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ASPHO Lectures 2021 > Clinical Pharmacology and Targeted Therapies > Flashcards

Clinical Pharmacology and Targeted Therapies Flashcards

1
Q

Mechanism of therapeutic action of radiation?

A
  • Interacts with intracellular components
  • Direct effects on DNA (25-75% of cells killed)
  • Indirect: ionizing water creating free hydroxyl radicals that damage
  • Lethal damage from accumulation of DSB in DNA
  • Sub-lethal damage from limited DSB, SSB, cross-links or base damage
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2
Q

Factors affecting radiation sensitivity?

A
  1. Cellular
    - Cell type
    - Growth and replicative activity
    - Cell cycle phase at the time of exposure
    - Genetic mutations in oncogenes and tumour suppressor genes
  2. Microenvironment
    - Vascularity
    - Oxygenation
    - Necrosis
  3. Underlying radiation hypersensitivity
    - Ataxia telangiectasia
    - Nijmegen breakage syndrome
  4. Concomitant medications (radiation sensitizer; also increased toxicity)
    - Doxorubicin, dactinomycin, gemcitabine
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3
Q

What is a Gray? How many rad in 1 gray?

A
  • The amount of radiation depositing 1 joule of energy in 1 kilogram
  • 1 Gy=100 rad
  • 1 rad=0.01 Gy or 1 centiGray (cGy)
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4
Q

Typical total dose of radiation? How much per fraction? Why in fractions?

A
  • 10.8 (e.g. Wilms)-65 (e.g. head and neck)
  • 1.5-2 Gy fractions
  • Fractionation balances tumour lethality and normal tissue injury and exploits the cell cycle of the cancer cell
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5
Q

Advantage of proton therapy?

A

Plateau dose distribution - deposits 90-100% of the dose at the point they stop in the tissue (Bragg peak); avoids an exit dose, may decrease normal tissue toxicity

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6
Q

Cranial irradiation for ALL includes _______ and _____.

A
  • Posterior half of eye

- C2

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7
Q

Flank irradiation for Wilms Tumour includes ________.

A

Whole vertebral body

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8
Q

Irradiation for tumour spillage and peritoneal metastases includes _________.

A

The pelvis

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9
Q

Whole lung irradiation may not be able to avoid _______.

A

The thyroid gland

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10
Q

Spinal irradiation includes _______ and extends to _____.

A
  • Thecal sac

- S3

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11
Q

What is MIBG? How does it work? What cancers is it used in?

A
  • 131-Meta-iodobenylguanidine
  • Delivers beta particles via neuroendocrine transporter
  • Neuroblastoma and pheochromocytoma
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12
Q

What enzymes involved in catabolism of mercaptopurine or thiopurines in general have clinically significant polymorphisms?

A
  • Thiopurine methyl transferase (TPMT) - catabolism of mercaptopurine - increased toxicity (neutropenia) from mercaptopurine. 1/300 people deficient
  • NUDIT-15 - polymorphisms associated with thiopurine intolerance
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13
Q

What enzyme involved in irinotecan metabolism can have clinically significant polymorphisms?

A
  • UDP-glucuronosyl-transerase 1A1 (Gilberts Disease)
  • Polymorphism in promoter of UGT1A1 associated with increased neutropenia in adults receiving bolus doses of inrotecan
  • Effect on diarrhea in protracted dosing in children is unclear
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14
Q

What super family of drug metabolizing enzymes are responsible for 70-80% of all phase 1 drug metabolism? Which enzyme specifically responsible for 50% of phase 1 drug metabolism?

A
  • Cytochrome P450

- CYP3A

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15
Q

Drug interactions based on inhibition of CYP3A4 include _____ and _____.

A

Fluconazole and vincristine

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16
Q

Strategies to circumvent the blood brain barrier and examples of drugs?

