W1P3 Flashcards
What are platelets
Cell fragments that function as part of hemostasis
- Initiate thrombus formation with overt vascular injury
- Proposed role in wound repair, innate immune response, metastatic malignancy
What is the lifespan of platelets
What is the normal count?
Life span of 7-10 days
Normal count 150 x 109/L – 450 x 109/L
1/3 of platelets are always transiently sequestered in the spleen
Platelet production
- how is production regulated?
Bone marrow production of megakaryocytes stimulated by thrombopoietin
Megakaryocytes shed platelets from their cytoplasm – each produces 1000-3000 platelets
Thrombopoietin induces megakaryocyte maturation and differentiation
Produced in liver
- c-mpl receptors expressed on circulating platelet mass provide feedback loop
- Decreased platelet mass = decreased amount of c-mpl receptors = decreased clearance of TPO = resulting increase in megakaryocyte production
What is Primary Hemostasis
- What are the four steps?
Hemostasis is process by which bleeding is stopped at site of injury with normal blood flow elsewhere
Four steps
- Adhesion to injured site
- Activation and secretion
- Aggregation
- Interaction with coagulation factors
What are some strong vs weak physiologic stimuli of platelets?
strong: collagen, thrombin
Weak: ADP, epinephrine
How does endothelium usually maintain anticoagulant surface?
- What happens in injury?
via. production of NO and prostacyclin
INJURY: exposes the subendothelial matrix -> exposed collagen activated platelets
What are the two major platelet-collagen receptors?
GPIa/IIa (alpha 2, betal 1) - platelet adhesion
GPVI - platelet activation
inheritied loss of GPIa = mild bleeding diathesis BUT
congenital absence of GPVI = spontaneous bleeding episodes
What receptor does Thrombin use to activate platelets?
platelets express PAR: G proteins coupled Protease-Activated Receptors
PAR1 - high affinity, PAR4- low affinity receptor
P2Y12 receptor involvement in platelets?
- What is it inhibited by?
ADP binds to two G-protein coupled purinergic receptors – P2Y1 and P2Y12
When activated, P2Y12 induces platelet secretion and stable aggregation
Activated platelets secrete ADP which works in a paracrine/autocrine manner to recruit and stimulate more platelets enhancing aggregation
Activity of the P2Y12 receptor is inhibited by clopidogrel
Platelet Adhesion
Platelet surface receptor GPIb/IX/V complex binds exposed von Willebrand factor (vWF) in the subendothelial matrix
Von Willebrand factor (vWf) is a large multimeric protein secreted by endothelial cells and megakaryocytes
A. vWf adheres to subendothelial collagen conformational change allowing it to bind to GPIb-V-IX
B. Rolling process slows platelet transit and allows platelet signalling receptor, GPVI to bind collagen
C. Signalling cascade leads to activation of integrin α2β1 (GPIa/IIa) platelet firmly adheres to vessel wall
Platelet Aggregation
GPIIb/IIIa complex (integrin alpha IIb beta 3) is most commonly expressed receptor on platelet surface
Stimulation of platelet induces conformational change in GPIIb/IIIa rendering it a high-affinity receptor for fibrinogen
GPIIb/IIIa binds vWF affixed to the subendothelial matrix cytosolic component of GPIIb/IIIa adheres to the platelet cytoskeleton and induces platelet spread and clot retraction
What are the two platelet granules
Dense granules:
Contain platelet agonists
-ADP, ATP, serotonin
Alpha granules:
Contents serve to enhance platelet adhesion
-Fibrinogen, vWF, fibronectin
Define sequestration
To hide or isolate
Relationship between platelet count and risk of bleeding?
Minimal at 50 x 10^9/L
spontaneous bleeding at <20 x 10^9/L
severe, fatal: <5 x 10^9/L
Thrombocytopenia causes
Decreased platelet production
Increased destruction or consumption (immune-mediated and non-immune-mediated)
Increased splenic sequestration of platelets with normal platelet survival
Pseudothrombocytopenia
Pseudothrombocytopenia
In vitro agglutination of platelets
15-30% of all isolated thrombocytopenia
Associated with use of EDTA as anticoagulant in tube
- Confirm by ordering smear of CBC showing thrombocytopenia with automated counting
*Can be avoided by using citrate/heparin as anticoagulant
What are the DDx for isolated thrombocytopenia?
