Haematology - Leukaemia Acute and Chronic Flashcards
List the four (4) main factors on which the classification of leukaemia is based (2)/ List the four (4) laboratory characteristics used in the diagnosis of haematological malignancies according to the WHO classification that can be used to differentiate CLL from other lymphoproliferative disorders (4x0.5 = 2)
Morphology, Immunophenotype, Cytogenetics, Molecular abnormalities
Outline three (3) environmental factors (with examples) that may be involved in the aetiology of leukaemia (3) (Super NB!)
Radiation – Previous radiotherapy and nuclear accidents increase the risk of secondary malignancies including acute leukaemia
Viruses – HIV, HTLV1 and Adult T-Cell Leukaemia/Lymphoma
o Leukemogenicity of viruses have been proven in various animal models & more conclusive proof is now emerging in humans
o HTLV 1 retrovirus is proven to transform human T- cells leading to adult T-cell leukaemia/lymphoma
o Epstein Barr virus is responsible for the development of endemic Burkitt’s lymphoma and has also now been proven to be the etiologic agent in Hodgkin’s lymphoma
Drugs – Prior treatment with chemotherapeutic drugs have increased incidence
Chemicals – Benzene and alkylating agents may cause secondary leukaemia
o Chemotherapeutic agents like alkylating agents which are widely used in treating leukaemia are themselves leukemogenic and can lead to secondary acute leukaemia
o Benzene is myelotoxic and leads to aplastic anaemia in certain cases while others develop acute leukaemia after exposure
o Smoking increases the risk for acute leukaemia
Describe three (3) features that determine the phenotype of a leukaemia (4½) (Super NB)
Cell lineage involved: Myeloid vs lymphoid
Proliferative rate: High proliferative rate in acute leukaemias, lower proliferative rate in chronic leukaemias
Degree of differentiation of the daughter cells in the malignant clone.
o Acute leukaemia: Accumulation of undifferentiated cells (blasts)
o Chronic leukaemias: Differentiation to mature cells.
Degree of apoptosis: Reduction in apoptosis may contribute to accumulation malignant cells.
Tabulate four (4) fundamental differences between acute and chronic leukaemia (4) (Super NB)
Age: All vs most elderly
Onset: Rapid vs slow
Progression: Immediately life-threatening vs slow (may live for years)
Cell origin: Early immature cells vs more mature cells
Treatment: Intense high dose chemo regimes vs lower less intense/biological/small molecules
In your opinion, is Mr Brink more likely to have acute or chronic leukaemia? List 3 features from his case to justify your answer (2)
Acute leukaemia. High blast count, No differentiation, No splenomegaly or lymphadenopathy, Short clinical history.
List the investigations that can be used to identify the type of leukaemia (2)
Blast morphology, Cytochemical stains (detect cell enzymes), Immunophenotyping (cell surface antigen detection), Cytogenetic analysis
Outline why it is important to determine the type of leukaemia a patient has [1]/ Outline why it is critically important to make an accurate diagnosis of the type of acute leukaemia (1) (Super NB)
Treatment regimen and prognosis differ for different types.
Briefly classify the leukaemias (3)
Acute: Lymphoid vs. Myeloid. Chronic: Lymphoid vs. Myeloid
An 18-year-old male presents with persistent pallor, fatigue and a sore throat. His GP requests a Full Blood Count (FBC) and a Differential Count (DIFFT). The results are as follows: FBC: WCC 100 HB 6.5 MCV 80 PLT 21. DIFFT: 75% blasts
State the diagnosis (1)
Acute leukaemia
List clinical features present that would alert you to consider acute leukaemia in your differential diagnosis (2½)
Tiredness, Epistaxis, Short duration of symptoms, Pallor, Bruises
List five (5) clinical features (symptoms and signs) that may be present at diagnosis of acute leukaemia (2) (Super NB)
Anaemia (Tiredness, pallor, etc.), Thrombocytopaenia (Bleeding gums, bruises etc.), Neutropaenia (Opportunistic infections), Hepatosplenomegaly, Lymphadenopathy, Testicular enlargement/ swelling, Bone pain, Gum hypertrophy
List the abnormalities in a patient’s Full Blood Count and Differential Count that would make leukaemia a likely diagnosis (2½)
Marked anaemia, Thrombocytopenia, High WBC, Neutropenia, Blasts
Identify 4 clinical and 4 laboratory features found in Dylan that alerted Dr Opperman to the possible diagnosis of acute leukaemia [8x½ = 4]
Clinical Laboratory
Tiredness Anaemia
Bruising Thrombocytopaenia
Gum bleeding Neutropaenia
Lymphadenopathy Blasts on differential count
Patients with acute leukaemia are predisposed to infections. Identify the reason [½]
Neutropaenia
List any four (4) specific presenting features and the underlying mechanism thereof in a patient with acute leukaemia (4) (NB)
Anaemia, bleeding tendency, infections. Mechanism = Bone marrow infiltration leading to decreased production of blood cells.
