THE LEUKEMIAS. Etiology:

Transcription

1 The Leukemias

2 THE LEUKEMIAS Definition 1: malignant transformation of the pluripotent stem cell, successive expansion of the malignant clone from the bone marrow to the tissues Definition 2: Heterogenous group of malignancies involving clonal expansion of hematopoietic precursor cells that become arrested at various stages of maturation. Characteristics: maturation arrest (high blas counts) and pancytopenia: missing normal cells Classification: morphology, cytochemistry, cytogenetics, immunophenotype analysis, gene rearrangement, gene expression profile

3 THE LEUKEMIAS ACUTE AML and ALL (any ages) CHRONIC CLL and CML (in the elderly) Etiology: genetic predisposition (twins,downs syndrome) Known environmental mutagens(ionizing radiation,atomic bomb survivors, chemical exposure like cytostatic agents) Viruses: HTLV I,II in adult T cell leukemias, EBV in L3

4 Blasts in peripheral blood smear and absence of normal blood counts

5 symptomes 1/ in the absence of normal granulocytes: septic fever, oral/anal ulcers 2/ in the absence of enough platelet: bleeding 3/ in the absence of normal red blood cell count: anemia, fatique

6 FAB Classification of de novo AL

7 Secondary leukemias preceeded by preleukaemic phase/mds

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9 The majority of acute leukaemia is B-ALL in childhood

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11 Difficulties to differentiate on the basis of morphology AML ALL Auer rods

12 L3 type leukemia AMoL AUL AMMoL

13 Cytochemistry POX positive AML Estereaze pozitive AML PAS positive ALL Acid phosphatase positive AML

14 Flow cytometry analysis based on CD antigen markers

15 Cluster of Differentiation Subtype CD markers MO CD34,33,13 M1 CD 34,33,13 M2 CSD33,13,15 M3 CD33,13, HLA DR - M4 CD 34,33,15,14,13 M5 CD33,15,14,13 M6 CD33,glycophorin M7 CD33,41 L1 CD10,19,34,Tdt L2 CD10,19,34,Tdt L3 CD19,20,sIg

16 Karyotype analysis

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18 Chromosomal changes mean molecular alterations

19 Those with normal karyotype might have several molecular changes

20 WHO classification of AML 2008

21 FAB / WHO classification of AML

22 Summary of prognostic variables in AML factor favourable unfavourable age <45 yr >60 yr leukemia De novo Pre-MDS,MPS Surface markers Cytogenetics molecular markers CD34-,14-,13- T(15;17) t(8,21) inv (16) FLt-3 negatíve NPM: negatíve CD34+ -7/7q-,-5/5q-, complex FLt-3 pozitive NPM: pozitive 3.

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26 Classical chemotherapy - mode of their action

27 High dose ArA-C (HIDA) plus anthracyclin Superior to any other therapeutical options so far Dose intensification of Ara-C plus G-CSF administration Idarubicin anthracyclin: cardioprotection Best supportive care: anti-mycotics, antibiotics, antiemetics, All the above measures contributed to better outcome: 60-80% of 5 yrs survival

28 Novel therapies I. For Ph + AML: Gliveec *imatinib For relapsed and/or refractory AML: Hypomethylating agents: decitabine, azacitidine -DNA demethylating Decitabine(iv:15 mg/m2/10d), -Histon deacetylase inhibitor: valopric acid ( p.os:35mg/ttkg). Consequence: CR:20% (because the so far repressed p15 suppressor gene deliberated by hypomethylation)(blood 2006; 108: ) For ALL: adding L-asparaginaze U/m2/10 d on d and in late intenzification, provided better results. To introduce children ALL protocol in adult ALL gives better chances for cure (higher dose MTX, without Etoposide)

29 Promising new anticancer drugs. Best effect when applied in combination with HIDA Second generation purine nucleoside analogue: clofarabine Monoclonal antibodies: gemtuzumab: CD33-ab, Wilms tu-ab FLT-3 inhibitor: PKC-412 ( midostaurin) Farnesyl transferase inhibitor: tipifarnib,lonafarnib mtor inhibitors: sirolimus; rapamycin Antiangiogens VEGF INH : BCL-2 antisense oligonucleotid, bevacizumab, Proteosome inhibitors: bortezomib topoizomeraze INH: Topotecan

30 Comparison of results BMT/conventional chemotherapy survival>3 yrs % Allo-BMT Auto-BMT Chemoth Acute Myelogenous Leukemia 1st remission nd remission <10 3rd remission Acute Lymphocytic Leukemia 1st remission nd remission <10 3rd remission

31 BMT: autologous, allogenic; myeloablative/ric in AML in CR1- otherwise : 50-80% relapse Autolog SCT in CR1 MUD (HLA-matched unrelated donor) UC ( Umbilical cord) RIC it is to be considered: Age, average condition,cr1 or CR2, refractory disease, In 57 register more than 10 million donor Finding donor takes mos, time elapsing to BMT: 4 mos. Problems: 1/ autolog SCT: high relapse rate- absence of good GVL effect, 2/MUD with myeloablative preconditioning: GVHD, high transplant related mortality (TRM), 3/ UMb.Cord:transplant insufficiency, long repopulation time, but: no CMV infection,low GVHD, easy access, no harm for the donor, 4/ RIC: reduced intensitiy conditioning including TBI: for elderly not fit persons. For RIC OS at 2yrs 48%, 5/ haploidentic stem cell transplantation ( difference in at least 3 HLA locus-relativ) How to choose donor: good preformance status, age<55-60: myeloablative MUD, elderly, comorbidities: RIC

32 Chronic leukemias CLL as a low risk NHL will be discussed together with lymphomas CML will be discussed together with myeloproliferatives neoplasms,mpns