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ACUTE LEUKAEMIA

ACUTE LEUKAEMIA. by DR. FATIMA AL-QAHTANI CONSULTANT HAEMATOLOGIST. Congenital Defects Down syndrome Bloom Syndrome Monosomy 7 syndrome Klinefelter Syndrome Turner Syndrome Neurofibromatosis Congenital Dysmorphic Syndrome. Marrow Failure Syndromes Fanconi Anaemia

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ACUTE LEUKAEMIA

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  1. ACUTE LEUKAEMIA by DR. FATIMA AL-QAHTANI CONSULTANT HAEMATOLOGIST

  2. Congenital Defects Down syndrome Bloom Syndrome Monosomy 7 syndrome Klinefelter Syndrome Turner Syndrome Neurofibromatosis Congenital Dysmorphic Syndrome Marrow Failure Syndromes Fanconi Anaemia Dyskeratosis Congenita Schwachman – Diamond Syndrome Amegakaryocytic Thrombocytopenia Blackfan – Diamond Syndrome Kostmann Agranulocytosis Familial Aplastic Anaemia ACUTE MYELOID LEUKAEMIAETIOLOGICAL FACTORSGENETIC DISORDERS

  3. Solvents (benzene) Smoking Ionizing radiation Atomic bomb exposure Nuclear power exposure Medical radiation Non ionizing radiation Chemotherapy Alkylating agents Topoisomerase II inhibitors Other drugs Chloramphenicol Phenylbutazone ACUTE MYELOID LEUKAEMIAETIOLOGICAL FACTORSEnvironmental Factors

  4. Acute Myeloid LeukaemiaCLINICAL FEATURES • Increasing incidence with age. Median age at diagnosis is 50 years. • Symptoms are due to marrow failure (anaemia, infection, haemorrhage) or hyperleucocytosis. • Rarely presenting symptoms are due to chloromas or CNS involvement.

  5. Acute Lymphoblastic Leukaemia (ALL)Clinical Features ALL can occur at any age but has a peak incidence between 2 - 10 years. It is characterized by: • bone marrow failure • lymphadenopathy • thymic enlargement in T-lineage ALL • bone pains which may be associated with radiological changes and fractures • tendency to relapse in the CNS and testis.

  6. Acute Myeloid Leukaemia DEFINITION Acute Myeloid Leukaemia (AML) is currently defined by the FAB criteria. The percentage of blasts, the presence of cytochemical myeloperoxidase, the major cell types present defined by morphology and esterase cytochemistry & the immunophenotype define the 8 FAB subtypes

  7. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISMORPHOLOGY • Myeloblasts are usually medium sized with an eccentric nucleus and open chromatin. Cytoplasm shows variable basophilia. Few granules or Auer rods may be present. • Maturing granulocytes may be normal or show the dysplastic features seen inMDS. • Monoblasts are generally very large with abundant grey-blue or basophilic cytoplasm. Nuclei are round or lobulated, and are central in the cell. Fine azurophil granules may be present but Auer rods are rarely, if ever, present. • Promonocytes and monocytes show abnormal nuclear maturation, granulation and loss of basophilia.

  8. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISMORPHOLOGY (Cont…) • Erythroid precursors may be normal or show varying degrees of dyserythropoiesis. • Eosinophils may be present in varying numbers, with normal or abnormal morphology. Specific abnormal appearances are linked with cytogenetic abnormalities (e.g. inv 16) • Basophils are rarely increased in AML, and if present show abnormal or poor granule formation and nuclear maturation. • Megakaryocytes may be reduced or increased. Dysplastic hyperlobated, hypolobated, multinuclear, small and blastic forms may be present

  9. Acute Myeloid LeukaemiaFAB Subtypes

  10. Acute Myeloid LeukaemiaFAB Subtypes M0-M5:>20% myelo/monoblasts by morphology or immunophenotype. M6: >50% erythroid precursors, >20% blasts in non-erythroid cells. M7: >20% megakaryoblasts present. Note: Cytogenetics, molecular genetics, previous MDS or MPD, previous chemo- or radiotherapy and the presence of trilineage myelodysplasia do not have any place in the FAB system. All these features which contribute to the definition of prognostically important sub-groups is included in the new classification system.

