Lecture 16/17 - Myeloid malignancies Flashcards
Myeloid cells: what are they?
- Granulocytes - eosinophils, neutrophils, basophils
- Monocytes - macrophages etc
- Erythroid and megakaryocytic lineages -
AML: what is it, what is it caused by, how is it detected, and what occurs when you suffer from AML?
Acute myeloid leukaemia
Myeloblasts
- Blast cell counts greater than 20% (either in bone marrow or blood - blast cells should not be released from marrow, if they are then they’re prematurely released - bad) - this applies to almost all (PML-RARA is an exception which can rely on translocation instead)
- Directly looking at blood for dysplasia (the presence of abnormal cells)
- Genetic/immunophenotypic markers and morphology
Myeloid accumulation in bone marrow or blood, infiltrate organs etc
AML incidence: who are most affected, how many are diagnosed per year, and what percentage of cases occur in those under 25?
Most common at 65yr+
~2000 diagnosed with AML every year
25% of cases in those <25
AML genetic mutations: how many are there, what are some of the most common examples, and what is a disease that can transform into AML?
Countless
- Translocations between chromosomes 8 and 21
- Translocations between chromosomes 15 and 17
Prior myelodysplastic/myeloproliferative syndrome/disease (MPD) causes excessive amounts of myeloid cells which overwhelm the bone marrow and prevent functioning cell production - may transform into AML
FAB scheme: What is it and what does it do?
French-American and British scheme - classifies AML within 8 sub-categories using different cytochemical stains, immunophenotypes, and molecular genetics
M0 - Undifferentiated blasts
M1 - Lightly granulated blasts
M2 - Granulated blasts often with auer rods
M3 - Promyelocytic leukaemia
M4 - Myelomonocytic leukaemia
M5 - Monocytic leukaemia
M6 - Erythroleukaemia
M7 - Megakarycotyic leukaemia
Auer rods: what are they?
Cytoplasmic inclusions found only in the leukaemic cells of some cases of AML
Red and needlelike crystals that contain peroxidase
FAB class M3 acute promyelocytic leukaemia (APML): what occurs
Chromosomal translocation - t15-17 blocking differentiation of the promyelocyte into a myelocyte causing promyelocyte accumulation
Promyekotic leukaemia gene and retinoic acid receptor a gene (PML-RARa) are fused and blocks promyleocyte differentiation, found in 98% of these cases
All-transretinoic acid (ATRA) - degrades the fusion product and now induces differentiation of the leukaemic cells
M2 AML: granulated blasts with auer rods
t8-21
AML1 gene on 21 and ETO gene on 8
Typically, AML1 encodes the alpha chain of the heterodimeric transcriptional apparatus ‘core binding factor’ which is critical for hematopoietic development
This translocation brings together RUNX1 (a transcription factor) and RUNX1T1 (a co-repressor)
RUNX1 should normally bind with CBF and promote hemopoietic differentiation, maturation, and apoptosis when required, but when bound with RUNX1T1, other co-repressors (including histone deacetylase) bind and myeloid differentiation is prevented
Clinical features of AML: what is the general process?
- Dominated by bone marrow failure - myoblast infiltration
- Anaemia, thrombocytopenia, infections
- Skin infiltration and CNS disease - mass infiltration of organs
AML: Diagnosis
Diagnosis based on:
* Full blood count
* Blood film looking for blasts
* Bone marrow smear - if they have 20% blasts
* Immunophenotyping - can use clusters of differentiation with monoclonal antibodies to detect which lineage/maturity is affected (CD33 is a common one(?))
