximal response (6-8
19、months) 3-5 million u/m once or twice weekly Dose should be reduced or teporarily discontinued if the white cell count less than 5000/l or platelet count less than 50000/l,Treatment Interferon alfa,Initial side effects of INFalfa: fever, fatigue, sweats, anorexia, headache, muscle pain, nausea, and
20、bone pain 50% of patients Later effects: apathy, insomnia, depression, bone and muscle pain, hepatic, renal and cardiac dysfunction, immunemediated anemia, thrombocytopenia, hypothyroidism, hypertriglyceridemia Hematologic improvement 75% of patients, cytogenetic remission 10%, molecular remission-
21、2% A polyethylene glycol-conjugated interferon-alfa (PEG-interferon)- better toleration, treatment once per week,CGP57148; STI571; imatinib; Glivec,Potent inhibition of Abl-K, c-kit and PDGF-RSalts are soluble in waterOrally bioavailableNot mutagenic,Cellular permeability,No PKC inhibition,TK inhibi
22、tory activity Stability to hydrolysis,Solubilisation,1992,Traetment Imatinib mesylate (Gleevec),Inhibits activity of mutant tyrosine kinase by blocking ATP binding Imatinib has less toxicity, is easier to administer, and induces higher hematologic (90 percent vs. 75percent), cytogenetic (40 percent
23、vs. 10 percent) and molecular (7% vs. 2 %) types of remission Dose: 400mg/d orally (maximal dose 600-800mg/d in two divided doses),Treatment Imatinib mesylate,Side effects: nausea, vomiting, edema, muscle cramps, diarrhea, headache, abdominal pain- usually low-grade The drug can be used prior the al
24、loSCT if eligible, or nonmyeloablative SCT for older patient,TK inhibitors 2007,Abl TK inhibitors Imatinib (Novartis) Nilotinib (AMN107, Novartis) Dual Abl/Src inhibitors Dasatinib (BMS 254825, Bristol-Myers Squibb) SKI-606 - bosutinib (Wyeth) AP23464 (Ariad Pharmaceuticals) AZD0530 (Astra-Zeneca) D
25、ual Abl/Lyn inhibitor NS-187 (INNO-406) (Nippon-Shinyaku) Non-ATP-binding inhibitors active against T315I ON 012380 (Onconova) VX-680 (Aurora kinase inhibitor) Merck 0457 - T315I SGX-70430 (SGX Pharma) GNF-2 (Genomics Novartis Foundation),Definitions of hematologic, cytogenetic, and molecular respon
26、se,European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML),Baccarani et al, Blood 2013;122:872-884,Baccarani et al, Blood 2013;122:872-884,European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML),Baccarani et al, Blood 2013;122:872-8
27、84,European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML),Baccarani et al, Blood 2013;122:872-884,European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia (CML),Baccarani et al, Blood 2013;122:872-884,CCyR rates for approved TKIs,Treatmen
28、t Early alloSCT,The early mortality in younger patient (below 40 years of age) 15 percent 5-year survival can be achieved in 60 percent of patients in chronic phase (some can be cured) There is 20 percent chance of relapse of CML in the years after succesful transplantation Donor lymphocyte infusion
29、 (DLI) can produce remission in transplanted patiens who have relapse of their disease,Treatment Risk of transplant-related mortality (TRM),Years,Probability of survival after HLA-matched sibling donor transplant for CML, by disease status and transplant year, 1998-2008,0,2,6,1,3,4,5,CP, 1998-2000 (N=2,302),Probability of Survival, %,CP, 2001-2008 (N=2,412),AP, 2001-2008 (N=314),AP, 1998-2000 (N=301),P 0.0001,
