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?
Simply, haematopoiesis is the 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.
3. 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.
Genetic risk factors + Environmental
risk factors +Uncertain, unproven or controversial factors +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:
Acute Lymphoid Leukaemia (ALL) Chronic Lymphoid Leukaemia (CLL) Acute Myeloid Leukaemia (AML) Chronic Myeloid Leukaemia (CML)
Acute disease: rapid onset and short but severe course.
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 disease: persisting over a long time.
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 SEE NEXT FLASHCARD
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
