Leukamia - Part 1 Blood Cell Abnormalities Flashcards
What disease is Leukamia
Disease of the bone marrow
How does the cancer arise and what are the two different types?
It is caused by mutation in the precursor cells.
Myeloid and lymphoid
Note that myeloid may include precursors of granulocytes and monocytes but also erythroid and megakaryocytic
Why does it differ from other cancer?
Cells circulate in the blood and migrate (cant apply concept of metastasis)
Can form localised tumours, which in fact are not inevitable from early stages of disease either
What are the two terms to describe leukamias and what do they mean instead of acute and chronic?
Acute - if untreated profound pathological effects and leads to death in a matter of days, weeks or months.
Chronic leukaemia - less impairment of function of normal tissue but eventually will lead to death
So to finalise - will get acute, chronic, lymphoid, myeloid
How does leukamia occur?
Mutations in primitive cell, has growth or survival advantage over normal cells undergone mutation.
Gives rise to clones
Which slowly replace normal cells
Mutations in proto oncogenes and sometime tumour suppressor genes.
Causes of acute lymphoblastic
Usually unknown Sometimes mutagenic agents Exposure to irradiation Chemicals in utero Delayed exposure to common pathogen or pathogens
Acute myeloid
Usually unknown
Sometimes irriadiation
Mutanogenic chemicals
Chemicals (benzene, cigarette smoke)
Chronic myeloid
Usually unknown
Rarely irradiation or mutanogenic drugs
Chronic lymphoid
Unknown but some families are predisposed
What behaviour can a leukaemic clone induce
Growth that occurs without dependence on growth factors
Continued proliferation without maturation
Failure to undergo normal cell death (apoptosis)
Say some clinical features of AML
- middle to old age
- demonstrated as a result of multiple mutations
- onset effect is usually acute but there is a smouldering or preleukaemic phase in about 15%
- survival for adults between 25-45 years old
Differences in blood film and blood count in AML
Haematological results
Anaemia present
Thrombocytopenia
Increased blast cells in peripheral blood
These cells might be myeloblasts, monoblasts, or both
Neutropenia and they might show dysplasia
Anisocytosis and poikilocytosis is common
Bone marrow is hypercellular and aspiration may be difficult.
Note that AML can be classified according to differentiation in myeloblasts, monoblasts, erythroblasts, megakaryoblasts
Some clinical features
From proliferation of leukaemic cells
- splenomegaly and hepatomegaly and often lymphadomegaly
-leukaemic cells can infiltrate the skin and gums when in monocytic differentiation
- in high white blood counts can lead to obstruction of blood vessels known as leucostasis
- can lead to stroke or resp impairment
Often promyelocytic is associated with DIC and prominent bleeding bruising
See common features for others
Treatment if AML
Intensive chemotherapy with drugs such as - daunorubicin and cytarabine which would make the initial leukaemic cells to disappear. This is them followed by consolidation therapy to eliminate any residual cells and prevent relapse. Usually several courses. And then maintained therapy, less toxic drugs given for one to two years
Note the patient always needs support with red cell, platelet transfusion, antibiotics, antivirals, antifungals.
Immunotherapy using a a myeloid antigen
Haemopoetic stem cell transplant
Prognosis in AML
70% of adults achieve remission but over half relapse within 2 years. Long term survival is 25%.
Long term results in children are better
How can blasts be recognised 4
Large size
High nuclei/ cytoplasm ration
Open chromatic pattern of nuclei
Prominent nucleoli
Some difference between chronic and acute
Acute - mutation in transcription factors which means inability to mature. Cells can still proliferate but there is an inability to mature. So this continued proliferation without maturation, they replace normal bone marrow cells and failure occurs
Chronic - mutation involves activation of signalling pathways within the cell. Cells can still proliferate without needing growth factors. Abnormal interaction with stroma and cell survival prolonged to steady expansion of the leukaemic clone and I the case of myeloid mature stem cells can still function. But in lymphocytic we get a steady expansion of the clones so functionally useless and impaired tissue function as more clones replace actual cells.
Prevalence of chronic myeloid leukaemia
Uncommon type with about 1-2 between 100000 per year
It is more common in adults than children
Haematological features of CML 4
Increase in white blood cells - leucocytosis
Particularly in granulocytes - eosinophils, basophils, neutrophils and monocytes
Platelet count is usually normal or high, may be anaemia which is usually severe.
Bone marrow is hypercellular because of increase in granulocytic and megakaryocytes
What causes CML ?