Primary immune thrombocytopenia (ITP)
Inherited thrombocytopenia
Marrow failure/myelodysplastic syndrome/malignancy
Splenic sequestration
ITP
Primary immune thrombocytopenia
-otherwise healthy looking kid (NORMAL CBC/smear) , minimal history/recurrence, apart from petechie
Immune-mediated destruction of otherwise normal platelets
- Triggered by viral infection, other immune phenomenon
- most commonly age 2-5 y/o
- Natural history is self-resolution within 6 months (75-80%)
- Most presentations include mild bruising, petechiae
IgG directed against platelet membrane antigens, most commonly GPIIb/IIIa ie integrin αIIbβ3
- Increased clearance by splenic macrophages
- Production inhibited
Management of ITP
Management options include observation or active therapy with corticosteroids, IVIg, or anti-D (if Rh-positive)
Treatment options include
IVIg (80% effective, increase within 24h, peak within 2-7d)
Short-course corticosteroids (70-80% effective, increase within 48h)
Other:
IV anti-D (“blackbox” warning)
Tranexamic acid may be used as adjunct (not if hematuria)
Platelet transfusion contraindicated except for acute life-threatening bleed or if urgent surgery required
Menorrhagia
- CBC finding
is a condition marked by abnormally heavy, prolonged, and irregular uterine bleeding. Women with this condition usually bleed more than 80 ml, or 3 ounces, during a menstrual cycle. The bleeding is also unexpected and frequent.
otherwise healthy looking, no pain, normal physical exam
CBC finding: HIGH Mean Platelet Volume (MPV)
What is used to measure platelet activation and aggregation in vitro?
Platelet agonists (ensure pts not on meds that interfere with platelets)
Common agonists are: ADP collagen Epi Ristocetin
Bernard- Soulier Syndrome
- characteristic symptoms?
- lab findings include?
Autosomal recessive platelet disorder
Deficiency of GPIb receptor for vWF, which leads to impaired platelet adhesion
RARE, affects males and females equally
Symptoms include spontaneous/excessive mucocutaneous bleeding; varying bleeding severity throughout life. Can be diagnosed in adulthood (can be mistaken for chronic ITP)
Lab findings and Management for Bernard-Soulier Syndrome?
Laboratory findings include
Macrothrombocytopenia, normal coagulation studies (PT, aPTT)
No aggregation with ristocetin, that is uncorrected by addition of plasma (vWD would correct)
Management includes
Avoidance of anti-platelet therapies
Transfusion for bleeding, or pre-procedural
What are Bone Marrow Cancers
- general lab findings
- progression of disease?
Myeloid malignancies – cancers derived from the hematopoietic stem or progenitor cell
- Affect predominately the bone marrow
- Effects are seen primarily in the blood
Lab Findings:
a. Cytopenias – decrease in one or more cell lines
Anemia, thrombocytopenia, leukopenia, neutropenia – etc
b. Pancytopenia – decrease in all cell lines
c. May also see elevation in one or more line
Erythrocytosis, thrombocytosis,leukocytosis, neutrophilia – etc
May be very aggressive or more indolent cancers
Define Leukemia
By definition a leukemia is a myeloid or lymphoid cancer that involves the bone marrow as its primary site.
May be acute or chronic
Acute Leukemia
Rapid proliferation of abnormal clone that overtakes bone marrow and prevents normal hematopoiesis
Severe anemia, thrombocytopenia, and neutropenia
Patients are symptomatic at the outset
- Rapidly progressive
- Death within weeks to months
Cells show impaired differentiation
- Immature appearance
- Little functionality
Chronic Leukemias
Differentiation is more or less intact.
Leukemic cells resemble mature, normal white cells and may even function normally
Clone grows such that for most of the disease course, the growth of normal blood cells is not significantly impaired.
- Generally follow a more indolent course
Patients often present because of an abnormal CBC (usually elevated white count)
often asymptomatic for long periods; life expectancy measured in years.
Can you have leukemia if you have a perserved blood cell function and numbers?
Yes, this is what CHRONIC leukemia looks like
Myeloproliferative Neoplasms
Cancerous stem cell disorder of the marrow
Excessive production of one or more cell lines- disordered proliferation of cells
Relatively intact differentiation
May affect WBC, RBC or platelets
May also see proliferation of other cells such as fibroblasts – myelofibrosis – and other, rarer entities
with accumulation of one or more mature cell lines in the marrow and blood
Myelodysplastic Syndromes
Cancerous stem cell disorder with
Impaired differentiation
Results in cytopenias:
Increased growth of cells inside the marrow
Decreased cell numbers outside the marrow
Faulty cells die (apoptosis) before they get into circulation
May evolve to acute myeloid leukemia over time.
