Introduction to leukaemia Flashcards
What is Leukaemia?
→ Leukaemia are malignancies of blood cells and their precursors.
“malignant disorders of haematopoietic stem cells characteristically associated with increase number of white cells in bone marrow or/and peripheral blood.”
→ It is a clonal disease - all the malignant cells derive from a single mutant stem cell.
→ Cells are made permanently active in proliferating
What is haematopoiesis?
→ Process through which the body manufactures blood cells.
→ It begins early in the development of an embryo, well before birth, and continues for the life of an individual.
→ The blood is made up of more than 10 different cell types. Each of these cell types falls into one of three broad categories:
- Red blood cells (erythrocytes): These transport oxygen and hemoglobin throughout the body.
- White blood cells (leukocytes): These support the immune system. There are several different types of white blood cells:
- Lymphocytes: Including T cells and B cells, which help fight some viruses and tumors.
- Neutrophils: These help fight bacterial and fungal infections.
- Eosinophils: These play a role in the inflammatory response, and help fight some parasites.
- Basophils: These release the histamines necessary for the inflammatory response.
- Macrophages: These engulf and digest debris, including bacteria.
- Platelets (thrombocytes): These help the blood to clot.
→ The process of hematopoiesis begins with an unspecialized stem cell.
→ This stem cell multiplies, and some of these new cells transform into precursor cells.
→ These are cells that are destined to become a particular type of blood cell but are not yet fully developed.
→ However, these immature cells soon divide and mature into blood components, such as red and white blood cells, or platelets.
Common Myeloid progenitor - leads to thrombocytes,erythrocytes, basophil, neutrophil, eosinophil,monocytes which become macrophages
Common Lymphoid Progenitor - leads to B and T Lymphocytes and natural killer cells
What are haematopoietic stem cells?
Haematopoietic stem cells (HSCs):
→ Multipotent - can give rise to cells of every blood lineage
→ Self maintaining - a stem cell can divide to produce more stem cells
What can progenitor cells do on the whole? What about Progenitor cells- Undifferentiated (the common myeloid and common lymphoid progenitors only at the start of haematopoiesis before specialising occurs) and Progenitor cells- Committed (the rest of the progenitors)?
Progenitor cells:
→ Can divide to produce many mature cells
→ But cannot divide indefinitely
→ Eventually differentiate and mature
Undifferentiated-(multipotent):
→ You cannot tell the difference between them morphologically because they do not show the characteristics of mature cells.
Committed (unipotent):
→ Already committed as to what they will become when they generate mature cells
How can leukaemia be diagnosed/what tests can be done?
Peripheral blood blasts test (PB):
→ To check for presence of blasts and cytopenia
→ >30% blasts are suspected of acute leukaemia.
Bone marrow test/biopsy (BM):
→ Taken from pelvic bone and results compared with PB.
Lumbar puncture:
→ To determine if the leukemia has spread to the cerebral spinal fluid (CSF).
Is there an exact cause of Leukaemia? (aetiology of Leukaemia) What are risk factors for leukaemia?
→ Exact cause is unclear.
→ Combination of predisposing factors.
1. Genetic risk factors
2. Environmental risk factors
3. Uncertain, unproven or controversial factors
4. Lifestyle-related risk factors
→ NOT usually hereditary
(except for some cases of Chronic Lymphocytic Leukaemia (CLL))
→ Some rare genetic diseases may predispose to leukaemia, e.g. Fanconi’s anaemia, Down’s syndrome
→ Gene mutations involving oncogenes (activation) or/and tumour suppressors (inactivation).
→ Involving genes common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia.
Chromosome aberrations:
→ Translocations (e.g. BCR-ABL in CML).
→ Numerical disorders (e.g. trisomy 21-Down syndrome).
→ Inherited immune system problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).
Radiation exposure
acute radiation accidents
atomic bomb survivors
→ Exposure to chemicals and chemotherapy
→ Cancer chemotherapy with alkylating agents (e.g. Busulphan)
→ Industrial exposure to benzene
Immune system suppression, e.g. after organ transplant
Lifestyle related risk factors include:
→ Smoking
→ Exposure
→ Excessive exposure to sun
→ Overweight
How can Leukaemia be classified?
- Acute or Chronic
- Lymphoid or Myeloid
i.e:
a) Acute Lymphoid Leukaemia (ALL)
b) Chronic Lymphoid Leukaemia (CLL)
c) Acute Myeloid Leukaemia (AML)
d) Chronic Myeloid Leukaemia (CML)
Acute disease: rapid onset and short but severe course.
