Lecture 7 - Leukemia And Lymphoma - Bench To Bed Side Flashcards Preview

Block 4 - Heamatology > Lecture 7 - Leukemia And Lymphoma - Bench To Bed Side > Flashcards

Flashcards in Lecture 7 - Leukemia And Lymphoma - Bench To Bed Side Deck (20)
1

Cytotoxic chemotherapy

- works primarily through the inhibition of cell division
- other rapidly dividing cells are affected

2

Targeted therapy

- interfere with specific molecules required for tumour development and growth
- molecules often mutated or overexpressed in tumours

3

Two main types of targeted therapy

- monoclonal antibodies
- small molecule inhibitors

4

Monoclonal antibodies

- fragment antigent binding of a monoclonal antibody
- highly specific targeting

5

Anticancer effects through a number of mechanisms

- recruit host immune system to attack the target cell
- bind to ligands or receptors, interrupting essential cancer cell processes
- carry a lethal payload, such as a radioisotype or toxin, to target the cell

6

B cell lymphoma

- account for about 85% of all NHL diagnosis
- indolent NHL: prolonged median survival but generally considered incurable. New treatments needed to prolong survival, ultimate goal is to provide cure
- aggressive NHL: characterised by rapid growth but with the potential for cure. Higher initial cre rates, less toxic therapies for old and frail patients

7

Treatment of B cell lymphomas

- chemotherapy and radiation: toxic, lack specific antitumor targeted activity

- B cell lymphoma: highly express cell-surface proteins, key potential targets for treatment

8

CD20

- B lymphocyte surface molecule
- has a role in the development and differentiation of B cells into plasma cells
- expressed on late pro-B cells through to memory cells
- not expressed on early pro-B cells or plasma cells
- regulates intracellylar calcium, cell cycle and apoptosis
- disease is associated with deficiency - common variable immunodeficiency
- enable optimal B cell immune response, specifically against T-independent antigens

9

CD20 expression and target

- Expressed in B-cell lymphomas, hairy cell leukemia and B cell chronic lymphocytic leukemia
- ideal target for passive immunotherapy: not shed, modulated, or internalized significantly upon antibody bingding

10

Rituximab

- chimeric (mouse and human) monoclonal antibody
- directed against the B-cell antigen CD20
- depletes B cells by several mechanisms: direct antibody-dependent cellular cytotoxicity, complement-mediated cell death, signalling apoptosis

11

Rituximab is currently PBS-subsidised for treatment of

- indolent lymphoma as initial therapy in combination with standard chemotherapy regimens
- relapsed and refractory indolent lymphomas as single-agent therapy and as initial therapy in combination with chemotherapy
- single agent maintenance therapy in follicular lymphoma
- in patient with DLBCL, it is approved for use as intiial therapy with chemotherapy
- use with chemotherapy in previously treated and untreated patients with CLL

12

Small molecule inhibitiors

- typically interrupt cellular processes
- interfere with the intracellular signalling of tyrosine kinases
- TK signallingL molecular cascade that can lead to cell growth, proliferation, migration and angiogenesis

- compared to monoclonal antibodies: usually administered orally rather than IV, cheaper, less specific targetting, required daily dosing because half life is only hours

13

CML

- disease characterised by massive myeloid hyperplasia with accumulation of immature and mature myeloid cell sin blood and BM
- affects both sexes most commonly between age 40-60
- incidence increase by prior irraidation
- not increased in frequency in MZ twins
- 3 phases: chronic, accelerated, blast crisis

14

Philadelphia chromosome

- translocation of chromosomal materal between chromosomes 9 and 22
- results in formation of BCR-ABL hybrid gene
- encodes a protein TK that gives the cell a message to divide
- seen on light microscopy preparations of dividing cells cases
- detected by molecular techniques in all cases of CML

15

Findings of CML

- FBC: neutrophilia, immature cells mainly myelocytes circulating in the peripheral blood, increase in circulating basophils. Anemia
- bone marrow biopsy: hypercellularity, increase in myeloid series, cytogenetic analysis and molecular analysis to detect BCR-ABL
- FISH: joint fusion

16

Treatment options in CML: imatinib

- new paradigm for cancer treatment
- specific targeting of causative molecular abnormality

- not a cure byt show heamtological remission, cytogenetic remission and even a bit of molecular remission

17

Induction of differentiation: acute promyelocytic leukemia and all transretinoic acid

- 5% of AML
- dont really know what causes it or how to treat it
- before treatment with retinoic acid people would die in days

18

Granulocytopoiesis

- Granulocytes: malignant cell in AML and APML
- give rise to neutrophils, eosinophils and basophils
- survive in peripheral blood for 3-6 hours
- differentiate from early progenitor cells in the BML takes 7-10 days
- myeloblasts: minimally granulated, scant cytoplasm, prominent nucleolus
- Promyelocyte: abundant primary granules
- Myelocyte: secondary or specific granules
- After myelocyte stage: cells are mature and non-dividing cells

19

APL mechanism

- translocation (15,17)
- PML- RARA protein -> recruitment of chromatin-modifying proteins -> aberrant repression of RARA target genes
- stops differentiation from promyelocyte to myelocyte
- predominant white cells are thus hypergranular promyelocytes

20

Immunophenotyping of APL

- CD34 and HLADr are characteristically negative
- CD13 and CD117 are usually positive
- CD33 and CD13 are expressed in APL
- CD16 and My4 are not expressed in APL