* Cytogenetics and molecular genetics - chromosomal antibodies
AML treatment
Supportive and specific:
* Often have to treat fever asw
* Treatment of bone marrow
Chemotherapy:
* Induction (remission-reduction)
* Consolidation (post-induction)
Treatment aims to achieve a complete remission (<5% blasts in bone marrow) and consolidation then aims to eliminate any residual cells
AML treatment drugs
Cytotoxic and nonspecific
Induction chemotherapy using cytarabine and an anthracycline (daunorubicin)
Consolidation treatment is based on prognostic features - those with favourable prognostic factors will get shorter, easier treatment
- Myelotoxic - limited selectivity: they destroy all marrow cells
- Bone marrow failure (as cells get destroyed)
Immunotherapy
Massive area of science
Involves using the immune system to reject and destroy tumours
Anti CD33 therapies
Specifically destroy granulocyte and macrophage precursors
Mylotarg: gemtuzumab ozogamicin - a monoclonal immunoconjugate targeted against CD33 to treat AML, originally controlled trials failed to demonstrate safety and efficacy using it with other chemotherapeutic agents but now can be used with daunorubicin and cytarabine
Stem cell transplantation
Autologous - patients own marrow used and collected while the patient is in remission
Allogenic - marrow from a normal donor with same tissue type (often using close relatives)
AML prognosis
Very vraiable
Dependent on age and prognostic factors like cytogenestics
Survival rate as age increases
Children - ~50%
Young adults - ~50%
Elderly (>65) - <5%
CML
Chronic myeloid leukaemia
Proliferation of mature granulocytes (n,e,b) and their precursors is the main finding
Most clinically researched haematological malignancy - first to be associated with a chromosomal abnormality (Philadelphia chromosome - t(9;22), BCR-ABL1+)
- Block between myelocyte and poly
- Accounts for ~15% of leukaemia
- May occur at any age
- Overall incidence of 5-10 cases/million population
- First to have significant reported success with a molecular targeted therapy - imatinib
Philadelphia chromosome: what occurs with it and
Reciprocal translocation between the long arm of chromosome 9 and 22, resulting in fusion between proto-oncogene ABL and the BCR gene on chromosome 22 resulting in a chimeric BCR-ABL protein which causes tyrosine kinase production and stimulation of abnormal blood cell production
ABL1: what does it stand for?
Abelson murine leukaemia viral oncogene homolog 1
BCR: what does it stand for?
breakpoint cluster region protein
Clinical features of CML: what are they and what is the largest form of diagnosis for it?
- Weight loss
- Night sweats
- Splenomegaly (spleen enlargement) frequently occurs
- Anaemia/bleeding/bruising common
In up to 50% of cases, diagnosis is made incidentally from a routine blood count
Lab findings of CML
- Leukocytosis - a common occurrence
- Increased basophils (common)
- Bone marrow is usually hypercellular with a raised myeloid/erythroid ratio.
- The Philadelphia chromosome is detected by cytogenetics - BCR-ABL fusion is detectable by FISH (or PCR)
The three phases of CML: what are they, how long do they last, how many blasts are present, what symptoms are present, and what are the relevant features?
Chronic phase:
* 5-6 years
* 10-15%
* Asymptomatic
* Expansion of myeloid compartment
Accelerated phase:
* 6-9 months
* 15-<30%
* Increased tiredness, weight loss, splenomegaly
* New cytogenetic abnormalities
Blast crisis:
* 3-6 months
* >30%
* Increased blood cells in bone marrow and blood, extramedullary disease
* Increased genomic instability
Treatment: How treatable are each of the phases and what is the actual treatment?
Chronic phase (CML-CP) - responds well to chemotherapy usually
Blast phase (CML-BP) - fatal, acute leukaemia
Tyrosine kinase inhibitors (TKI) - 4 licensed for use: imatinib and second-generation TKIs bosutinib (not NICE-approved), dasatinib, and nilotinib
‘Tinib’ meaning
nib - inhibitors
Tinib - tyrosine kinase inhibitors
NICE
National institute for health and care excellence
Imatinib: what is it, what does it do, how does it do this, and what issues are there with it?
BCR-ABL tyrosine kinase inhibitor Imatinib (Glivec)
It controls the blood count, clears the marrow of malignant cells, increases the chronic phase, and reduces the risk of acute transformation
Mode of action:
* Block the binding of ATP to BCR-ABL
* Inhibits the activity of the kinase and
* Inhibits the proliferation of BCR-ABL cells.
But…the drug is specific - molecular resistance to Imatinib emerging and second-generation tyrosine kinase inhibitors and beyond (?????)
IRIS study: what is it and what did it do?
The International Randomized Study of Interferon and STI571 (IRIS) trial - compared the efficacy and safety of imatinib (IM) with that of interferon-alpha plus low-dose cytarabine in 1106 patients with newly diagnosed chronic-phase CML
Dasatinib
- Broad multikinase inhibitor
- Effective in many cases where BCR-ABL1 has acquired mutations rendering it resistant to Imatinib
Nilotinib
- A similar mechanism of action to Imatinib
- Higher affinity for BCR-ABL1 kinase