Gum hypertrophy, lymphadenopathy, splenomegaly, CNS disease. Mechanism = Tissue infiltration by leukaemic blasts
Outline the mechanisms of the patient’s: (2)
i) Anaemia and thrombocytopaenia (1)
ii) hepatomegaly and splenomegaly (1)
Bone marrow failure owing to marrow infiltration.
Infiltration of liver and spleen by leukaemic blasts
List six (6) clinical features commonly associated with ALL (3) (NB)
Bleeding, Infection, Anaemia/Tired, Pain – bone, Lymphadenopathy, Hepatosplenomegaly, Fever, CNS disease
Identify 4 clinical features in Mr Brink that would alert you to consider leukaemia in your differential diagnosis. For each, state the laboratory result that you think identifies the cause of the clinical feature (4)
Tiredness (low Hb), Pallor (low Hb), Nose bleeds (low platelets), Petechiae and bruises (low platelets)
List ten (10) clinical features (symptoms and/or signs) that may be found in patients with ALL & For each, state the reason why it occurs (15)
Bone marrow failure
Anaemia – pallor, lethargy, dyspnoea
Neutropenia – fever, malaise, infections
Thrombocytopenia – bruises, purpura, epistaxis
Organ infiltration
Bone pain
Lymphadenopathy
CNS disease – meningism (neck stiffness), headache
Testicular swelling
Mediastinal compression – shortness of breath
List four (4) clinical features present in Siyamthanda, which would cause you consider leukaemia in the differential diagnosis (4x½ =2)
Tiredness, Bleeding gums, Pallor, Lymphadenopathy, hepatosplenomegaly
List four (4) clinical features present in Sarah, which would have alerted you to the possibility of a diagnosis of leukaemia. For each, state the cause of that feature (4)
Sore legs (bone pain) – marrow infiltration
Gums bleeding – thrombocytopenia
Pallor – anaemia from marrow infiltration
Lymph node enlargement – leukaemic infiltration
Splenomegaly – leukaemic infiltration
Explain why Vuyo has an enlarged spleen and lymph nodes (1)
These organs are enlarged as a result of infiltration by the malignant cells.
List four (4) clinical features in Ms Dastile that would alert you to consider leukaemia in your differential diagnosis.
For each, state the laboratory result which reflects the probable cause of the clinical feature (4)
Tiredness - anaemia
Menorrhagia - thrombocytopenia
Nose bleed
Petechiae
Pallor - anaemia
Enlarged lymph nodes – blasts in blood – leukaemic infiltration
Recurrent infections-decreased functioning WBC
List five (5) clinical features present in Ms Siwisa that would cause you to consider leukaemia in the differential diagnosis. b) For each symptom or sign state the underlying cause/s (5
Tiredness – anaemia
Swollen gums (hypertrophy) – leukaemic infiltration
Bleeding gums - thrombocytopenia
Petechiae - thrombocytopenia
Splenomegaly – leukaemic infiltration
List four (4) common presenting features of CLL
Coincidental (asymptomatic), Lymphadenopathy, Tiredness, Abdominal discomfort (Hepatosplenomegaly), Recurrent infections, Haemolytic anaemia
Define the term pancytopaenia [1]
The reduction of all three major haemopoietic cells lines - Erythrocytes (red blood cells), leucocytes (white blood cells), platelets.
