What are the 4 basic leukaemia classifications?
- Acute myeloid (myeloblastic) leukaemia =
- Chronic myeloid (granulocytic) leukaemia
- Acute lymphoid (lymphoblastic) leukaemia
- Chronic lymphoid (lymphocytic) leukaemia
What is the differentiation between acute and chronic leukaemias?
- Acute - undifferentiated leukaemias characterised by immature WBC - i.e. blast cells.
- Chronic - differentiated leukaemias characterised by mature WBC.
Give 2 examples of hybrid oncogenes that cause leukaemias.
- BCR-ABL - in CML.
- PML-RARA - in AML M4.
Which virus is a predisposing factor to adult T-cell leukaemia?
Name 2 rare genetic diseases that predispose to leukaemia.
- Fanconi's anaemia
- Down's syndrome
Outline the treatment options used in leukaemias.
- Chemotherapy - cytotoxic drugs
- Stem cell and bone marrow transplant (SCBMT)
- Disease specific agents - including oncogene targeted drugs
Name 2 examples of chemotherapy drugs used in leukaemia and describe their mechanisms of ation.
- Cytosine analogue
- Interferes with deoxynucleotide synthesis
- Prevents successful DNA replication
- Binds to tubulin dimers
- Inhibits microtubule formation
- This prevents mitotic spindle formation
Outline the side effects of chemotherapy.
- Cytotoxic drugs kill normally dividing cells.
- GI epithelium - nausea and diarrhoea.
- Hair follicles - hair loss.
- Loss of fertility.
- Haematopoeitic progenitors - bone marrow suppression.
Explain how stem cell and bone marrow transplant (SCBMT) is used to treat leukaemia.
- Give intense chemotherapy and total body irradiation.
- Wipes out leukaemic cells and normal stem cells.
- Reconstitute bone marrow with transplanted stem cells.
- Transplanted cells may attack leukaemic cells - "graft vs leukaemia" effect.
What are the disadvantages of SCBMT in treatment of leukaemia?
- Shortage of HLA matched donors.
- High mortality of procedure in older and sicker patients.
Outline the signs and symptoms of acute leukaemias.
- Typical symptoms due to bone marrow suppression.
- Thrombocytopenia - leads to purpura (bruising), epistaxis (nosebleed), bleeding gums.
- Neutropenia - recurrent infections.
- Anaemia - lassitude, weakness, shortness of breath.
Describe how acute leukaemias are diagnosed.
- Peripheral blood - blast cells, cytopenias.
- Bone marrow aspirate - > 30% blasts is diagnostic of acute leukaemia.
Outline the pathophysiology of acute leukaemias.
- Blast cells - maturation arrest.
- Blast cell pool is very large.
- Cell death halted due to undifferentiated blasts.
Outline the signs and symptoms of chronic lymphocytic leukaemia.
- Recurrent infections - neutropenia and suppressed lymphocyte function
- Lymph node enlargement
Outline the outcomes of acute and chronic leukaemias.
- ALL - 90% childhood cases long-term remission/cure, adult cases have poorer prognosis - due to different cell of origin and different oncogene mutations.
- AML - > 80% long-term remission in young adults with aggressive treatment, elderly unable to tolerate aggressive chemotherapy or SCBMT.
- CLL - mainly seen in elderly, controlled by regular chemotherapy - most survive > 2 years and many > 12 years.
Outline the signs and symptoms of chronic myeloid leukaemia.
- Night fever/sweats
Describe how chronic myeloid leukaemia is diagnosed.
- Neutrophilia - very high WBC count
- Left shift in blood and bone marrow.
- Presence of Philadelphia chromosome - BCR-ABL translocation.
How is chronic myeloid leukaemia treated?
- Imatinib - first line drug - tyrosine kinase inhibitor - specific to BCR-ABL.
- Survival on treatment measured in years.
- Progresses to accelerated phase and blast crisis.
- Blast crisis resembles acute leukaemia and is hard to treat.
- Allogeneic bone marrow or stem cell transplant curative.
- Autologous transplant sometimes tried.
- Most patients > 50 years old, don't tolerate transplant.
What is the Philadelphia chromosome and what is its clinical significance?
- Philadelphia chromosome (Ph') = 22q- = shorter than normal short arm of chromosome 22.
- Balanced reciprocal translocation of chromosome 22 to chromosome 9: t(9;22) - resulting in 9q+.
- Translocation leads to hybrid BCR-ABL oncogene - BCR fragment from Chr22, ABL on Chr9.
- 95% of CML cases have detectable Ph' chromosome.
- Of remaining 5% some have BCR-ABL gene, some have a different disease requiring distinct therapy.
Describe in detail the pathophysiology of CML and the Philadelphia chromosome.
- ABL previously known to be an oncogene.
- ABL protein is a tyrosine kinase - tightly regulated.
- BCR-ABL hybrid leads to constitutive activity of tyrosine kinase - i.e. unregulated.
- Causes proliferation of progenitor cells in the absence of growth factors.
- Decreased apoptosis.
- Decreased adhesion to bone marrow stroma.
How is the response to treatment monitored in CML patients?
- Reverse transcription-PCR.
- BCR-ABL mRNA converted to ds cDNA by reverse transcriptase.
- PCR with BCR and ABL specific primers.
- Only get products if BCR and ABL on same molecule.
- Quantification of PCR products indicates the extent of residual disease.
Explain why imatinib is the first line treatment for CML and describe its limitations.