What is the Origin of Myeloid Cancers
All of these cancers occur as the result of genetic changes in the hematopoietic stem cell
Effects maturation and growth of all progenitor cells
Several changes likely necessary to achieve transformation
Changes may be at chromosomal or molecular level.
What cytogenetic changes are associated with development of Leukemia and related disorders
Changes at the level of the chromosome involving large amounts of DNA at a time
May result in deletion of whole genes, even whole chromosomes
Duplication of DNA may also occur
Translocations of DNA from one chromosome to another
May result in fusion genes
Molecular genetic changes:
a. Smaller changes at critical points in DNA
Insertions/deletions
Point mutations
Missense and nonsense mutations
b. Epigenetic changes
Modifications to DNA and chromosomes that alter transcription without changing the base sequence
Methylation of cytosine
histone acetylation
What are the 4 broad categories of Leukemias?
Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML)
Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)
The Blast Cell
- what amount signifies Acute leukemia?
Immature hematopoietic cell with minimal differentiation
Characterized by:
Somewhat larger size than most hematologic cells
Large nucleus
Very “lacy” or “open” nuclear material
- DNA is not condensed as in mature blood cells
May have a prominent nucleolus or nucleoli
By definition having a blast count > 20% in the bone marrow is an acute leukemia (myeloid or lymphoid)
CLL
- Subtype?
- Marker?
- Clinical course?
Chronic Lymphoid Leukemia
- A subtype of B cell lymphoma
Cells are mature B lymphocytes that may circulate in blood or grow in lymphoid organs (spleen, nodes) - Atypical CD5 expression (CD5 is a T cell marker)
Cells appear indistinguishable from small lymphocytic lymphoma (SLL) cells
Clinical course is like an indolent lymphoma
Natural history measured in years to decades in most (but not all) cases
Responds to many of the same agents as B cell lymphomas
What is the Pathobiology of Acute Leukemia
Occurs in a single stem or progenitor cell - Evidence for this includes:
- shared chromosomal abnormalities
- rearrangement of Ig or TcR genes in ALL
Mutations appear to be common in mechanisms affecting transcription and gene modification
- e.g. 25% of all AML is initiated by a mutation in the gene DNA methytransferase-3
What are some clinical manifestations of Acute Leukemia?
Pancytopenia from marrow failure
- May or MAY NOT have leucocytosis with circulating blast cells
Constitutional Symptoms: Fevers Fatigue Bone pain* Malaise
Direct Tissue Infiltration by blast cells
Leukostasis syndromes
Tumour Lysis Syndrome
Coagulation Disturbances
Usually short duration of symptoms (weeks to months)
What is Pancytopenia
- Combo of what three CBC findings?
A condition in which there is a lower-than-normal number of red and white blood cells and platelets in the blood
- Neutropenia/Impaired immunity:
- infections, sepsis
- Usually bacterial
- Fungal infections if pronlonged neutropenia - Anemia:
- fatigue, pallor
- Cardiac ischemia in extreme cases - Thrombocytopenia
- bleeding, bruising
- disseminated intravascular coagulation
Leukostasis
Accumulation of blasts in microcirculation with impaired perfusion
- lungs: hypoxemia, pulmonary infiltrates
- CNS: altered mental status, stroke
Risk Features
- WBC»_space; 50 x 109/L (not frequent)
- AML > ALL
- Monocytic/monoblastic features
Infiltration by blast cells
- Is common sign of ____
- What does this involve?
Acute Leukemias
Involves:
- Enlargement of liver, spleen, lymph nodes
- Gum hypertrophy
- Bone pain
Other organs: CNS, skin, testis, any organ…
Laboratory features of Acute Leukemia
Pancytopenia
- WBC my be low or elevated (blasts)
Coagulation abnormalities
Electrolytes and renal disturbances
- auto tumour lysis syndrome (hyperuricemia, high K, PO4, creat)
Increased liver function tests
Bone Marrow Studies in Acute Leukemia
Usually necessary for diagnosis
Cell morphology must show > 20% immature cells (blasts) to make the diagnosis
Confirmation of blast characteristics
- Large nuclei with open chromatin and promenent nucleoli are classic features of blasts
Myeloid/Lymphoid by morphology
Cytochemistry or Flow cytometry
Cytogenetics can be done on malignant cells
Molecular testing for specific gene defects becoming more routine and bring important information to treatment decisions
Acute Promyelocytic Leukemia (APL)
A subtype of AML
Different treatment and prognosis:
Presents as AML
- Pancytopenia
- Coagulation disturbances
- Frequent
- Severe
- Lethal
- Characteristic morphology
t(15;17) in most cases
Rare variants
About 5-10% of AML
Different treatment
***Curable
Clinical features of Acute Lymphoblastic Leukemia (ALL)
B lineage vs T lineage
80% are pre B ALL, 20% are T ALL
Pre B-ALL is primarily a disease of children
75% of cases occur in children under the age of 6
Most common malignancy among children
Peak incidence in children is approximately 2 to 3 years of age
Increased risk among children with Downs syndrome
About 20% of acute leukemias in adults
AML rate in adults vs kids?