List three (3) causes of pancytopaenia [1.5]
Bone marrow infiltration (e.g. leukaemia, lymphoma, metastatic tumour), Aplastic anaemia, Infection (e.g. disseminated TB; RVD), Megaloblastic anaemia
Following cytotoxic chemotherapy the full blood count showed low haemoglobin, white cell and platelet counts [3]
What is the most likely reason for the patient’s low blood count? [1]
Explain briefly why the patient may now be more susceptible to infections [2]
Cytotoxic effect of chemotherapy preventing bone marrow from replenishing blood cells.
The neutrophil count is markedly decreased. This results in immunosuppression predisposing the patient to opportunistic infections.
List three (3) features of bone marrow failure. For each, state the clinical consequences and the method of treatment (4½)
Anaemia with fatigue and pallor – RBC XF
Neutropenia and susceptibility of infections – Antibiotics
Thrombocytopenia causing bleeding – Platelet XF
Outline why the antigens present on the surface of leukaemic cells must be analysed in new cases of acute leukaemia (2) (NB)
To determine the cell lineage (½) of leukaemic cells, which is essential for accurate diagnosis (½), treatment (½) & prognosis (½)
Outline two (2) molecular mechanisms that may give rise to acute leukaemia (2)
Gain of function of proto-oncogenes, Mutations in tumour suppressor genes, Defects in apoptotic pathway so cells do not die but accumulate.
Outline the pathogenesis of Acute Leukaemia (4)
- Malignant transformation occurs at level of haemopoietic stem cell or early progenitor cell.
- Genetic damage results in…
o Excessive proliferation of malignant cells
o Reduced apoptosis
o Block in cellular differentiation - Together these together result in the accumulation of blasts in the bone marrow, which then may accumulate in blood and other tissues (e.g. spleen, lymph nodes)
State three (3) laboratory features that support this diagnosis (AL) (1½)
Low Hb, Low platelets, 89% blasts on peripheral blood
List four (4) specialised laboratory investigations you would recommend when investigating a new case of possible acute leukaemia, and for each explain how it would assist you in making an accurate diagnosis (6)
FBC, Morphology, Cytochemistry, Cytogenetics, Bone marrow biopsy, Immunophenotyping, Genetic studies, Renal function & electrolytes, DIC screen (3)
List four (4) laboratory investigations that may be used to identify the type of acute leukaemia (4) For each test, state a result that may be found in AML & ALL respectively (8) (Super NB)
AML ALL
Blast morphology on blood or marrow smear
Auer rods No Auer rods
Cytochemical staining of blasts (detect cell enzymes) MPO positive MPO negative
Immunophenotyping (cell surface Ag detection)
CD33 etc. T or B cell markers
Cytogenetic analysis t(15;17), t(8;21) etc t(4;11) or t(8;14)
Molecular analysis (PCR or FISH)
Outline two (2) morphological differences between ALL and AML blasts (2)
AML blasts: Cytoplasm with granules and auer rods. ALL blasts: Cytoplasm with no granules and no auer rods
State four (4) factors that may influence the prognosis of acute leukaemia. (4x½ = 2)
Age (older patients fare worse than younger), High WBC, Cytogenetics of malignant cells, Time taken to respond to induction chemotherapy
List three (3) factors that influence the prognosis in acute leukaemia (1½)
AML Cytogenetics of the malignant cells Performance status of patient Age Primary vs secondary AML White cell count at diagnosis Response to induction chemotherapy Prognosis is also affected by the type of therapy:
ALL (NB)
Age >35yrs
High white cell count at diagnosis
CNS disease at presentation
Certain cytogenetic abnormalities such as t(9;22) and t(4;11)
If it takes more than 4 weeks of induction chemotherapy to achieve remission
Briefly explain why the chromosomal analysis of the leukaemic cell is important in the diagnosis of acute leukaemia. Give one (1) example (3)
The presence of certain cytogenetic abnormalities is important for the diagnosis, treatment and prognosis of the leukaemia. Examples in the computer tutorial.
List four (4) types of chromosomal abnormalities that may be found in acute leukaemia (2)
Hyperdiploidy, Hypodiploidy, (gain or loss of chromosomes), Deletions, Translocations
Outline 4 (four) medical interventions (other than chemotherapy) used in the management of Acute Leukaemia (4)/ Outline three (3) complications of acute leukaemia and/or its treatment, stating the management in each case (3) (Super NB)
Anaemia: Red blood cell transfusions (filtered irradiated packed red cells to maintain Hb >8g/dl)
Thrombocytopenia: Platelet transfusions if indicated
DIC: Supportive – FFP and cryoprecipitate
Prevention of infections (Neutropenia)
o Nursed in a single room in a special unit with reverse isolation.
o Regular handwashing by staff and visitors
o Avoiding contact with anybody with an obvious infection.
o Fresh fruit and raw vegetables are not allowed.
o Antibiotic and antifungal prophylaxis are given in most units.
o Special attention to mouth care prevents oral infections.