  11. ACUTE MYELOID LEUKAEMIASWHOCLASSIFICATION • Acute myeloid leukaemia with reccurent genetic abnormalities Acute myeloid leukaemia witht(8;21)(q22;q22);(AML1(CBFa)/ETO) Acute myeloid leukaemia with abnormal bone marrow eosinophils inv (16)(p13q22) or t(16; 16)(p13;q22);(CBFb/MYH11) Acute promyelocytic leukaemia(AML with t(15; 17)(q22;q12)(PML/RARa) &variants Acute myeloid leukaemia with11q23(MLL) abnormalities • Acute myeloid leukaemia with multilineage dysplasia • Acute myeloid leukaemia and myelodysplastic syndromes, therapy related

  12. ACUTE MYELOID LEUKAEMIASWHO CLASSIFICATION • Acute myeloid leukaemia not otherwise categorized Acute myeloid leukaemia minimally differentiated Acute myeloid leukaemia without maturation Acute myeloid leukaemia with maturation Acute myelomonocytic leukaemia Acute monoblastic and monocytic leukaemia Acute erythroid leukaemias Acute megakaryoblastic leukaemia Acute basophilic leukaemia Acute panmyelosis with myelofibrosis Myeloid sarcoma • Acute leukaemia of ambiguous lineage Undifferentiated acute leukaemia Bilineal acute leukaemia Biphenotypic leukaemia

  13. M0 M1 M2 M3 M4 M5a M5b M6 M7

  14. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISCYTOCHEMISTRY • Myeloperoxidase (MPO): identify blast cells as myeloid. Auer rods are detected twice as frequently as on Romanowsky stains. Dysplastic neutrophils may be negative. Eosinophil granules are always positive. Monoblasts and promonocytes may be negative. Sudan Black B gives identical results. Myeloperoxidase (MPO)

  15. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISCYTOCHEMISTRY • Chloroacetate Esterase (CAE) specifically identifies cells of the granulocyte lineage, from the early promyelocyte stage to mature neutrophils. Chloroacetate Esterase

  16. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISCYTOCHEMISTRY • α -Naphthyl Acetate (Nonspecific) Esterase (ANAE) stains monocytes and megakaryocytes at all stages of maturation. Nonspecific Esterase

  17. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISCYTOCHEMISTRY • Periodic Acid Schiff (PAS) stains many cell types. It is not lineage specific but the pattern of staining may be helpful, e.g. positive monoblasts, NRBC, megakaryoblasts…

  18. Acute Lymphoblastic LeukaemiaLaboratory DiagnosisFAB Classification

  19. Acute Lymphoblastic LeukaemiaLaboratory Diagnosis

  20. Acute Lymphoblastic LeukaemiaLaboratory DiagnosisMorphology Blast morphology is variable • some are small with high nuclear / cytoplasmic ratios and indistinct nucleoli (so-called L1 blasts) • while others are larger with more prominent nucleoli and more abundant cytoplasm(L2). • A third type (L3) shows large blasts with moderately abundant highly vacuolated basophilic cytoplasm Blast morphology does not correlate with cell lineage and cytochemistry is of little value.

  21. Acute Lymphoblastic LeukaemiaLaboratory Diagnosis - FAB Classification ALL (L1) ALL (L2) ALL (L3)

  22. Acute Lymphoblastic LeukaemiaLaboratory Diagnosis CYTOCHEMISTRY PAS Ac. Phos (T-ALL)

  23. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISTREPHINE BIOPSY HISTOLOGY • Helpful when there is severe cytopenia and a dry tap, e.g. in megakaryoblastic AML. • Useful for identifying megakaryocyte dysplasia and dyserythropoiesis. • Immunophenotyping is possible when the diagnosis is in doubt. • Not suitable for fine classification which is based on percentages of cell types and cytological detail.

  24. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISFLOW CYTOMETRY • Myeloid blasts express combinations of CD34, CD13, CD33, CD117, HLA-DR, CD14, CD15. Glycophorin A and CD42b identify erythroid and megakaryocyte lineage blasts respectively. • Essential to separate undifferentiated AML (M0) from ALL. May need supplementation with APAAP staining for cytoplasmic immunoreactive MPO.

  25. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISFLOW CYTOMETRY (Cont…) • Essential for diagnosing biphenotypic leukaemias and detecting aberrant (promiscuous) antigen expression. • Can identify patient specific unique blast cell phenotypes. • Can identify blasts of megakaryocyte, erythroid, monocyte and granulocyte lineages. • Can identify leukaemic contamination of 'remission' marrow harvests. • Can identify early relapse.

  26. Acute Lymphoblastic LeukaemiaLaboratory DiagnosisFlowcytometry ALL is derived from precursor lymphocytes that are undergoing antigen receptor gene (Ig and TCR) rearrangement. B-lineage ALL The precursor nature of the cells is established by demonstrating lack of surface Ig, the presence of nuclear TDT and sometimes the expression of CD34. Sub classification is as follows: • Pre-pre B-ALL: CD19+ CD10- cytoplasmic mu heavy chain negative. • Common ALL: CD19+ CD10+ cytoplasmic mu present in <20% of cells • Pre B-ALL: CD19+ CD10+ cytoplasmic mu present in >20% of cells • Blasts of all subgroups will express cytoplasmic CD22 and CD79b.

