Oncology - Haematological malignancies Flashcards
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
4) Genetics
- M>F
- 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)
- myeloma
- myelodysplastic syndrome
- NHL
- severe aplastic anaemia
- myelofibrosis
- 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.
