This document discusses acute leukemias, focusing on acute myeloid leukemia (AML). It defines AML and describes its classification, epidemiology, etiology, pathophysiology, symptoms, diagnostic tests, prognostic factors, and management. Specifically:
1. AML is a heterogeneous group of malignant disorders characterized by uncontrolled clonal proliferation and accumulation of blast cells in the bone marrow and tissues.
2. It is classified based on morphological features and genetic abnormalities. Common subtypes include AML with t(8;21), inv(16), and t(15;17).
3. Prognostic factors that determine treatment include age, white blood cell count, and cytogenetic risk factors
This document discusses acute leukemias, focusing on acute myeloid leukemia (AML). It defines AML and describes its classification, epidemiology, etiology, pathophysiology, symptoms, diagnostic tests, prognostic factors, and management. Specifically:
1. AML is a heterogeneous group of malignant disorders characterized by uncontrolled clonal proliferation and accumulation of blast cells in the bone marrow and tissues.
2. It is classified based on morphological features and genetic abnormalities. Common subtypes include AML with t(8;21), inv(16), and t(15;17).
3. Prognostic factors that determine treatment include age, white blood cell count, and cytogenetic risk factors
This document discusses acute leukemias, focusing on acute myeloid leukemia (AML). It defines AML and describes its classification, epidemiology, etiology, pathophysiology, symptoms, diagnostic tests, prognostic factors, and management. Specifically:
1. AML is a heterogeneous group of malignant disorders characterized by uncontrolled clonal proliferation and accumulation of blast cells in the bone marrow and tissues.
2. It is classified based on morphological features and genetic abnormalities. Common subtypes include AML with t(8;21), inv(16), and t(15;17).
3. Prognostic factors that determine treatment include age, white blood cell count, and cytogenetic risk factors
This document discusses acute leukemias, focusing on acute myeloid leukemia (AML). It defines AML and describes its classification, epidemiology, etiology, pathophysiology, symptoms, diagnostic tests, prognostic factors, and management. Specifically:
1. AML is a heterogeneous group of malignant disorders characterized by uncontrolled clonal proliferation and accumulation of blast cells in the bone marrow and tissues.
2. It is classified based on morphological features and genetic abnormalities. Common subtypes include AML with t(8;21), inv(16), and t(15;17).
3. Prognostic factors that determine treatment include age, white blood cell count, and cytogenetic risk factors
ACUTE LEUKEMIAS • Define : heterogenous group of malignant disorders which is characterised by uncontrolled clonal proliferation and accumulation of blasts cells in the bone marrow and body tissues • Sudden onset • If left untreated is fatal within a few weeks or months ACUTE LEUKEMIAS • Classification : – Acute • Acute lymphoblastic leukemia (T-ALL & B-ALL) • Acute myeloid leukemia ACUTE MYELOID LEUKEMIA Definition • Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Acute Leukaemogenesis
• Immune response - T and B lymphocytes - NK cells Pathophysiology • Acute leukemia cause morbidity and mortality through : – Deficiency in blood cell number and function – Invasion of vital organs – Systemic disturbances by metabolic imbalance Pathophysiology Deficiency in blood cell number or function results in: • Infection - Most common cause of death - Due to impairment of phagocytic function and neutropenia Pathophysiology Deficiency in blood cell number or function results in:
Hemorrhage - Due to thrombocytopenia or 2o DIC or liver disease Anaemia - normochromic-normocytic - severity of anaemia reflects severity of disease - due to ineffective erythropoiesis Pathophysiology Invasion of vital organs (brain, lungs) associated with: 1. Hyperleukocytosis: - causes increase in blood viscosity - predisposes to microthrombi or acute bleeding
