Acute Leukaemias PDF

ACUTE LEUKAEMIAS The term “Leukemia” is used to describe a group of malignant blood disorders resulting from clonal proliferation of haemopoietic stem cells in the bone marrow thereby leading to the accumulation of immature (blasts)or abnormal white blood cells in both peripheral blood and bone mar...

ACUTE LEUKAEMIAS The term “Leukemia” is used to describe a group of malignant blood disorders resulting from clonal proliferation of haemopoietic stem cells in the bone marrow thereby leading to the accumulation of immature (blasts)or abnormal white blood cells in both peripheral blood and bone marrow Leukamia is caused by the somatic mutation and malignant transformation of the BM pluripotent stem cells The neoplastic expansion in the BM results in the production of abnormal leukemic cells with impaired production of red cells, neutrophils and platelets The mutant clone usually demonstrate unique morphologic, cytogenetic and immuno-phenotypic features which can be used in classification, diagnosis and prognosis In acute leukemia, there must be presence of 20% or more blasts (immature cells) in the blood and bone marrow to make a diagnosis. Classification of leukemia Acute Chronic Myeloi d Acute Myeloid Chronic Myeloid Leukemia Leukemia (AML) (CML) origin Acute LymphoidLymphoblastic Chronic Lymphocytic Leukemia (ALL) Leukemia (CLL) origin  ALL naïve B-lymphocytes Plasma Lymphoid cells progenitor T-lymphocytes AML Hematopoietic Myeloid Neutrophils stem cell progenitor Eosinophils Basophils Monocytes Platelets Red cells Myeloid maturation myelobla promyelocyte myelocyte metamyelocyte band neutrophil st MATURATION Adapted and modified from U Va websit Classification of Acute Leukaemia Broadly divided into 2 groups:  Acute myeloblastic leukaemia (AML)  Acute lymphoblastic leukaemia (ALL) Has also been classified based on age of onset as :  Childhood leukaemias  Adult leukaemias Comparison of acute leukemia ALL AML mainly children mainly adults M > F M > F curable in 70% of children curable in minority curable in minority of adults of adults Clincal manifestations symptoms due to: marrow failure tissue infiltration leukostasis constitutional symptoms other (DIC) – Disseminated intravascular Coagulopathy usually short duration of symptoms ACUTE MYELOBLASTIC LEUKAEMIA(AML) Synonyms:  Acute Myeloid Leukaemia Acute myelogenous Leukaemia Acute myeloblastic Leukaemia AML is a malignant clonal disorder of the myeloid cell line involving the accumulation of myeloblasts in blood, bone marrow or other tissues The blasts often show either myeloid or monocytic differentiation About 80% of patients with AML will demonstrate chromosomal abnormalities There is 20% or more blasts present in blood and marrow Epidemiology  Can be found at any age  The incidence of AML increases with age  Accounts for 80% of acute leukaemia in adults and 20% of acute leukaemia in children  Although very rare, it is the predominant form of congenital leukaemia which occurs in the neonatal period (commonly associated with Down’s syndrome or Trisomy 21)  Incidence of AML is slightly higher in males than females  There is increased incidence in developed and more industrialized countries  There is very little difference in incidence between blacks and whites at any age Causes of acute myeloid leukemia idiopathic (most) underlying hematologic (myeloproliferative) disorders e.g. MDS, PNH, PRV, MF Chemicals (hydrocarbons) Benzene or petroleum products  drugs (cytotoxic drugs) ionizing radiation viruses (HTLV I) hereditary/genetic conditions e.g. Down’s syndrome, Turner’s syndrome, Klinefelter’s syndrome, Fanconi’s anaemia, frequency higher in monozygotic twins compared with dizygotic twins AML could be primary (de novo AML) or Secondary (MDS, PNH, MF, PRV)/chemical/drugs Clinical Features  The signs and symptoms in AML are related to the bone marrow suppression and organ infilteration by the malignant myeloblasts  symptoms due to:  marrow failure  tissue infiltration  Leukostasis from excessive accumulation of WBC in circulation  constitutional symptoms – fever, headaches, night sweats, anorexia, nausea, vomiting  Others - bleeding tendency from thrombocytopenia or DIC (AML M3)  usually short duration of symptoms (within weeks or few months if untreated Clinical Findings in Acute Leukemia Bone Marrow Infiltration Neutropenia Fever, infection Anemia Pallor, dyspnea, lethargy Thrombocytopenia Bleeding, petechiae, ecchymosis, intracranial hematoma and gastrointestinal or conjunctival hemorrhage (rare Medullary Infiltration Bone pain and tenderness, limp, Marrow arthralgia Extramedullary Infiltration Liver, spleen, lymph