A
  1. High-dose chemotherapy
    - Methotrexate, cytarabine
  2. Drugs with penetrate the BBB based on lipophilicity, molecular weight, degree of ionization, plasma concentration of free drug (protein binding)
    - Nitrosoureas, thiotepa, topotecan
  3. Disruption of the BBB
    - Osmotic, radiation, vasoactive compounds
  4. Regional chemotherapy
    - Intra-carotid chemotherapy (cisplatin, methotrexate)
    - Intrathecal injection (methotrexate, cytarabine)
    - Intratumoral (carmustine)
    - Convection enhanced delivery
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17
Q

CSF is a fixed volume that reaches ____ of adult volume by age ___ years. Why is IT chemo dose based on age?

A
  • 80%, 3 years
  • Study 1977, 1983: IT MTX dosing based on BSA, children <18 months had higher rate of isolated CNS relapse (being underdosed).
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18
Q

Volume of CSF is _____.
CSF is produced in the ______ and _____of ______ at a rate of _______.
Flow is via ______ synchronized with _____.

A
  • 135-150ml
  • Produced in choroid plexus and ependyma of ventricles at a rate of 0.35-0.4ml/min.
  • Flow via pulsatile motion synchronized with cardiac systole.
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19
Q

Dosing of intrathecal MTX and Cytarabine?

A 
MTX:
<1 yo: 6mg
1 yo: 8mg
2 y o: 10 mg
>/=3 y o : 12 mg
Cytarabine:
<1 yo : 15mg
1 y o: 30 mg
2 y o: 50 mg
>/=3 y o : 70mg
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20
Q

Definition of chemotherapy? Definition of cytotoxic therapy? Definition of molecularly targeted therapy?

A
  • Chemotherapy: drugs administered to treat cancer
  • Cytotoxic therapy: refers to ability to directly kill cancer cells through non-specific mechanisms of action such as induction of DNA damage and apoptosis that result in cell death. Is non-selective (both cancer and rapidly dividing normal cells are affected; usually myelosuppressive (except vincristine). Can target cytotoxic drugs to cell surface antigens using antibody drug conjugates
  • Molecularly targeted therapy: refer to drugs that interfere with pathways critical to oncogenic phenotype of cancer cells. Greater selectivity for cancer cells alters the side effect profile (have class effect toxicities). Are non-myelosuppressive or minimally myelosuppressive.
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21
Q

What is the Goldie-Coldman hypothesis?

A
  • Cancer cells mutate and become resistant to therapy at a rate that depends on the cancer’s inherent genetic instability
  • The probability that a cancer contains a resistance clone is dependent on the mutation rate and size of the tumour
  • Even when the tumour burden is low, there is likely to be at least one drug resistant clone
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22
Q

Three basic principles of chemotherapy for cancer in children?

A
  1. Combination therapy
  2. Adjuvant chemotherapy
  3. Dose intensity
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23
Q

Definition of adjuvant chemotherapy? 2 Examples?

A
  • Administration of chemotherapy when disease burden is minimal but risk of recurrence is high
  • -Continuation of systemic therapy after local control in localized cancer e.g. 1987 Osteosarcoma: improved 3 y EFS when chemo administered after complete resection of localized tumour (20% surgery alone vs. 65% surgery + chemo)
  • -Maintenance therapy: ALL - MTX, 6MP; RMS: vinorelbine +cyclophosphamide (2019)
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24
Q

Definition of neoadjuvant chemotherapy? Advantages?

A
  • Administration of systemic chemotherapy prior to definitive local control
  • -Reduces tumour burden at primary site prior to definitive local therapy (surgery/radiation)
  • -Controls disease not amenable to local therapy (metastases)
  • -Assesses the sensitivity of the tumour to chemotherapy by measuring tumour response
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25
Q

What does dose intensity refer to? How is it calculated? Examples?

A
  • Maximizing the dose rate of chemotherapy - highest possible dose at shortest tolerable interval
  • Calculated by normalizing the dose rate (mg/m2/week) for a drug and comparing to the dose rate of a reference drug or prior regimen
  • Eg:
  • -Interval compression improved EFS in localized EWS - JCO 2012
  • -Dose intensity of 4 drug induction in NBL correlates with response and survival (JCO 1991)
  • -Children with ALL have improved survival with standard dose vs. half dose MTX and MP in maintenance (Cancer 1971)
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26
Q

Broad classification of chemotherapies and examples?