Chronic disease: persisting over a long time.
What is the difference when comparing ‘acute’ and ‘chronic’ in leukaemia?
Acute leukaemia:
→ Undifferentiated leukaemia
→ Characterised by uncontrolled clonal and accumulation of immature white blood cells (-blast)- ie myeloblasts and lymphoblasts
→ mainly children
→ sudden onset
→ duration weeks to months
→ white blood cell count is variable
Chronic leukaemia:
→ Differentiated leukaemia
→ Characterised by uncontrolled clonal and accumulation of mature white blood cells (-cyte)
→ middle age and elderly
→ onset is insidious (proceeding in a gradual, subtle way, but with very harmful effects)
→ duration is years typically
→ white blood cell count is high
What is acute leukaemia?
What are typical symptoms due to bone marrow suppression?
Characterized by a large number of lymphoblasts (ALL) or myeloid blasts (AML) in bone marrow and blood- “undifferentiated leukaemia”.
Typical symptoms due to bone marrow suppression:
Thrombocytopenia: purpura (bruising), epistaxis (nosebleed), bleeding from gums.
Neutropenia: Recurrent infections, fever.
Anaemia: lassitude, weakness, tiredness, shortness of breath.
Summarise Acute Lymphoblastic Leukaemia (ALL) and Acute Myeloblastic Leukaemia (AML)
→ Acute Lymphoblastic Leukaemia (ALL):
Prevalence: Commonest cancer of childhood (overall still not very common).
Origin: Cancer of immature lymphocytes (lymphoblasts or blasts).
Classification: B-cell & T-cell leukaemia.
Treatment: Chemotherapy. Long term side effects are rare.
Outcome: 5 year event-free survival (EFS) of 87% in 2010. 1 out of 10 ALL patients relapse. Remission in 50% percent of them after second chemotherapy treatment or bone marrow transplant.
Adult ALL- poorer prognosis because disease presents different cell of origin and different oncogene mutations.
→ Acute Myeloblastic Leukaemia (AML):
Prevalence: 70 children aged ≤16 y/o diagnosed in the UK every year (very rare).
Origin: Cancer of immature myeloid white blood cells.
Classification: based on FAB system (French-American-British): M0-M7.
Treatment: Chemotherapy, monoclonal antibodies (immunotherapy) +/- allogeneic bone marrow transplant.
Outcome: 5 year event-free survival (EFS) of 50-60%.
What is chronic leukaemia characterised by?
Characterised by an increase number of differentiated cells -“differentiated leukaemia”.
Summarise Chronic Lymphocytic Leukaemia (CLL) and Chronic Myeloid/Granulocytic Leukaemia (CML)?
→ Chronic Lymphocytic Leukaemia (CLL):
Prevalence: 3,800 new cases diagnosed in the UK every year (average diagnosis age= 70).
Origin: Large numbers of mature (clonal) lymphocytes in bone marrow and peripheral blood.
Symptoms: Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement, hepatosplenomegaly
Treatment: Regular chemotherapy to reduce cell numbers.
Outcome: 5-year event-free survival (EFS) of 83%. Many patients survive >12 years.
→ Chronic Myeloid/Granulocytic Leukaemia (CML):
Prevalence: 742 new cases diagnosed in the UK every year (peak rate = 85-89y/o).
Origin: Large numbers of mature myeloid white blood cells.
Symptoms: Often asymptomatic and discovered through routine blood tests.
Diagnosis: Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome.
Treatment: Targeted therapy: Imatinib
Outcome: 5-year event-free survival (EFS) of 90%. Eventually progresses to accelerated phase and then blast crisis.- allogeneic bone marrow transplant.
What do we know about BCR-ABL Oncogene?
→ 95% of cases of CML have a detectable Philadelphia chromosome (Ph’)
BCR:
→ Encodes a protein that needs to be continuously active + ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition) =
BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity
What can Unregulated BCR-ABL= tyrosine kinase activity cause?
→ Proliferation of progenitor cells in the absence of growth factors
→ Decreased apoptosis
→ Decreased adhesion to bone marrow stroma
What does giving Imatinib do?
→ Therapy: Drugs that specifically inhibit BCR-ABL. e.g. Imatinib (Glivec®, STI571). Cases negative for BCR-ABL require different therapy
→ Diagnosis: 95% of cases of CML have a detectable Ph’ chromosome.
→ Used for detection of minimal residual disease
→ Remission induced in more patients, with greater durability and fewer side effects
→ Some patients become drug resistant