  27. Acute Lymphoblastic LeukaemiaLaboratory DiagnosisFlowcytometry T-lineage ALL • The precursor nature of the cells is established by demonstrating TDT and sometimes CD34 positivity and the lack of surface TCR/CD3. • T-cell lineage is demonstrated by the expression of CD7 and/or CD1a. • Expression of the other pan-T cell markers is variable.

  28. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISIMMUNOHISTOCHEMISTRY / IMMUNOFLUORESCENCE • APAAP staining for cMPO, cCD3 and cCD79 should be done in all cases of undifferentiated acute leukaemia. • Immunofluorescent staining for nuclear PML protein should be done in all cases of suspected acute promyelocytic leukaemia. A microparticulate pattern is diagnostic of APML.

  29. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISCYTOGENETICS • An abnormal karyotype is found in 50-60% of AML cases at presentation. • t(15;17), t(8;21) and inv/del/t(16) are associated with specific morphology, younger patients and a good prognosis. • Complex karyotypes and abnormalities of chromosomes 5 and 7 are associated with older patients, trilineage dysplasia and a poor response to treatment. • Other karyotypic abnormalities are prognostically neutral.

  30. Acute Myeloid LeukaemiaLABORATORY DIAGNOSISMOLECULAR GENETICS • The 3 major good prognosis translocations are all detectable by RT-PCR, which can be used to detect up to 40% more cases than are found by metaphase cytogenetics. • All translocations with cloned breakpoint genes are theoretically detectable by RT-PCR. • Real time multiplex PCR may become available for routine diagnosis. • RT-PCR is used for monitoring speed of response to treatment and may be predictive for relapse

  31. Acute Lymphoblastic LeukaemiaLaboratory DiagnosisCYTOGENETICS Hyperdiploidy is common. A number of balanced translocations have been identified in ALL: • t(12;21) - this is the commonest translocation in ALL (30% of cases). It results in the TEL-AML fusion gene and is primarily associated with the common phenotype. • t(9;22) - this is commoner in adults and is associated with a very poor prognosis. • t(4;11) - this translocation results in the MLL-AF4 fusion gene. It is associated with pre-pre B-ALL and is associated with a poor prognosis. • t(1;19) - associated with pre-B ALL and results in the formation of the E2A-PBX fusion gene. These translocations are demonstrable by RT-PCR techniques. TAL-1 deregulation is the commonest genetic abnormality in T-ALL. This may occur as the result of the t(1;14) or more commonly due to chromosome 1p32 deletions.

  32. Acute Lymphoblastic LeukaemiaPROGNOSTIC FACTORS The following are poor prognostic factors in ALL: • age <1 year and >10 years • male sex • CNS disease at presentation • high white cell count • t(9;22) • t(4;11) • hypodiploidy

  33. Acute Lymphoblastic LeukaemiaOUTCOME AND THERAPY The treatment of ALL consists of the following "phases": • Remission induction - vincristine, prednisolone, daunorubicin, asparaginase. • Consolidation - various combinations of chemotherapeutic agents. • CNS directed therapy - high dose systemic and intrathecal methotrexate. • Maintenance therapy - vincristine, prednisolone, mercaptopurine and methotrexate for 2 years. Childhood ALL is associated with 75% long term survival. Minimal residual disease assessment using PCR based strategies appear to be able to predict relapse although they are not yet in routine clinical use. Allogeneic transplantation is the treatment of choice at relapse. The outlook in adult ALL is poor with approximately 20% long-term survivors. Allogeneic transplantation is advisable in first remission.

  34. ACUTE LEUKAEMIACLASSIFICATION • Acute lymphoblastic leukaemia Early pre-B-cell ALL Pre-B-cell ALL B-cell ALL T-cell ALL • Acute nonlymphocytic leukaemia Acute myelocytic leukaemia, minimally differentiated (AML-M0) Acute myelocytic leukaemia, without maturation (AML-M1) Acute myelocytic leukaemia, with maturation (AML-M2) Acute promyelocytic leukaemia (APL, AML-M3) Acute myelomonocytic leukaemia, (AMMoL, AML-M4) Acute monocytic leukaemia, (AMoL, AML-M5) Acute erythroleukaemia, (AEL, AML-M6) Acute megakaryocytic leukaemia, (AMegL, AML-M7) • Biphenotypic (mixed lineage) leukaemia • Acute undifferentiated leukaemia