AML represents 80% of acute leukemia in adults, but only 20% of acute leukemia in children
Morphological Features of Acute Myeloid Leukemia (AML)
Morphology
- Usually larger than lymphoblasts, up to the size of a monocyte
- Moderate to abundant cytoplasm with or without granules
- May contain Auer rods
- Sometimes convoluted nucleus with diffuse chromatin and one or more nucleoli
Cells usually stain positive for Sudan black or myeloperoxidase
Classification of AML is based on?
Degree of differentiation of the blast (defined morphologically and by surface markers)
AML M0, M1 and M2 – poorly differentiated and may or may not contain granules
M0 and M1 may be difficult to distinguish from ALL
AML M4 is similar with a mixture of monocytic and granulocytic features
AML M5 cells resemble monocytes
Developing targeted therapy in AML
Specific mutations in certain genes appear to be critical in driving the disease
Inhibiting function of mutated genes may alter biology and improve outcomes
- Easy to inhibit overexpressed or overactive processes
- Less clear what to do in cases of gene loss or loss of function
Small molecules, antibodies
Targets currently in development include
- ***FLT-3 – a protein tyrosine kinase overactive in about 30% of AML: inhibitor shown to improve AML outcomes
more common in patients over 60, however must consider whether treatment is worth it past that age
What is the molecular lesion in APL?
Translocation between
- Retinoic acid receptor gene (chromosome 17)
- PML gene (chromosome 15)
Resultant PML-RARa gene drives disease (normally would have stimulated promyelocytic maturation)
Translocation can be detected rapidly with FISH or RT-PCR
Treatment of APL
Early recognition of APL
Early correction of coagulation abnormalities
Early institution of All-trans Retinoic Acid (ATRA)
- Specific treatment of APL
- Ligand for the PML-RAR protein
Addition of arsenic trioxide +/- chemotherapy now considered largely curative in nearly all cases of disease
Morphology of ALL?
Blasts are usually small with a high nuclear to cytoplasmic ratio
The bone marrow aspirate is usually hypercellular and infiltrated with blasts.
To make the diagnosis of ALL, 20% or more of nucleated cells in the bone marrow must be blasts.
Cytogenetics in ALL
Prognostically important in B-ALL, less so in T-ALL
can help determine if the prognosis is favourable or poor.
Prognosis of ALL
Children – Excellent – between 60-90% cure with chemotherapy
Infants < 1 year are the exception with poor outcomes
Adults – Fair – Only about 40% cure
Pediatric regimens appear to be more effective although more toxic to adults
Adults treated on pediatric regimens may do better
Principles of Acute Leukemia Treatment
Initial chemotherapy is directed at remission induction
Decreasing blast count in marrow to < 5%
Restoration of normal hematopoesis
Usually ~ 4 week period of treatment
- Heavy transfusion needs
- High risk of infection
Usually several more cycles of treatment needed to achieve long-term disease control
- Many, but not all patients will ultimately relapse
What is Car-T
- What is it used to treat?
- What cells does it involve?
Immunotherapy – Adoptive Chimeric AntiGEN RECEptor T cells (Car-T)
Best established for diseases of B cells expressing CD19
(ALL, CLL, NHL)
- T cell collection from pt
- T cell transfection: CAR cell membrane insertion
- T Cell Adoptive Transfer
- Patient monitoring
Immunotherapy for ACUTE leukemias
blinatumumab Bi-specific, T cell Engager Antibody *Anti CD19/CD3 Brings T cells into proximity to target cells (tumour cells) Enhanced immunologic response
Clinical progression of Myeloproliferative Disorders
Usually patients are asymptomatic for long periods of time
After several years may develop to more aggressive disease that mimics acute leukemia
In some cases (essential thrombocytosis, polycythemia vera) there is also a tendency for thrombosis to occur
What are the four major subtypes of Myeloproliferative Neoplasms
- Chronic Myeloid Leukemia – mainly white blood cells affected
- Essential Thrombocytosis – mainly platelets affected
- Polycythemia vera – mainly rbc cells affected
- Myelofibrosis – mainly accumulation of bone marrow fibroblasts
Chronic Myeloid Leukemia
- fall under which type?
