Flashcards in Oncology - Haematological malignancies Deck (63):
What is leukaemia?
Leukaemias are neoplastic proliferations of white blood cell precursors. This proliferation results in some common features of leukaemia:
- diffuse replacement of normal bone marrow by leukaemic cells with variable accumulation of abnormal cells in the peripheral blood
- infiltration of organs such as the spleen, liver, lymph nodes, meninges and gonads by leukaemia cells
Bone marrow failure with anaemia, neutropaenia and thrombocytopaenia is the most important consequence, particularly in the acute leukaemias.
What is the aetiology of leukaemia?
Leukaemias are caused by a block in stem cell differentiation leading to a monoclonal proliferation of neoplastic leukocytes behind the block:
- acute leukaemia - block occurs at an early stage of stem cell development
- chronic leukaemia - block occurs at a later stage of stem cell development (some evidence of maturation in chronic leukaemia)
Leukaemia cells replace most of the bone marrow and crowd out normal haematopoiesis. They enter the peripheral blood and metastasize throughout the body.
What factors are associated with the development of leukaemia?
1) Ionising radiation
2) Cytotoxic chemicals - alkylating agents can induce myeloid leukaemia after a latent period of several years. Industrial benzene exposure is also associated
3) Retroviruses - one rare form of T cell leukaemia is associated with retroviral infection
- increased incidence in Down's syndrome
- ethnic variation; CLL rare in Chinese populations
5) Immunology - immune deficient states (e.g. hypogammaglobulinaemia) are associated with an increased risk of haematological malignancy
What age group do acute leukaemias affect the most?
Acute leukaemias occur at all ages.
ALL has a peak incidence in children aged 1-5 years.
AML occurs mainly over the age of 50.
In acute leukaemia there is proliferation of primitive stem cells leading to an accumulation of blast cells in the bone marrow, which causes bone marrow failure. Eventually, this proliferation spills into the blood. The presenting features are usually anaemia, bleeding and infection.
What investigations are most useful in suspected cases of acute leukaemia?
FBC usually shows anaemia and thrombocytopaenia. The leucocyte count varies from as low as 1 to as high as 500 or more. Appearance of blast cells on the blood film is usually diagnostic.
Bone marrow aspiration is the most valuable investigation. The marrow is typically hypercellular with loss of fat spaces, and replacement of normal cells by leukaemic blast cells in varying degrees. The presence of Auer rods in the cytoplasm of blasts cells indicates MYELOBLASTIC LEUKAEMIA.
Immunophenotyping can help determine the subtype of acute leukaemia present.
What are blast cells?
Blast cells are immature leucocytes precurosrs that typically have large, irregular, eosinophilic nuclei. Sometimes they have Auer rods present in the cytoplasm indicating acute myeloblastic leukaemia.
Outline the approach to treatment of acute leukaemias
All acute leukaemias follow a similar course of treatment.
1) Remission induction involves destroying the bulk of the tumour by combination chemotherapy. The patient goes through a period of severe bone marrow hypoplasia, requiring intensive inpatient support
2) Remission consolidation: residual disease is attacked by several courses of chemotherapy. This again results in a period of bone marrow hypoplasia. In poor prognosis leukaemia, this phase may include stem cell transplantation
3) Maintenance: If the patient is still in remission after the consolidation phase for ALL, a period of outpatient maintenance therapy is given, consisting of repeating cycles of drug administration. In ALL prophylactic cranial irradiation and intrathecal chemotherapy (methotrexate) are used to ensure chemotherapy penetrates the CNS (CNS involvement is common in ALL).
Before embarking on specific therapy, underlying infection should be treated, anaemia and thrombocytopaenia should be corrected with red cell and platelet transfusion.
How is anaemia treated in leukaemia?
Anaemia can be both a product of the leukaemia and aggressive chemotherapy causing bone marrow failure. Anaemia is treated with regular red cell transfusions.
How is bleeding managed in the leukaemic patient?