  35. ACUTE LYMPHOBLASTIC LEUKAEMIABlast Cell Characteristics Early Pre-B CellPre-B CellB CellT Cell Gene rearrangement Heavy chain+* ++ - Light chain+/-+/-+- Immunologic features Cytoplasmic U -+ - - Membrane Ig - -+ - CD 10 (CALLA) + +/- +/-+/- Ia/HLA-DR + + + - CD24, CD19, CD20 + + + - CD2, CD5, CD7 - - - + Cytochemical features Nuclear TDT + + - + 5’-Nucleotidase + + - + Acid phosphatase - - - + Cytogenetic abnormalitiest(12;21)t(1;19)t(8;14), t(2;8), t(8;22)t(1;14), t(11;14), del(9p) Morphology FAB L1 90%90%10%95% FAB L2 10%10%15%5% FAB L3 0 075%0

  36. ACUTE NONLYMPHOBLASTIC LEUKAEMIABlast Cell Characteristics

  37. Myelodysplastic Syndrome (MDS)WHO Classification • There are 8 categories of MDS in the WHO system. • Refractory anemia (RA) • Refractory anemia with ringed sideroblasts (RARS) • Refractory cytopenia with multilineage dysplasia (RCMD) • Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) • Refractory anemia with excess blasts-1(RAEB-1) • Refractory anemia with excess blasts-2(RAEB-2) • Myelodysplastic syndrome, unclassified (MDS-U) • MDS associated with isolated del(5q)

  38. Myelodysplastic Syndrome (MDS)WHO Classification

  39. Myelodysplastic Syndrome (MDS)WHO Classification

  40. Etiologic Factors in Acute Leukaemia ---------------------------------------------------- Chromosome Abnormalities Down’s syndrome Bloom’s syndrome Fanconi’s anaemia Radiation Exposure

  41. Etiologic Factors in Acute Leukaemia (continued) ------------------------------------------------------------------------------------------------------------------------------------- Marrow Toxins 1. Benzene 2. Chloramphenicol 3. Phenylbutazone 4. Anticancer chemotherapeutic drugs, especially alkylating agents. Antecedent Hematopoietic Disorders 1. Paroxysmal nocturnal hemoglobinuria 2. Myelodysplastic syndromes (preleukemias) 3. Myeloproliferative disorders (chronic myelogenous leukaemia, polycythemia vera) -------------------------------------------------------------------------------------------------------------------------------------

  42. Clinical Manifestations • General • Related to anaemia, decrease WBC, decrease Plt. • Lymphadenopathy, hepatosplenomegaly: • Uncommon Big Spleen: AML blast crisis of CML • Organ infiltration • Rare: Granulocytic sarcomas • Uric Acid: Nephropathy, Gout • DIC: All forms especially promyelocytic (M3)

  43. Presenting manifestations of acute leukaemia ---------------------------------------------------------------------------------------------------------------------------------------------------- Common Anaemia Fever, malaise Haemorrhagic manifestations Less common Infection of the mouth and pharynx Pains in bones and joints (childhood especially) Upper respiratory tract infection (childhood especially) Superficial lymph node enlargement

  44. Presenting manifestations of acute leukaemia(continued) -------------------------------------------------------------------------------------------------------------------------------------------- Occasional Diarrhoea and/or vomiting Acute abdominal pain Mediastinal pressure (childhood) Nervous system manifestations Skin rash

  45. Acute Myelogenous Leukaemia (AML) Definition & Epidemiology ----------------------------------------------------- • It is also known as: Acute non-lymphoblastic leukaemia • A clonal malignant disease characterised by: - Proliferation of abnormal blasts in the BM. - Impaired production of normal blood cells.

  46. Acute Myelogenous Leukaemia (AML) Definition & Epidemiology (Continued) ----------------------------------------------------- • A neoplastic proliferation of: Haemopoietic stem cell. • Constitutes around 80% of adult cases. • There is no major differences in geographical incidence between urban and rural areas. • Slightly more common in males than females.

  47. Acute Myelogenous Leukaemia (AML) Diagnosis ----------------------------------------------------- • Complete Blood Count (CBC): * WBC: High, Normal, Low 30% of cases > 10 X 109/L Hypogranular neutrophils Blasts are usually seen * RBC & Hb: Low * Plat: Low

  48. Acute Leukaemia Morphological (FAB) Classification ------------------------------------------------------------------------------------------------------------------------------------------------------------ • Lymphoblastic (ALL): L1: Small, Monomorphic L2: Large, heterogenous L3: Burkitt-cell type • Myeloid (AML): M1: Myeloblastic without maturation. M2: Myeloblastic with maturation. M3: Hypergranular promyelocytic M4: Myelomonocytic M5: Monocytic: Poorly differentiated (M5a) Well differentiated (M5b) M6: Erythroleukaemia. M7: Megakaryoblastic

  49. Acute Leukaemia Cytochemical Reactions in AML & ALL

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