nodes, Organomegaly thymus Neurological complications Central nervous system including dizziness, headache, vomiting, alteration of mental function Gums, mouth Gingival bleeding and Skin hypertrophy Gum hypertrophy Purpuric/petechial rashes Subcutaneous nodule/chloromas/granulocytic sarcomas Classification AML is classified mainly based on the morphology of the myeloblasts/molecular and cytogenetic abnormalities There are 2 methods of classification:  French-American-British(FAB) classification  WHO classification FAB Classification of AML This divides AML into 8 types (M0 – M7) Designation Descriptive Name M0 Acute myeloblastic leukemia, minimally differentiated or undifferentiated myeloblasts M1FAB Classification of AML Acute myeloblastic leukemia with differentiated myeloblasts but without maturation M2 Acute myeloblastic leukemia with myeloblasts’ maturation M3 Acute promyelocytic leukemia, hypergranular M3 variant Acute promyelocytic leukemia, hypogranular, bilobed M4 Acute myelomonocytic leukemia M4 Eo Acute myelomonocytic leukemia with eosinophilia M5a Acute monoblastic leukemia, poorly differentiated M5b Acute monoblastic leukemia, with differentiation M6 Erythroleukaemia World Health Organisation (WHO) classification of AML Although the FAB classification has provided a morphological classification of AML for almost 30 years the correlation between morphology and both genetic and clinical features is imperfect. The WHO classification attempts to correlate morphological, genetic and clinical features to categorise cases of AML into unique clinical and biological subgroups WHO Classification Cont’d This divides AML into 5 categories/groups: 1. Acute myeloid leukemia with recurrent genetic abnormalities Acute myeloid leukemia with t(8;21) (q22;q22) Acute myeloid leukemia with abnormal bone marrow eosinophils- inv(16)(p13q22) or t(16;16)(p13;q22) Acute promyelocytic leukemia (AML with t(15;17)(q22;q12) Acute myeloid leukemia with 11q23 Cont’d 2. Acute myeloid leukemia with multi-lineage dysplasia -Following MDS or MDS/MPD - Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 or more myeloid lineages 3. Acute myeloid leukemia and myelodysplastic syndromes, therapy-related - Alkylating agent/radiation-related type - 2 Topoisomerase II inhibitor-related type (some may be lymphoid) - Others Cont’d 4. Acute myeloid leukemia not otherwise categorized Acute myeloid leukemia minimally differentiated Acute myeloid leukemia without maturation Acute myeloid leukemia with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma Cont’d 5. Acute leukemia of ambiguous lineage Undifferentiated acute leukemia Bilineal acute leukemia Biphenotypic acute leukemia Laboratory Investigations Full blood count – low PCV, WBCc and platelet counts Peripheral blood film – anaemia, neutropaenia, Thrombocytopaenia, myeloblasts > 20% Bone marrow aspiration – usually hypercellular (but could be normocellular or hypocellular), myeloblasts in excess of 20% Tests for DIC (PT, PTTK, TT, FDPs) are positive in AML M3 Serum and urinary lysozymes – raised in monocytic leukaemias Special cytochemical stains in AML - Sudan black (SB), myeloperoxidase(MPO) and esterase reactions(chloroacetate and non- specific esterase) stains are positive in AML and negative in ALL ( 60 yrs Onset of disease Primary (de novo) secondary BM response to CR or 20% blasts after induction after first course first course chemotherapy Take a Break !… 39 Acute Lymphoblastic Leukaemia (ALL) ALL results from accumulation of lymphoblasts in both peripheral blood and bone marrow It is the most common leukaemia in childhood though could still occur in adults Accounts for about 76% of all leukaemias diagnosed in children below 15 yrs More males are affected than females Aetiology The etiology of ALL is unknown in the vast majority of cases Environmental agents, such as ionizing radiation and chemical mutagens, have been implicated There is evidence to suggest a genetic factor in some patients. Children with Down syndrome have an increased risk of leukemia, particularly precursor B lymphoblastic leukemia Chronic exposure to childhood infections (mainly viral) has also been implicated Classification ALL may be classified based on - the morphology of the lymphoblasts - immunological markers present on the lymphoblasts Morphological Classification (French–American–British, FAB) L1 Small monomorphic type—small homogeneous blasts (high N:C ratio), with single inconspicuous nucleolus, regular nuclear outline; commonest subtype. L2 Large heterogeneous type (low N:C ratio)—larger blasts, more pleomorphic and multinucleolate, irregular frequently clefted nuclei with conspicuous nucleoli. L3 Burkitt cell type—large homogeneous blasts, abundant strongly basophilic cytoplasm with vacuoles; associated with B-cell phenotype. ALL L1 ALL L2 ALL L3 Immunological classification of ALL B lineage  Pro B-ALL: HLA-DR+,TdT+,CD19+ (5% children; 11% adults).  