Thrombocytopaenic bleeding requires platelet transfusions. Prophylactic platelet transfusion should be given to maintain the platelet count >10. Coagulation abnormalities should be treated appropriately, usually with fresh frozen plasma.
What constitutes neutropaenic sepsis in a chemotherapy patient? How is it managed?
Fever (>38) lasting over 1hr in a significantly neutropaenic patient (neutrophil count <1.0) indicates possible septicaemia. IV broad spectrum antibiotic therapy is essential. Empiric therapy is given with a combination of an aminoglycoside (e.g. gentamicin) and a broad spectrum penicillin (e.g. piperacillin/ tazobactam). This combination is synergistic and bactericidal.
Organisms most commonly associated with neutropaenic sepsis are skin based gram positive organisms such as staph aureus and staph epidermidis which gain entry via cannulae and central lines. Gram negative organisms from the GIT are also involved.
What organism are patients with ALL susceptible to?
Patients with ALL are susceptible to infection with Pneumocystis jirovecii which causes severe pneumonia. They should receive prophylactic co-trimoxazole during chemotherapy. Diagnosis may require sputum induction and if negative bronchoalveolar lavage. Treatment is with high dose IV co-trimoxazole.
What fungal infections are patients on chemotherapy susceptible to?
Patients receiving intensive chemotherapy receive prophylaxis against fungal infections with itraconazole or posaconazole. Systemic fungal infection with Candida or Aspergillus is treated with IV liposomal amphotericin or viroconazole.
What viral infections are common in patients receiving chemotherapy?
Herpes simplex infection occurs frequently around the lips and nose during chemotherapy and is treated with aciclovir. Herpes zoster should be dealt with early using high dose aciclovir, as it can be fatal in immunocompromised patients.
What metabolic problems are common in patients receiving chemotherapy?
Continuous monitoring of renal and hepatic function is necessary. Renal toxicity occurs with some antibiotics (e.g. aminoglycosides) and antifungal agents (amphotericin). Cellular breakdown during induction therapy increases uric acid production, which may cause renal failure; allopurinol and IV hydration are given as prophylaxis against this.
In what patients is haematopoietic stem cell transplantation indicated?
HSCT may be the only cure for many blood diseases. It is indicated in the following:
- leukaemias (ALL, AML, CML)
- myelodysplastic syndrome
- severe aplastic anaemia
- severe immune deficiency syndromes
The type of HSCT is defined according to the donor and source of stem cells.
What is an allogenic HSCT?
Stem cells from a donor - either related (usually an HLA identical sibling) or a closely HLA matched volunteer unrelated donor - are infused after planned ablation of the patients own marrow. In addition to restoring marrow function, donor immune cells can attack recipient malignant cells ("graft versus host disease").
It carries considerable morbidity and mortality. The best results are obtained in young patients with minimal residual disease. Around 25% die from GVHD and there remains a significant risk of disease relapse.
What is graft versus host disease?
GVHD is due to cytotoxic activity of donor T lymphocytes that become sensitised to their new host, regarding it as foreign.
Acute GVHD: this occurs in the first 100 days after transplant in around 1/3 of patients. It varies from mild to lethal, causing rashes, jaundice and diarrhoea. Prevention includes HLA matching of the donor and immunosuppressant drugs
Chronic GVHD: this may follow acute GVHD or arise independently. It often resembles collagen vascular diseases and is usually treated with corticosteroids and prolonged immunosuppression (e.g. ciclosporin)
What is an autologous HSCT?
Here, stem cells are harvested from the patients bone marrow or peripheral blood and frozen until required. After aggressive chemotherapy, stem cells are reinfused to restore marrow function. Autologous HSCT is used to allow aggressive chemotherapy for diseases that spare the marrow or those in which very good remission can be achieved.
What is the prognosis of acute leukaemia?