- Which chromosome is involved
- accumulation of which cell type?
- differentiation?
- The prototype of the myeloproliferative disorders
Transforming event occurs in the hematopoetic stem cell
t(9;22) – Philadelphia chromosome
bcr-abl fusion gene
Results in accumulation of uncontrolled granulocytes
Platelets and rbc affected to a lesser extent
Differentiation is largely intact in the early stages
What are the three phases of CML?
Chronic Myeloid Leukemia
1. Chronic Phase Generally asymptomatic Sometimes vague symptoms (fatigue, night sweats, weight loss) may have enlarged spleen Lasts for 4-7 years
- Accelerated Phase
Increasing numbers of immature (blast cells)
Rising or falling platelets, enlarging spleen
Evidence of new genetic changes in marrow studies - Blast Phse
Acute illness occurring when blasts > 20%
Rapid collapse of bone marrow with pancytopenia
Very similar to AML, but often with higher resistance to chemotherapy
Death usually within 6 months if untreated
What is the treatment for CML?
Imatinib: abl-kinase inhibitors are mainstay of therapy*
Block the action of the fusion protein allowing restoration of normal hematopoiesis
Prevent progression to more severe disease and restore normal hematopoiesis
Not curative and must be taken indefinitely
What are the Myelodysplastic Syndrome (MDS)
The MDSs are characterized by the development of cytopenias, most commonly anemia. Patients may require considerable support with transfusion and other agents to maintain blood counts. In addition to the expected problems from low blood counts:
Low white blood cells – frequent infections
Low platelets – frequent and serious bleeding
Low red blood cells – marked anemia and even ischemia
Transfusion-dependent anemia
May also have low platelets and/or white blood cells
Genetic disease with an enhanced risk of transformation to acute myeloid leukemia.
Highly variable prognosis
life expectancy a few months to several years
What are the causes of MDS
Primary or de novo
Usually occurs above age 60
No clear provoking cause
Some association with toxins such as benzene, rubber and solvents
Therapy-related MDS
Secondary to chemotherapy, radiotherapy
Usually occurs 3 – 7 years after exposure
Worse prognosis with faster transformation to AML
MDS may occur secondary to other hematologic disorders
Aplastic anemia
Myelproliferative neoplasms
Paroxysmal nocturnal hemoglobinuria
TReatment options for pts with MDS
Myelodysplastic Syndrome
low risk: RBC and platelet transfusions
high risk: immunosuppresions, chemotherapy, stem cell transplants
Which type of disease is driven by bcr-abl kinase?
Myeloproliferative Disease:
Increased cell number but intact differentiation
May affect one ore more cell lines
CML – protoype disease driven by bcr-abl kinase
Which type of disease has risk of transforming to AML
Myelodysplastic disease:
Low and high risk disease – may transform to AML
Impaired Differentiation
Increased bone marrow cells with decreased circulating cells
Which type of leukemia is most common in adults?
Acute Myeloid Leukemia
- Most common in adults
- Variable prognosis depending on cytogenetics
Which Leukemia has good prognosis with All-trans-Retinoic Acid treatment?
Acute Promyelocytic Leukemia (M3)
- PML-RARa gene from translocation of chromosomes 15 and 17
- Good prognosis with All-trans-Retinoic Acid
Which Leukemia is most common in children?
Acute Lymphoblastic Leukemia
- Most common in children
- Excellent response to multiagent chemotherapy if in childhood, prognosis worse in adults
What are some cancers of the blood
- Leukemia
• Lymphoma
• Multiple myeloma
Which cancer is most common for ages 0-14?
Leukemia!
Define Cancer
Define the “ideal” Cancer treatment
Cancer: altered regulation of cell proliferation and differentiation
“Ideal” cancer treatment: eradicate cancer cells without harming normal cells
What are the 4 types of Chemotherapeutic drugs?
DNA Alkaylation: Covalently binding DNA
Anti-metabolites: blocking DNA replication
Microtubules: Messing up the process of cell division
Topoisomerase Inhibitors: blocking DNA replication phase
These^ are all NON specific, so they will target ALL rapidly proliferating cells. Yet they are still useful, and still used.
What are examples of DNA alkylation drugs?