Prompt treatment of infections: Immediate empiric antibiotics after blood cultures and cultures from other sites like sputum and urine have been sent off. If no response within 72 hours, anti-fungal treatment should be added
Prevention of gout and tumour lysis syndrome Hydration, alkalinise urine, allopurinol
Prevention of nausea due to chemotherapy Anti-emetics
Name the type of acute leukaemia that is most common in children (½) (NB)
Acute lymphoblastic leukaemia
CML is a clonal disorder of the myeloid cell line. Briefly explain the genetic abnormality underlying this disorder (4)
Reciprocal translocation between chromosomes 9 & 22. (t(9;22)/ (1) Philadelphia chromosome) with formation of BCR-ABL fusion gene (1). Gene product has enhanced tyrosine kinase activity (1) with constitutive activation of various signal transduction pathways (1)
List four (4) peripheral blood features seen in the chronic stable phase of this disease (2)
Leukocytosis, peaks in myelocytes and neutrophils, no significant dysplasia, occasional blasts (usually less than 2%), basophilia (invariable), eosinophilia (common), platelet numbers normal or increased.
Explain the mechanism of action of imatinib (Gleevec) in CML (3)
Blocks the ATP binding site on the BCR/ABL fusion protein. Prevents:
Phosphorylation of tyrosine residues on the BCR/ABL substrate
Phosphorylation of downstream effector molecules
Transcription of genes that drive proliferation & prolonged survival
Thus effectively prevents cellular proliferation in CML
Write short notes on the BCR/ABL fusion gene (5)
Results from translocation of genetic material between chromosomes 9 and 22
The fusion gene has enhanced tyrosine kinase activity
This results in increased (granulocyte) proliferation, decreased adherence of bone marrow haemopoietic cells to the stroma and prolonged survival.
If found BCR/ABL positive on molecular testing, this result is in keeping with the diagnosis of CML or ALL
A 55-year-old man presents with left upper quadrant abdominal pain and is found to have splenomegaly. FBC shows: White cell count 60x109/l (N = 4-10), Hb 9.5g/dl (13-17), Platelets 400x1012/l (137-373). The peripheral blood smear shows predominance of granulocyte precursors (promyelocytes, myelocytes and metamyelocytes). Basophils and eosinophils are also increased.
List four (4) differential diagnoses (½x4 = 2)
CML, Severe bacterial infection, Malignancy (G-CSF secreting), Acute blood loss/shock, Tissue trauma/surgery, Severe inflammation/infection
List the investigations you would perform to determine the diagnosis (½x4 = 2)
Bone marrow biopsy, cytogenetics, FISH, PCR BCR/ABL, Cultures, Imaging for tumours
Briefly describe three (3) mechanisms that may result in anaemia in patients with CLL. For each describe a clinical finding or one special investigation and its result that may suggest this is a cause of anaemia (3x2 = 6) (NB)
Immune haemolysis (typically warm AIHA): Reticulocytosis, + DAT, increased LDH/ unconjugated bilirubin, low haptoglobin, spherocytes and polychromasia on PB smear
Pure red cell aplasia (immune mechanism): Low reticulocyte count, bone marrow biopsy with reduced/ absent RBC precursors
Reduced erythropoiesis due to bone marrow infiltration: Low reticulocyte count, bone marrow biopsy with lymphocytic infiltrate and reduced haematopoiesis
Splenic sequestration of RBCs (hypersplenism): Splenomegaly clinically/ radiologically
List two (2) reasons for the predisposition to infection in CLL (2x½ =1)
Hypogammaglobulinaemia, Neutropenia, Defective cellular immunity
Not all patients with CLL require chemotherapy. List two (2) indications for treatment (1x2 = 2)
Bulky lymphadenopathy, problematic organomegaly, bone marrow infiltration with cytopenias, autoimmune manifestations.