Without treatment, the median duration of survival of acute leukaemia is 5 weeks. Around 80% of adults <60 years of age achieve remission with specific therapy. Remission rates are lower for older patients. However, the relapse rate continues to be high. The introduction of the drug tretinoin for acute promyelocytic leukaemia has greatly reduced the death rate from bleeding.
What is CML?
CML is a myeloproliferative stem cell disorder resulting in proliferation of ALL haematopoietic lineages but predominantly the granulocyte series. Cell maturation proceeds fairly normally.
The peak incidence is at the age of 55 years.
What is the pathogenesis of CML?
The cause in most cases of CML is unknown. Leukaemic cells represent transformed pluripotent stem cells with predominantly granulocytic differentiation.
95% of cases of CML have a chromosome abnormality (Philadelphia chromosome, Ph), a shortened chromosome 22 formed by reciprocal translocation with chromosome 9. A resulting chimeric gene (BCR ABL) codes for a protein (p210) with tyrosine kinase activity, which activates downstream signalling pathways for cell differentiation, proliferation, survival and adhesion.
What are the clinical features of CML?
CML has 3 phases:
1) Chronic phase - the disease is responsive to treatment and is easily controlled. Formerly, this stage lasted 3-5 years, but since the advent of imatinib therapy can be prolonged to >8 years in many patients
2) Accelerated phase - disease control becomes more difficult
3) Blast crisis - the disease transforms into acute leukaemia (AML in 70%, ALL in 30%), which is relatively refractory to treatment and often fatal. Imatinib therapy greatly reduces the number of patients per year who transform to blast crisis
Common symptoms include lethargy, weight loss, abdominal discomfort, and sweating. About 25% of patients are asymptomatic at diagnosis. Splenomegaly is characteristic and may be massive; hepatomegaly occurs in 50% of cases.
What investigations should be performed in suspected cases of CML?
FBC: usually shows normocytic, normochromic anaemia
Leucocyte count varies from 10 to 600
Platelet count very high in one third of patients - up to 2000
Blood film: neutrophils are the predominant cell type, although the full range of granulocyte precursors are seen. The number of circulating blasts increases dramatically as the disease enters blast transformation.
Chromosome analysis of the bone marrow: reveals the Ph chromosome, and RNA analysis the BCR ABL gene defect.
How is CML managed?
Chronic phase - imatinib specifically inhibits BCR ABL tyrosine kinase activity and reduces white cell proliferation. It is first line therapy in chronic phase CML, producing a complete response at 18 months in 76% of patients. Monitoring is by bone marrow until cytogenetic response occurs, then by measuring BCR ABL mRNA in blood. Alternative agents such as dastinib or nilotinib are used in non responders. Allogenic HSCT can provide a cure for younger patients in the chronic phase who are imatinib resistant.
Accelerated phase and blast crisis - blast crisis is the main cause of death in patients with CML. Tyrosine kinase inhibitors should be tried if patients have not already had these. Otherwise, blast crisis is treated as acute leukaemia but responds poorly, and supportive therapy alone may be appropriate in elderly patients.
What is the epidemiology of ALL?
ALL is the most common leukaemia and cancer in children (newborn to 14)
- adults can also develop ALL
- adults have a poorer prognosis
Peak incidence is 2 to 10 years of age.
How is ALL classified?
Immunologic classification of ALL is:
(1) Early pre B cell acute lymphoblastic leukaemia (80%) of cases
(2) Pre-B, B-, and T cell acute lymphoblastic leukaemia
What is the pathogenesis of ALL?
ALL is a clonal lymphoid stem cell disease.
Majority have numerical or structural chromosome changes (e.g. hyperploidy).
Which patients are most affected by AML?
The median age of presentation is 50 years old, with a range from 30 to 60 years old.
Risk factors include:
- genetic factors: Downs syndrome, Turners, Kleinfelters
- chemicals: benzene and alkylating agents
Mutations on chromosome 8 and t(8;21) translocation are commmon cytogenetic abnormalities.
What clinical findings are commonly associated with AML?
Weakness, fatigue, bleeding and fever (infection).