2. Leucostatic tumour - Rare - in vascular system forms macroscopic pseudotumour –> erode vessel wall cause bleeding Pathophysiology Metabolic imbalance: due to disease or treatment - Hyponatremia vasopressin-like subst. by myeloblast - Hypokalemia due to lysozyme release by myeloblast - Hyperuricaemia- spont lysis of leukemic blast release purines into plasma Epidemiology • 75-80% of acute leukemias • Incidence: variable (1.8-3/100,000) • Rare in childhood (10%-15%) Differentatial diagnosis 1. Reactive leukocytosis 2. Mononucleosis 3. Blast crisis CML 4. Bone marrow aplasia 5. CLL Diagnostic tests • Anamnesis + physical examination • Blood test results + manual smear blood • Blood type • Biochemical and coagulation test results • Imaging studies ( usg, chest radiography) • Lumbar puncture to detect leukaemic cells in the cerebrospinal fluid, indicating involvement of the CNS(ALL and AML M4&M5) + histopathological examination & flow cytometry Diagnostic tests 1. BM aspiration biopsy a/ ≥ 20% blasts in the smear b/ cytochemical study( reactions: POX, PAS, esterase, Sudan) c/ immunophenotyping ( cluster of differentation-CD): - immune type - prognostic factors - MRD d/ genetic tests: - cytogenetic (classical, FISH) - molecular (PCR) 2. Trepanobiopsy (histopathology) Clinical symptoms * anemia- normochromic, normocytic * granulocytopenia (WBC –high (usually) >200x109/l, WBC-low (less) <1.0x109/l and presence of blasts in PB * thrombocythopenia : <10x109/l
* bleeding disorder * fewer of unknown origin * infections * weakness Clinical symptoms • splenomegaly • hepatomegaly • lymphadenopathy • skin infiltration • bone pain • signs of CNS seizure • metabolic disorders : hypercalcemia, hyperuricemia • thromboembolic complications • DIC Clinical symptoms-leukemic infiltration in the tissues Clinical symptoms-bleeding disorder Classification of AML
• FAB classification- based on morphological features,
completed by cytochemistry and immunophenotyping
• WHO classification - based on genetic abnormalities FAB Classification M0 minimally differentiated acute myeloblastic leukemia M1 acute myeloblastic leukemia, without differentation M2 acute myeloblastic leukemia, with granulocytic maturation t(8;21)(q22;q22), t(6;9) M3 promyelocytic, or acute promyelocytic leukemia (APL) t(15;17) M4 acute myelomonocytic leukemia inv(16)(p13q22), del(16q) M4eo myelomonocytic together with bone marrow eosinophilia inv(16), t(16;16) M5 acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b) del (11q), t(9;11), t(11;19) M6 erythroid leukemia, including erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b) M7 acute megakaryoblastic leukemia t(1;22) M8 acute basophilic leukemia WHO Classification Acute myeloid leukemias with specific genes alterations AML with t(8;21)(q22;q22)(AML1/ETO) AML with inv(16)(p13;q22) or t(16;16)(p13;q22)(CBFβ/MYH11) APL with z t(15;17)(q22;q21)(PML/RARα) and variants AML with 11q23 (MLL); t(9;11)(p22;q23)(MLLT3/MLL) AML with t(6;9)(q23;q34)(DEK/NUP214) AML with inv(3)(q21;q26.2) or t(3;3)(q21;q26.2)(RPN1/EVI1) Acute megakaryoblastic leukemia with t(1;22)(p13;q13)(RBM15/1MKL1) AML with NPM1 mutation AML with CEBPA mutation WHO Classification II. AML followed by MDS lub MDS/MPD III. AML associated with the previous treatment IV. Myeloid sarcoma V. AML associated with Down syndrome Prognostic factors at the time of the diagnosis High risk 79% (CR: 40-60%, EFS: 5-10%) - meet any of the criteria: * age >60 years old * severe state at the diagnosis * secondary AML * Initial leukocytosis >20G/l * Unfavorable cytogenetic factors: 11q23, del9q, monosomy 5, 7, del(5q), del(7q), t(3,3), inv(3), t(6,9), t(9,22), 20q, 21q, 17p, complex karyotype changes ≥ 3 Prognostic factors at the time of the diagnosis Intermediate 16% (CR: 70 - 80%, EFS: 20-40%)
Patients non meeting two other criteria with:
normal karyotype, trisomy +8, +6, +21, +22, del-Y
Prognostic factors at the time of the diagnosis Favorable 5% (CR: 80-90%, EFS: 50-70%) - meet all of the criteria: * age <60 years old * good initial state * AML de novo * leukocytosis <20G/l * favorable cytogenetic alterations: t(8,21), inv(16), t(16,16), t(15,17), t(11;17), t(15;17), dup(17) Management Supportive care 1.Central venous catheter inserted to : • facilitate blood product • adm. of chemotherapy and antibiotics • frequent blood sampling Management 2.Blood support : • platelet con. for bleeding episodes or if the platelet count is <10x109/l with fever • fresh frozen plasma if the coagulation screen results are abnormal • packed red cell for severe anaemia Management 3.Prevention and control infection • barrier nursed • Intravenous antimicrobial agents if there is a fever or sign of infection Specific Treatment Cytotoxic chemotherapy. • Aim : • To induce remission • (absence of any clinical or conventional laboratory evidence of the disease) • To eliminate the hidden leukemic cells Specific treatment • Anti-metabolites – Methotrexate – Cytosine arabinoside • Act: inhibit purine & pyrimidine synt or incorp into DNA • S/E : mouth ulcer, cerebellar toxicity • DNA binding – Daunorubicin • Act : bind DNA and interfere with mitosis • S/E : Cardiac toxicity, hair loss Specific treatment • Mitotic inhibitors – Vincristine – Vinblastine • Act : Spindle damage, interfere with mitosis • S/E : Neuropathy, Hair loss • Others – Corticosteroid • Act : inhibition or enhance gene expression – Trans-retinoic acid • Act : induces differentiation First step of AML treatment