Common ALL: HLA-DR+,TdT+,CD19+,CD10+ (65% children; 51% adults). PreB-ALL:HLADR+,TdT+,CD19+,CD10―,cytoplasmic IgM+(15% children; 10% adults). B-cell ALL: HLA-DR+,CD19+,CD10―,surface IgM+ (3% children; 4% adults) T lineage  Pre-T ALL: TdT+, cytoplasmic CD3+,CD7+ (1% children; 7% adults).  T-cell ALL: TdT+, cytoplasmic CD3+, CD1a/2/3+,CD5+ (11% children; 17% adults). Clinical Features  Acute presentation is usual; child is often critically ill due to effects of bone marrow failure.  Symptoms of anaemia: weakness, lethargy, breathlessness, lightheadedness and palpitations.  Infection: particularly chest, mouth, peri-anal, skin (Staphylococcus, Pseudomonas, HSV, Candida). Patients will present with Fever, malaise, sweats.  Haemorrhage: purpura, menorrhagia and epistaxis, bleeding gums, rectal, retina.  Signs of leucostasis e.g. hypoxia, retinal haemorrhage, confusion or diffuse pulmonary shadowing Cont’d  Mediastinal involvement occurs in about 15% of patients and may cause SVC obstruction CNS involvement occurs in 6% of patients at presentation and may cause cranial nerve palsies especially of facial (VII) nerve, sensory disturbances and meningism. Signs include widespread lymphadenopathy in 55%, mild to moderate splenomegaly (49%), hepatomegaly (45%) and orchidomegaly. Investigations and diagnosis  FBC and blood film examination – will show normocytic normochromic anaemia, thrombocytopaenia, leucocytosis >50 x 109/L, presence of lymphoblasts on film >20%  Bone marrow aspirate± biopsy – hypercellular marrow with >20% lymphoblasts  Bone marrow cytogenetics – to detect presence of chromosomal abnormalities  Lumber puncture for CSF examination – to determine CNS involvement  Biochemical tests - ↑LDH, ↑Uric acid in serum, LFTs and renal funtion tests as baseline before starting chemotherapy  CXR – may show thymic or mediastinal Lymph Node enlargement  Immunophenotyping of blood or BM blasts Treatment of ALL Supportive treatment Provide explanation on the diagnosis and offer counselling Insertion of a central venous catheter for administration of drugs and blood products RBC and platelet transfusion support - will continue throughout the treatment period Start neutropenic regimen either as prophylaxis or active treatment against infections – antibiotics, antifungal or antiviral agents Start allopurinol to prevent hyperuricaemia and tumor lysis syndrome Prevent vomiting by using antiemetic drugs – metoclopamde or chlorpromazine Specific treatment Treatment for ALL consists of four contiguous phases: 1. Remission induction using vincristine, prednisolone, daunorubicin and L-Asparaginase to achieve complete remission 2. CNS prophylaxis - generally combines cranial irradiation and/or intrathecal (IT) chemotherapy (methotrexate ― cytarabine or prednisolone given early in the consolidation phase 3. Consolidation therapy - to reduce tumour burden further and reduce risk of relapse and development of drug-resistant cells. May be followed by Allogeneic SCT Maintenance therapy - necessary for all patients who do not proceed to a stem cell transplant Prognostic Factors in ALL Parameter Good Poor TWBC at diagnosis Low (< 50x109/L) High >50x109/L) Sex Female Male Age Children Adults or infants < 2yrs Immunophenotype cALL B-ALL Cytogenetics Normal or Ph+ or hypoploidy hyperploidy CNS disease Absent Present Biphenotypic Acute leukaemias A minority of acute leukaemias (~7%) have two distinct leukaemic cell populations on phenotyping and are characterised as biphenotypic leukaemias Most commonly these cell populations express B-lymphoid and myeloid markers These patients have variable response rates Choice of treatment protocol may be problematic Summary Points Leukemia is caused by the mutation of the bone marrow pluripotent stem cells. Individuals with acute leukemia will present with variable white counts, anemia, and low platelet counts. When blasts cells accumulate in the bone marrow and peripheral blood, the leukemia is classified as acute. Hepato-splenomegaly or lymphadenopathy is more prominent in chronic leukemias than in acute leukemias. According to the WHO, the peripheral smear must contain 20% myeloblasts or greater for a diagnosis of acute leukemia. Cytochemical staining can assist in the diagnosis and differentiation of acute leukemias based on the staining patterns of the blasts.  END OF LECTURE-----------------