Hepatosplenomegaly and generalised painless lymphadenopathy.
Gum infiltration (common in acute monocytic luekaemia [M5]).
What is chronic lymphocytic leukaemia?
CLL is the most common type of leukaemia, typically presenting between the ages of 65 and 70 years (alos most common cause of generalised lymphadenopathy in this age group). There is uncontrolled proliferation of immuno-competent B cells, leading to impaired immunity and haematopoiesis.
These B cells are often called "virgin" B cells (i.e. those that are unable to differentiate into plasma cells)
What are the clinical features of CLL?
The onset is very insidious. In 70% of patients, the diagnosis is made incidentally on routine FBC. Presenting problems include:
- lymphadenopathy (painless)
- systemic symptoms such as night sweats and weight loss
There is an increased incidence of immune haemolytic anaemia
- warm (IgG) or cold (IgM) immune haemolytic anaemia may occur
What are the laboratory findings in CLL?
Peripheral blood shows a mature lymphocytosis (>5).
Immunophenotyping confirms the monoclonal origin of the B cells.
Serum immunoglobulins indicate the degree of immunosuppression (hypogammaglobulinaemia occurs because neoplastic B cells do NOT develop into plasma cells)
Direct Coombs test may show autoimmune haemolytic anaemia.
Bone marrow examination may be helpful in difficult cases, to monitor response and judge progress.
Thrombocytopaenia and neutropaenia also occur.
Numerous "smudge" cells (fragile leukaemic cells)
What are the clinical stages of CLL?
A (60% of patients): no anaemia or thrombocytopaenia; <3 areas of lymphadenopathy
B (30%): as for A, but >3 areas of lymphadenopathy
C (10%): anaemia and/or thrombocytopaenia
How is CLL managed?
Most stage A patients do NOT require treatment
- treatment is indicated if there is bone marrow failure, massive lymphadenopathy, splenomegaly, systemic symptoms, rapidly increasing lymphocyte count or autoimmune anaemia or thrombocytopaenia.
Initial therapy for stages B and C is with oral alkylating agents CHLORAMBUCIL or the purine analogues FLUDARABINE. Retuximab may also increase remission rates.
Supportive care is required in progressive disease, e.g. transfusions for symptomatic anaemia or thrombocytopaenia and prompt treatment of infections.
The main prognostic factor is stage of disease. Older patients with stage A disease have a normal life expectancy. Patients with advanced CLL are more likely to die from their disease or infectious complications. In those treated with chemotherapy or retuximab, 90% are alive at 4 years.
What is adult T cell leukaemia?
Adult T cell leukaemia is a form of leukaemia associated with HTLV-1 infection. It may present as malignant lymphoma.
What is the pathogenesis of adult T cell leukaemia?
HTLV-1 activates the TAX gene, which in turn inhibits the p53 tumour suppressor gene. Neoplastic CD4 T helper T cells undergo monoclonal proliferation.
What are the clinical features of adult T cell leukaemia?
Hepatosplenomegaly and generalised painless lymphadenopathy are present.
Skin infiltration causing lesions is common in all T cell malignancies.
Lytic bone lesions (raised Ca++)
- lymphoblasts release osteoclast activating factor
- lytic lesions may produce hypercalcaemia
What are the laboratory findings in adult T cell leukaemia?
Peripheral WCC raised
- numerous lymphoblasts
- lymphoblasts are positive for CD4 marker and negative for TdT
Normocytic aneamia and thrmbocytopaenia.
Bone marrow replaced by CD4 lymphoblasts.
What is hairy cell leukaemia?
This is a type of B cell leukaemia.
It occurs predominantly in men between ages of 40 and 60 years.
It is caused by overexpression of cyclin D1 protein (important cell regulator)
What are the clinical findings of hairy cell leukaemia?
Splenomegaly is common (90%)
- spleen is the primary site for proliferation of neoplastic cells
Lymphadenopathy is very uncommon (<10%)
Autoimmune vasculitis and arthritis
What are the laboratory findings in hairy cell leukaemia?