A
  1. Alkylating agents: Classical & Non-classical
  2. Antimetabolites: Folate, purine, pyrimidine
  3. Topoisomerase inhibitors: Anthracyclines, epipodophyllotoxins, camptothecins, dactinomycin
  4. Tubulin inhibitors: Vinca alkaloids, taxanes
  5. Miscellaneous: Corticosteroids, asparaginase, bleomycin
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27
Q

List the common toxicities of cytotoxic chemotherapy

A
  • Myelosuppression
  • Nausea and vomiting
  • Alopecia
  • Oro-intestinal mucositis
  • Hepatotoxicity
  • Allergic reactions
  • Cutaneous reactions
  • Local tissue damage
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28
Q

List some unique toxicities of specific cytotoxic chemotherapies:

A
  • Anthracyclines: cardiotoxicity
  • Cyclophosphamide, ifosfamide: hemorrhagic cystitis
  • Vinca alkaloids, cisplatin: peripheral neuropathy
  • Asparaginase: coagulopathy
  • Cisplatin: ototoxicity
  • Methotrexate, cisplatin: nephrotoxicity
  • Methotrexate: leucoencephalopathy
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29
Q

Rescues for specific toxicities?

A
  • Myelosuppression: Cytokines (G-CSF), Marrow/stemm cell re-infusion, individualized dosing
  • Nausea/vomiting: antiemetics
  • Hemorrhagic cystitis (cyclophosphamide, ifosfamide): Mesna
  • Nephrotoxicity (cisplatin): Hypertonic saaline (chloruresis(
  • Cardiotoxicity (anthracyclines): Dexrazoxane
  • Myelosuppression/mucositis (methotrexate): Leucovorin, carbodypeptidase
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30
Q

Which chemo can cause tissue necrosis if extravasates? What can be given locally in addition to a surgery consult?

A
  • Doxorubicin

- Local injections of DMSO and more recently a form of dexrazoxane

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31
Q

What is the mechanism of action of alkylating agents?

A

Damage to the DNA template (alkyl adducts) induces apoptosis

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32
Q

What is the mechanism of action of bifunctional alkylators (e.g. nitrogen mustards)?

A

Damage results from formation of crosslinks (inter-strand, intra-strand, DNA-protein)

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33
Q

Temozolamide and dacarbazine mechanism of action?

A

Mutations (G-C to A-T) with methylation

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34
Q

The effects of alkylating agents are ____-independent or _____ independent. Their effect is related to ____.

A
  • Schedule, cell cycle

- AUC

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35
Q

Alkylators have a ____ dose-response curve and ______ therapeutic index.

A

Steep (log-linear), narrow

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36
Q

Classical alkylating agents?

A
  • Mechlorethamine, bendamustine, melphalan (nitrogen mustards)
  • Ifosfamide, cyclophosphamide (oxazaphosphorines)
  • Thiotepa (ethylenimines)
  • Carmustine, lomustine (nitrosureas)
  • Busulfan (alkyl sulfonate)
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37
Q

Non-classical alkylating agents?

A
  • Dacarbazine, temozolamide (triazenes)

- Cisplatin, carboplatin, oxaliplatin (platinums)

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38
Q

Which alkylating agents are prodrugs?

A

-Cyclophosphamide, ifosfasmide, dacarbazine, temozolomide

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39
Q

_____ may ameliorate ototoxicity in some treatment regimens and patient groups.

A

Sodium thiosulfate

-Lancet Oncology 2017

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40
Q

What causes hemorrhagic cystitis related to cyclophosphamide and ifosfamide? How does MESNA work?

A
  • Irritation of bladder lining by metabolite acrolein

- MESNA chelates acrolein in the bladder

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41
Q

Antimetabolites mechanism of action? Effects are ____ and ____ specific, and therefore ______-dependent.
What does methotrexate inhibit?

A
  • Inhibition of synthesis of nucleic acids or their building blocks
  • Incorporation into DNA or RNA, resulting in a defective product
  • Inhibition of enzymes required for DNA or RNA synthesis
  • Effects are cell-cycle and S-phase specific, and therefore schedule-dependent (effect related to prolonged exposure above threshold concentration)
  • Methotrexate inhibits dihydrofolate reductase
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42
Q

Purine (adenine, guanine, hypoxanthine, xanthine) analogs?