Remission induction: 1012 of blasts (1kg) -> 109
of blasts (1g)
Complete remission(CR): < 5% blasts in the BM, normal blood test results, no changes in physical examination
APL : AIDA regimen (Tretynoin + Idarubicin)
Other regimens: DA 3+7 (Daunorubicin + Cytarabin)
PALG: DAC (Daunorubicin + Cytarabin + Cladribine) The next steps of AML treatment Consolidation of remission: 109 of blasts (1g)-> <1012 of blasts (1kg) -> <106 of blasts (1 mg) Regimens with HD Ara-C
Maintenance - Elderly patients - AML associated with low risk of relapse
● The most common type before the age of 15 and at the same time represents 76% of all acute leukemias in this age group, peak disease - 2-5 years (6.2 per 100 000) ● The lowest incidence at age 25-45 years (0.4 per 100 000) later, steady growth (2.4 per 100 000 - more than 75 years) ● Adult ALL represents about 20% of all types of acute leukemias Morphology of lymphoblasts Types L1, L2, L3 acc. FAB Morphology of lymphoblasts Types L1, L2, L3 acc. FAB The FAB classification
WHO proposed classification of acute lymphoblastic leukemia cytogenetic subtypes Precursor B ALL I. ALL with strictly specified genetic abnormalities t(9;22)(q34;q11.2); BCR-ABL t(v;11q23); rearangements within MLL t(12;21)(p13;q22); TEL-AML1 ALL associated with hyperdiploidy ALL associated with hypodiploidyr t(5;14)(q31;q32)IL-3-IGH t(1;19)(q23;p13.3) E2A-PBX1 II. Precursor B ALL non specified III. Precursor T ALL ALL BCR/ABL+ Clinical characteristics: ● ALL BCR/ABL+ -elderly patients
● pre-B with co-expression of CD34, CD13, CD33 >T-ALL (< 1% vs 22%)
● associated with WBC (58,0 G/l vs 49,0 G/l)
● frequent infiltration of CNS (in relapse)
● OS (22% vs 41%) MRD investigation in ALL ● MRD (Minimal residue disease) -> only genetic/flow cytometric tests can reveal the presence of blasts when complete hematological remission was achieved ● Persistent cell blasts can cause leukemia and full relapse (60-70%)
● Other tests: 1. Immunophenotyping - allows the detection of a 1 leukemic cell in 1,000 -10,000 marrow cells (0.1 to 0.01%) and may use two strategies : - a qualitative study based on the phenotype aberrantny(„quadrans”) - quantitative study based on a study power of expression of antigens („empty spaces”) 2. RQ-PCR - to detect rearrangments within the genes encoding immunoglobulin(B- ALL), TCR (T-ALL)/ rearrangments in fusion genes like BCR/ABL+ This method allows the detection of a 1 leukemic cell in 100000 - 1 mln of bone marrow cells (0,001% do 0,0001%) Risk in ALL acc. PALG Standard risk (SR) Meet all of the criteria: • Age < 35 years old • WBC < 30 G/l • common lub pre-B lub cortical-T • Ph(-) / BCR/ABL(-) • t(4;11)(-) / MLL/AF4(-) • MRD(-) post induction/or consolidation
High risk(HR) meet only one criteria: • Age > 35 years old • WBC > 30 G/l • pro-B lub mature-B lub pro-T lub pre-T lub mature-T • Ph(+) / BCR/ABL +) • t(4;11)(+) / MLL/AF4(+) • MRD(+) post induction/or consolidation • no CR after one induction Treatment - Induction I
Pre-treatment Prednisone 60 mg/m2 po (≥ 35 lat: 40 mg/m2); days: -7 do -1
Induction - EVAP Prednisone 60 mg/m2 po (≥ 35 lat: 40 mg/m2); dni 1 do 28 Vincristin 1,5 mg/m2 (do 2 mg); days: 1, 8, 15, 22 Epirubicin 50 mg/m2 (≥ 35 lat: 40 mg/m2); days: 1, 8, 15, 22 Peg-Asparaginase 1000 IE/m2 ; day 13
3 x lumbar puncture with administration of MTX / Ara-C / Dexa
In case of agranulocytosis – G-CSF
After 34-35 days – control BM biopsy -> clinical response and MRD Post remission ALL
Standard risk group
Consolidation Remission maintenance– evaluation of MRD every 3 months.
High risk group
Patients with donors (related/unrelated) – allo Patients without donors– auto Patients with ALL Ph+, without donors– autoBMT with administration of imatinib and searching for a donor (then alloBMT) Novel drugs Cytostatics Clofarabine, nelarabine, forodesine
Hypomethylating drugs Azacytidine, decytabine
Monoclonal antibodies gemtuzumab (anty- CD33)
TKI Imatinib, dazatinib, nilotinib, FLT3 inhibitors (ABT-869; AC 220)
Farnesyltransferase inhibitors Tipifarnib Thank you