Leukaemic cells have hair like cytoplasmic projections
- marrow is packed with neoplastic cells
- reticulin fibres are increased
Neoplastic cells stain positive for tartrate resistant acid phosphatase (TRAP) stain
How is hairy cell leukaemia treated?
Drugs of choice are purine analogues.
Complete remission is induced in 80% of cases.
What are the myelodyspastic syndromes?
Myelodysplastic syndromes predominantly affect elderly patients and is characterised by peripheral blood cytopaenias and abnormal looking (dysplastic) blood cells. It inevitably progresses to AML (>30% of cases).
What is the pathogenesis of myelodysplastic syndromes?
MDSs is characterised by acquired clonal disorders that affect stem cells. They characteristically have cytopaenias (bleeding, anaemia and infection) and hypercellular bone marrow.
a) refractory anaemia
b) refractory anaemia with ringed sideroblasts
c) chromic myelmonocytic leukaemia
d) refractory anaemia with excess blast cells in transformation
What are the laboratory findings of myelodysplastic syndromes?
Severe pancytopaenia is common:
1) Normocytic to macrocytic anaemias
- dimorphic RBC population (microcytic and macrocytic) is commonly present, which increases the RBC distribution width (RDW)
2) leukoerythroblastosis (any anaemic condition resulting from a space occupying lesion in the bone marrow)
Bone marrow findings:
1) Ringed sideroblasts (nucleated RBCs with excess iron) are present
2) Myeloblasts account for <20% of granulocytes
- if myeloblasts are >20% then it has progressed to AML
How is myelodysplastic syndrome treated?
MDS is usually incurable. Supportive care with red cell and platelet infusions is the main treatment. Erythropoietin and granulocyte - colony stimulating factor (G-CSF) may improve Hb and WCC in selected individuals. Allogenic HCST may afford a cure in younger patients. In low risk patients, median survival is 5.7 years and time for 25% of patients to develop AML is 9.4 years.
What are the myeloproliferative disorders?
These conditions are characterised by clonal proliferation of marrow precursor cells, and include polycythaemia rubra vera, essential thrombocythaemia, myelofibrosis and chronic myeloid leukaemia. Although most patients have one of these disorders, some have overlapping features or progress from one to another, e.g. PRV to myelofibrosis. A mutation in the gene encoding the signal transduction molecule JAK-2 has been found in >90% of PRV cases and 50% of those with essential thrombocythaemia and myelofibrosis.
What is myelofibrosis?
In myelofibrosis, the bone marrow is initially hypercellular, with an excess of normal megakaryocytes that release growth factors, resulting in fibroblast proliferation. As the disease progresses, the marrow becomes fibrosed.
It primarily occurs in persons >50 years old and is the most common cause of massive splenomegaly in this group.
What are the clinical features of myelofibrosis?
Most patients present over the age of 50 years with fatigue, weight loss and night sweats. The spleen may be massively enlarged due to extramedullary haematopoiesis and painful splenic infarcts may occur. These are also associated with left sided pleural effusions.
What investigations should be performed in a patient with suspected myelofibrosis?
There is anaemia with a leucoerythroblastic picture (circulating immature red cells and granulocyte precursors). Teardrop cells (damaged RBCs) are commonly present.
WCC and platelet count may be high, normal or low (but platelets are morphologically abnormal). Increased cell turnover commonly leads to high urate levels and folate deficiency. Bone marrow is often difficult to aspirate; trephine biopsy shows replacement by fibrous tissue. Finding the JAK-2 mutation supports the diagnosis.
Leucocyte alkaline phosphatase is normal or increased. Recall that in CML it is decreased and increased in polycythaemia vera.
How is myelofibrosis managed?