Cyclophosphamide
Dacarbazine
- non specific drugs
What are examples of Anti-metabolite drugs?
Methotrexate
R-Fluorouracil
Cytarabine
Examples of Microtubule drugs
Vincritine
Vinblastine
Taxols
Example of Topoisomerase inhibitor drugs
Daunorubicin
DNA damage: Bleomycin
Dacarbazine
- type
- mechanism
DNA alkylating agent
- Methylates guanine at the o-6 and N-7 positions
What cells does the toxicity of alkylating agents affect?
What does Resistance to alkylating agents look like?
To rapidly proliferating cells
- Hematopoietic system
- GI tract
- Gonads
Resistance to alkylating agents
- Increased inactivation
Nucleophilic "trapping agents'
- Increased DNA repair
- Decreased activation
Methotrexate
Anti metabolite drug, non specific cancer treatment
- it is a folic acid analogue; competively binds to dihydrofolate reductase and inhibits cell division pathway (methyl transfers)
5 - Fluorouracil
DNA base modification
type of anti-metabolite drug, non specific cancer treatment
Cytarabine
Type of anti-metabolite, non specific cancer drug
Modification to the sugar: it competitively inhibits DNA polymerases. it’s incorporation into the DNA produces strand break and triggers apoptosis
Vinca Alkaloids
from a plant, transformed to Vincristine/Vinblastine
- Bind to tubulin, terminate assembly, cause depolymerization of microtubules and mitotic arrest
a Microtubule* type of non specific cancer drug
Taxols
promote microtubule assembly and inhibit disassembly
a microtubule type of non specific cancer drug
Daunorubicin (Doxorubicin)
- Used to treat?
- TYPE
- Mechanism
AML
ALL
CML
Topoisomerase inhibitors, non specific cancer drug
mechanism: Intercalates in DNA and inhibits topoisomerase II: causes DNA strand breaks
Bleomycin
topoisomerase inhibitor type non specific cancer drug
Binds to DNA and iron, forms free radicals (ROS), leading to DNA single and double strand breaks and chromosomal aberrations.
Prednisone
A type of SPECIFIC target cancer drug
Steroid hormone receptor is the target
this is a type of glucocorticoid
can alter gene expression
Imatinib
- What is it used to treat
this is a SPECIFIC cancer drug
Cancer specific Tyrosine Kinase Inhibitor (Fused BCR-Abl) fromed by translocation
Used to treat CML, chronic myeloid leukemia and ALL, acute lymphocytic Leukemia
Rituximab
- mechanism
- used to treat?
Specific cancer drug: modifies the immune response,
it is Anti CD20
mechanism: destroys both NORMAL and MALIGNANT B cells
Treats:
B cell non Hodgkins Lymphoma that is CD20+
Chronic Lymphocytic Leukemia CLL
What are drugs that block T cell priming?
Ipilimumab: block CTLA-4
Premrolizumab, Nivolumab: block PD-1/PD-L1
treats: Hodgkin Lymphoma plus other cancers
Brentuximba Vedotin
What is it?
What does it target?
What does it treat?
what is it: : an antibody-drug conjugate
Targets tumor cells expressing CD30 (HL). Conjugated via a protease-cleavable linker to a potent anti-microtubule agent
treats: specific lymphomas
Venetoclax
- Target
- Treats?
Targets BCL2, increasing apoptosis
Treats: B cell malignancies
CAR T cell therapy
- steps
- remove blood to get T cells
- Make CAR T cells in the lab, proliferate
- Infuse CAR T cells into patients
- CAR T cells bind to cancer cells and kill them
Principles of Classical Cancer chemotherapy
- High dose- maximize cell kill with tolerable toxicity
- Intermittent
- Drug Combinations
Drug combinations - delay resistance
What are the four principles
- Efficacy
- Toxicity
- Optimum scheduling
- Mechanism of interaction
What is the drug approach to Acute Lymphoblastic Leukemia?
Vincristine
Prednisone
Doxorubicin/Daunorubicin
What is the drug approach to Chronic Myelogenous Leukemia
Philadelphia chromosome^
drug: Imatinib*
Sample approach to Hodgkin Lymphoma
Think ABVD
Doxorubicin (Adriamycin)
Bleomycin
Vinblastine
Dacarbazine
Brentuximal vedotin
Nivolumab or Pembrolizumab
Sample drug approaches to Non-Hodgkin Lymphoma
Think CDVP Cyclophosphamide Doxorubicin Vincristine Prednisone
*Rituximab
