Leukemia Flashcards
1
Q
What is a leukemia?
A
- Over-production and uncontrolled proliferation of non-functional leukocytes
- These cancerous cells take up place normally occupied by functional haemopoietic cells and cause decreases normal haematpoiesis which causes:
1. Anemia
2. Immune dysfunction
3. Thrombocytopenia
2
Q
What is the difference between acute and chronic leukemias?
A
Acute leukemias:
- Rapid onset and aggressive
- Lethal if not treated
- Accumulation of leukemic ‘blasts’ in bone marrow and blood
Chronic leukemia:
- Indolent disease
- Patients often live for a long time with the disease
- WBC is elevated, but cell differentiation is ‘normal’
3
Q
What are the 4 common type of leukemia?
A
- Acute myeloid leukemia:
- Most deadly
- Heterogeneous with an average of 5 driver mutations - Chronic myeloid leukemia:
- Single driver mutation t(9;22) chromosome translocation that produces BCR-ABL fusion oncogene - Acute lymphoblastic leukemia:
- Occurs in both B cell lineage (B-ALL) and T cell lineage (T-ALL)
- 5-10 driver mutations in each case - Chronic lymphoblastic leukemia:
- Heterogenous genetics
4
Q
What are the general clinical features of acute myeloid leukemia?
A
- Neutropenia:
- Low neutrophils and comprimsied immune system
- Increased infections - Anaemia:
- shortness of breath and fatigue - Thrombocytopenia:
- excessive bleeding and purpura (bruising) - Infiltration and dissemination of leukemia:
- After overwhelming bone marrow the leukemic blats can disseminate often to skin and gums
5
Q
How is AML diagnosed?
A
- Blood smears:
- Large blast like cells (very large nuclei)
- Low RBC counts
- Few platelets - Peripheral blood analysis:
- Much greater WBC content (consisting of blasts) - Bone marrow aspirate smear:
- numeous ‘blast’ cells, reduced RBCs, lymphocytes and megakaryotcytes
6
Q
Describe the different features of AML subtypes M0-M7:
A
M0: minimally differentiated AML
- No differentiation of blasts (immature and extremely minimal cytoplasm)
- Few/no Auer rods
- Arises from mutations in common myeloid progenitor
M1: AML without maturation:
- Blasts have little cytoplasm and no maturation
- Few/no Auer rods
- Arises from mutations in myeloblasts
M2: AML with maturation:
- MPO positive
- Auer rods present (azurophilic granules)
- can be caused by t(8;21) ETO translocation
- arises from mutation in myeloblasts
M3: Acute promyelocytic leukemia (PML):
- Accumulation of immature granulocytes
- MPO positive
- Auer rods present
- Caused by t(15;17) PML- Retinoic-acid receptor alpha mutation and thus can be targeted with ARTA and ATO
M4: Acute myelomonocytic leukemias:
- Arises frommutations in monoblasts, promonocytes and myeloblats
- MPO negative
- Esterase positive
- Auer rods common
- Caused by inv(16)
M5: Acute monocytic leukemia:
- Accumulation of mutated monoblasts and promonocytes
- MPO negative
- Esterase positive
- Very poor prognosis
- Caused by del (11q), t(9;11) and t(11;19) which give rise to MLL-fusion oncogenes
- Used experimentally to give rise to AML in mice
M6-M7: Acute Erythro Leukemia and Acute Megakaryocytic leukemia:
- Very rare
7
Q
How is acute myeloid leukemia treated?
A
MO-M5 (excuding M3):
- Chemotherapy using:
1. Nucleotide analogue- cytarabine
2. Anthracyclines- daunorubicin - Often done in induction 7+3 pattern of treatment
M3: PML treatment
- Has a targeted treatment that treats the PML-Rara mutation
- Treatment is all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)
- ATRA and ATO often combined with chemotherapy
- Increases 5 year survival rate to 91.7%
8
Q
What are some favourable and adverse cytogenic and molecular risk factors in AML?
A
- Favourable:
- Inv(16) M4
- t(8;21): M2 (AML1-ETO)
- t(15;17) M3 (PML) - Intermediate:
- Normal cytogenics - Adverse:
- Complex
- translocations of ch5 and cr7
- Del(11q), t(9;11), t(11;19) M5
- FLT3-ITD mutation
9
Q
What is the overall survival rate of AML?
A
- Under 30% 5 year survival rate
- In older patients that relapse average survival is 5-10 months
10
Q
What is chronic myeloid leukemia?
A
- Uncontrolled proliferation of granulocytes
- Increased expansion of erythroid cells and megakaryocytes
- Patients can be asymptomatic or experience bruising, bleeding and fatigue
- Caused by t(9;22) philedephia chromosome that results in formation of BCR-Abl fusion protein
3 phases:
- Chronic phase: <10% myeloblasts in bone marrow
- Accelerated phase: 10-19% in bone marrow
- Blast crisis: >20% myeloblasts in bone marrow
11
Q
How is CML treated and what is its prognosis?