Supportive treatment includes red cell transfusions for anaemia. Folic acid should be given to prevent deficiency. Cytotoxic therapy with hydroxycarbamide may help reduce the WCC and spleen size, but splenectomy may be required for massive splenomegaly. HSCT may be considered in younger patients. Survival is variable with a median of 4 years.
What is essential thrombocythaemia?
This is characterised by a raised level of circulating platelets that are often dysfunctional. Reactive causes of increased platelets must be excluded before making the diagnosis. The JAK-2 mutation supports the diagnosis but it is not universal. Patients present at a median age of 60 years with vascular occlusion or bleeding events. A small percentage may transform into acute leukaemia or myelofibrosis.
Bleeding is usually gastrointestinal and associated with iron deficiency anaemia. Splenomegaly is also a feature.
What are the laboratory findings in essential thrombocythaemia?
Thrombocytosis with abnormal platelet morphology.
Mild neutrophilic leucocytosis.
Basophilia is common.
Bone marrow is hypercellular and contains numerous megakaryocytes that appear abnormal (dysplastic).
How is primary thrombocythaemia treated?
Aspirin should be considered for all patients to reduce the risk of thrombosis. Hydroxycarbamide may be used to control high platelet counts.
Name some other causes of thrombocythaemia
Platelet count can be raised as part of the inflammatory process (reactive thrombocytosis), as with infection, connective tissue disease, malignancy or GI bleeding. Chronic iron deficiency and splenectomy are also causes.
What is polycythaemia?
Polycythaemia is an increase in Hb, Hct and RBC count. Plasma volume varies with the type of polycythaemia.
What is reactive polycythaemia?
This is the most common form of polycythaemia and is defined as an increase in RBC count (number of RBCs per microliter of blood) due to an increase in plasma volume - e.g. volume depletion from sweating.
RBC mass is normal because there is no increase in bone marrow production.
EPO and SaO2 are normal.
Simple fluid replacement corrects the polycythaemia.
What is absolute polycythaemia?
This is defined as an increase in bone marrow production of RBCs, leading to an increase in RBC count AND RBC mass. It can be further divided into appropriate absolute polycythaemia and inappropriate absolute polycythaemia.
Appropriate absolute polycythaemia = hypoxic stimulus for EPO synthesis - e.g. primary lung disease, congenital cyanotic heart disease and high altitude.
The SaO2 is decreased, but RBC count, mass and EPO level are all increased. Plasma volume is normal.
Inappropriate absolute polycythaemia = No hypoxic stimulus for EPO synthesis, which is normally caused by ectopic release from renal cell carcinoma and hepatocellular carcinoma. SaO2 is normal, RBC, mass and EPO levels are all increased but normal plasma volume.
What is polycythaemia rubra vera?
PRV mainly occurs in patients over the age of 40 years. It is characterised by increased erythropoiesis due to a primary increase in marrow activity.
What is the pathogenesis of PRV?
Myeloid stem cells undergo clonal expansion due to a mutation in the JAK2 gene. This gene plays a role in the signalling pathways that tell the body to generate haematopoietic stem cells. The same mutation occurs in myelofibrosis and essential thrombocythaemia. In PRV there is increased production RBCs, granulocytes, (neutrophils, basophils, eosinophils) mast cells and platelets.
What are the clinical features of PRV?
Patients present with the incidental finding of a high Hb, or with symptoms of hyperviscosity syndrome such as lassitude, headaches, dizziness, visual disturbances, and pruritis. Some present with manifestations of peripheral arterial disease or CVA. There is increased risk of VTE. Peptic ulceration is common and sometimes complicated by bleeding (increased histamine release from mast cells stimulates gastric acid production). Patients are often plethoric and have splenomegaly.
What are the laboratory findings of PRV?
RBC count, mass and plasma volume are increased.
EPO is DECREASED, because oxygen content is increased. SaO2 is normal. Bone marrow can be hypercellular, which develops at a later stage.
Major and minor criteria:
- Major: Hb, Hct, RBC count, RBC mass, and a test for JAK2 mutation
- Minor: bone marrow exam, EPO level