From specific chromosomal translocation in the chromosome 9 and 22
In a single haemopoetic stem cell
So turns form a ABL1 gene which codes for tyrosine kinase enzyme which has a tighly regulated activity
But the new mutation is BCR- ABL1 (oncogene) which leads to uncontrolled tyrosine kinase and gives rise to a leukaemic clone
This results to an abnormally short chromosome 22 which is called the Philadelphia chromosome (first chromosome found to link to malignancy)
The mutation gives the cells growth and survival advantage which gives rise to the leukaemic clone
All the haemoatological results above could be due reactive neutrophilia. So the cytogenic analysis is needed for for confirmation of the diagnosis
Some clinical features or CML not the general ones
- splenomegaly
- tyrosine kinase - phosphorylate the tyrosine residues. Key in cell proliferation. When growth factor attaches to the cell then tyrosine kinase start signal and proliferation occurs
Treatment for CML
Most successful treatment is the tyrosine kinase inhibitors
Key features for acute lymphoblastic leukaemia
Childhood disease peak age 2-5 years old
85% cured, much worse in adults than children this is because Philadelphia translocation is rare in children
Heterogeneous group of disorders, 75-80% are of the B lineage and the rest of the T lineage
Describe briefly about ALL
Increase of lymphoblastic with failure to develop into mature lymphocytes
= results to impaired haemopoisis and the lymphoblastic circulate peripheral blood
Clinical features of ALL
- effects can result from direct effects of proliferation of leukaemic cells or from bone marrow impairement or over crowding of haemopoetic stem cells
Common infiltrations-
But also testicular infiltration, renal infiltration or CNS one
So with high WBC you can have renal failure and other metabolic disturbances, as a result of tumour lysis syndrome.
Paleness and bruising
If in T cell lineage then there is enlargement of the thymus which can be seen in a chest x ray.
Haematological features of ALL
- anaemia normocytic, normochromic
- leukocytosis with lymphoblasts in the blood
- thrombocytopenia
- replacement of normal bone marrow cells by lymphoblasts
Why is cytogenetic and molecular genetic analysis done in ALL and what does it show
Useful because it gives us information about the prognosis and give us more targeted development targeted treatment
Hyper diploidy is a good prognosis
With translocation in chromosomes 12 and 21
But a bad prognosis is associated with some other translocations such as 4, 11. Chromosomes and the others such as the 9 and 22 one which is the Philadelphia chromosome.
Treatment for ALL
Two fold so supportive therapy and then a combo of chemotherapy and attack to leukaemia.
So first supportive- red cells, platelets and antibiotics if infection occurs.
Careful fluid management is key.
Chemotherapy has a few different stages — remission/induction, consolidation, maintenance.
Systemic chemotherapy, can give drugs to cerebrospinal fluid, by a lumbar puncture and drugs that can cross the blood brain barrier.
Cranial irridiation can sometimes occur and if Philadelphia chromosome is present then there is a chance of tyrosine kinase inhibitors used. And for poor prognosis then there is a chance is a allogeneic stem cell transplantation offer the only chance of a cure.
Chemo is tailored to the translocation and genetics in general.
Can have both long term and short term toxicity. Short term is reversible to normal tissue and bone marrow suppression.
But long term can result to infertility, mild cognitive impairment. And a slight risk of developing AML by damage to normal haemopoietic stem cells by chemotherapy. So it is really important to balance the good and the bad of this illness.
Key features of chronic lymphocytic leukamia
Early middle age and to elderly
Median age is 70s. Commonest leukaemia in Western Europe and Northern America
And more common in men than in women.
What can we see in CLL, haematological features
mature but abnormal T B and NK cells.
Lymphocytosis
With more advanced disease there is more bone marrow infiltration.
See 4 mature CLL lymphocytes
And a smear or smudge characteristic.
So small mature lymphocytes with clamped chromatin and scanty (small and insufficient quantity) cytoplasm these are small and fragile cells and result to smear cells.
(Seeing the profile of the cell surface markers expressed at lymphocytes helps determine the cause of lymphocytosis, or to cytometry to see a specific pattern)
Treatment for CLL
Most don’t need treatment but the ones that do may be given cyclophosphamide, fludarabine, rituximab which is immunotherapy and gives good results overall.
Vaccinate against influenza and meningococcus
What are the direct effects of proliferation of leukaemic cells 4
Bone pain
Hepatomegaly
Splenomegaly
Lymphadenomegaly
What are the indirect effects of leukaemia of cell proliferation
This leads to replacement of normal bone marrow cells by leukaemic cells causing anaemia, thrombocytopenia, neutropenia
Clinical features include 6 sub parts with symptoms
- fatigue, lethargy, pallor (anaemia)
- fever and infections (neutropenia)
- bruising and petechiae (thrombocytopenia)
- bone pain (bone marrow expansion)
- abdominal enlargement (hepatomegaly, splenomegaly)
- lumps and swelling (lymphadenomegaly)
What are some key investigations needed?
- full blood count
- blood film
- characterise cell surface markers by a technique known as flow cytometry
- bone marrow sample, to perform a cytogenetic/molecular analysis on blood markers such as the Philadelphia chromosomes
This gives information about prognosis and how to approach treatment.
Can mutations happen in pluripotent lymphoid myeloid stem cells?
Yes they can and include both myeloid and lymphoid cells.
Where do lymphomas occur? And what are the two different types?
They develop in other tissues
Non Hodgkin lymphoma - may be B T or NK lineage. Divided to lymphoblastic lymphomas which are similar to lymphoblastic leukaemia. And then of each different lineage of B or T or NK
Hodgkin - the neoplastic cell of B lineage which lacks some B cell features