A
- CML has a targeted treatment known as imatinib/gleevec which targets the BCR-Abl fusion tyrosine kinase receptor and blocks its activity by competing with ATP for the binding site
- Significantly improved prognosis (up to 71% 5 year survival rate)
12
Q
What are the 4 different types of lymphoid malignancies?
A
- Acute Lymphoblastic Leukemia (ALL):
- Malignancy of very immature (lymphoid progenitor) blast cells - Chronic lymphocytic leukemia:
- Malignancy of more mature lymphocytes e.g. immature/naive B cells - Lymphoma:
- Malignancy arising in the lymph nodes
- Hodgkins and non-Hodgkins - Myeloma:
- Malignancy of fully mature antibody producing B plasma cells
13
Q
Describe Acute Lymphoblastic Leukemia and its clinical presentation:
A
- Mutation of the early lymphoid progenitors
- Predominatly pediatric and the most common childhood cancer
- Can be due to pre-B cells in the bone marrow (B-ALL) = 75%
- Pro-T cells in the thymus (T-ALL) = 25%
Clinical Presentation:
- Reflective of bone marrow failure and include:
1. Fatigue, bruising or bleeding and fever and infection
2. Pancytopenia (deficiency of WBCs, RBCs and platelets)
3. Organ infiltration (Lymph nodes, spleen, liver and CNS)
14
Q
How is AML Diagnosed?
A
Blood smears:
- Low RBCs
- Low mature WBCs
- Low platelets
- Presence of immature blast cells in peripheral blood
- Expression of TdT
15
Q
How is ALL treated?
A
- There are no targeted therapies, diverse chemotherapy is given and cure rate is 90% in children (10% of children relapse)
- Cure rates of adult ALL is very poor (8% for adults >60)
- Steroids that have specific toxicity to lymphocytes (dexamethasone) are sued
- Cranial radiation is used if there is CNS infiltration
- CAR T-Cell therapy is used for relapsed B-ALL by targeting CD19
16
Q
How does CAR T-Cell therapy treat relapsed B-ALL?
A
- The CAR T-Cells are engineered to bind CD19 which is only expressed on B cells and B cell precursors
- The CAR T-cells are able to bind to B cells in a MHC independent manner and initiate signaling via their CD3 and co-receptor domains
- The CAR T-cells target and kill all CD19+ cells in the patient and they remain as memory T-cells and prevent relapse
- The therapy is possible for B-ALL as survival without B cells is possible
17
Q
Describe the genetic drivers of T-ALL:
A
- Usually chromosomal transolations leading to overexpression of haematpoietic transcription factors
e. g. Lmo2 gene transocation to chromosome 7 or 14
18
Q
What models are used for leukemia and lymphoma research?
A
- Cell lines derived from a leukemia/lymphoma:
- cheap and easy to grow
- may not reflect in vivo disease - Transgenic mice:
- Can use mouse genetics
- Expensive and may not reflect human disease - Patient-derived xenografts:
- Transfer of human LSCs to immuno-comprimised mouse
- good for testing novel drugs
- difficult to perform genetic studies
19
Q
Describe chronic lymphocytic leukemia:
A
- Chronic disease of B-cells in the blood (smaller cells with more cytoplasm that ALL blasts)
- Disease of the elderly
- Disease can be indolent or require immediate treatment
20
Q
How is CLL treated?
A
- Indolent disease usually treated with a watch and wait approach
- If the disease progresses/has aggressive markers (e.g. high ZAP70 or CD38) it is treated with FCR treatment:
- Chemotherapy with ritiximab (an antibody that targets CD20+ cells)
- Treatments targeting BCL-2 are being trialled
21
Q
What is a lymphoma? What are the 2 main categories?
A
Lymphoma:
- Malignancies that arise in the germinal centres from precursor B and T cells (mainly B cells)
- Can be divided into Hodgkins lymphoma and non-Hodgkin’s lymphoma
22
Q
Describe Hodgkin’s lymphoma:
A
- 20% of lymphomas
- Arises from B cells
- Has characteristic Reed-Sternberg cells
- Has a 90% cure rate with chemotherapy
- Targeted with anti-CD30 antibodies
23
Q
Describe non-Hodgkin’s lymphoma:
A
- 80% of lymphomas
- Includes diffuse large B cells (most common type and aggressive) and follicular (chronic and diagnosed late)
- Non-Hodgkins lymphoma (especially DLBC) is generally more aggressive than Hodgkins
24
Q
What are the symptoms of lymphoma?
A
- Swelling of lymph nodes
- Unexplained fevers and weight loss
- Night sweats
- Enlarged spleen
- Fatigue
- Itchy skin
