The Leukemias
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
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
Blasts in peripheral blood smear and absence of normal blood counts
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
FAB Classification of de novo AL
Secondary leukemias preceeded by preleukaemic phase/mds
The majority of acute leukaemia is B-ALL in childhood
Difficulties to differentiate on the basis of morphology AML ALL Auer rods
L3 type leukemia AMoL AUL AMMoL
Cytochemistry POX positive AML Estereaze pozitive AML PAS positive ALL Acid phosphatase positive AML
Flow cytometry analysis based on CD antigen markers
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
Karyotype analysis
Chromosomal changes mean molecular alterations
Those with normal karyotype might have several molecular changes
WHO classification of AML 2008
FAB / WHO classification of AML
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.
Classical chemotherapy - mode of their action
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
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; 108:3271-9.) For ALL: adding L-asparaginaze 30.000 U/m2/10 d on d. 36-45. 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)
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
Comparison of results BMT/conventional chemotherapy survival>3 yrs % Allo-BMT Auto-BMT Chemoth Acute Myelogenous Leukemia 1st remission 30-70 30-60 20-50 2nd remission 30-50 20-40 <10 3rd remission 10-30 20 0 Acute Lymphocytic Leukemia 1st remission 40-60 20-40 10-50 2nd remission 20-40 20-30 <10 3rd remission 10-20 0
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 1.5-2 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
Chronic leukemias CLL as a low risk NHL will be discussed together with lymphomas CML will be discussed together with myeloproliferatives neoplasms,mpns