A
  • Thiopurines: Mercaptopurine, thioguanine
  • Deoxyadenosine analogs: Fludarabine, cladribine, flofarabine
  • Deoxyguanosine analogs: Nelarabine (Ara-G)
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43
Q

Pyrimidine (cytosine, thymine, uracl, orotic acid) analogs?

A

Cytarabine (Ara-C), gemcitabine, fluorouracil

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44
Q

Folate analog?

A

Methotrexate

45
Q

All antimetabolites are _______.

A

Prodrugs

46
Q

Most frequent toxicities of antimetabolites?

A
  • Myelosuppression
  • Hepatotoxicity
  • Mucositis
  • Nausea, vomiting
  • Neurotoxicity
  • Rash
  • Dermatitis
  • Pulmonary toxicity
47
Q

Drug specific effects of antimetabolites?

A
  • Nephrotoxicity: High dose MTX (HDMTX >1g/m2)
  • Radiation recall: Gemcitabine
  • Veno-occlusive disease/sinusoidal obstructive syndrome: Thioguanine
  • Immunosuppression: Fludarabine, cladribine
  • Flu-like symptoms: cytarabine, gemcitabine
48
Q

Describe neurotoxicity related to IV (HD) or IT MTX. Onset? Resolution? Incidence?

A
  • Acute encephalopathy: headache, nausea/vomiting, altered mental status, hemiparesis, aphasia, seizure
  • Chronic encephalopathy
  • Onset 5-14 days
  • IV HDMTX (osteo) - 5%
  • Leukemia/lymphoma - 0.8%
  • Resolution of acute: 1-7 days, 10-50% recur
  • Chronic is permanent
49
Q

Describe neurotoxicity related to IV HD cytarabine. Onset? Resolution? How many with residual deficit?

A
  • Acute cerebellar syndrome: nystagmus, ataxia, dysmetria, dysarthria
  • Onset day 3-8
  • Resolution typically ~1week
  • 30% have residual cerebellar deficit
50
Q

Describe neurotoxicity related to IV nelarabine. Resolution?

A
  • CNS: somnolence, seizures
  • Peripheral: “Guillain-Barre-like” weakness, parasthesia LE>UE
  • Gradually reversible (not transient)
51
Q

Describe neurotoxicity related to IV HD fludarabine.

A
  • Progressive leukoencephalopathy
  • Dose >/= 100mg/m2 daily
  • Delayed onset demyelination
  • Can be fatal
52
Q

Maximum infusion/exposure duration for MTX is ___hours. _____ rescue should start no later than ____ hours from the ____ of the MTX infusion.

A
  • 42 hours
  • Leucovorin
  • 42 hours
  • start
53
Q

Leucovorin doses greater than approx _____ should be administered IV.

A

25mg/m2

54
Q

HD MTX induced nephrotoxicity is a medical emergency that results in __________, _________ and _________.

A
  • High output acute renal failure
  • decreased MTX excretion leading to prolonged exposure to high concentratinos of MTX
  • enhanced MTX toxicity (myelosuppression, mucositis, dermal, hepatic)
55
Q

Emergency measures for management of HD MTX-induced nephrotoxicity?

A
  • Hydration and alkalinization (improve solubility of MTX)
  • Adjust (increase) leucovorin dose and administer more frequently
  • Glucarpidase (fast and effective)
  • Dialysis (slow and inefficient)
56
Q

What is glucarpidase (CPDG2) and mechanism of action?

A

Enzyme that rapidly cleaves circulating methotrexate into less active metabolite (DAMPA) and glutamic acid
DAMPA cross reacts with standard MTX assays - if used HPLC, would see dramatic reduction in MTX level

57
Q

When would you consider using glucarpidase?

A
  • Plasma MTX >/=10uM at 42h or more after start of MTX OR

- Serum creatinine >/=1.5xULN and plasma MTX >/= 2SD above the mean

58
Q

Treatment regimen for glucarpidase?

A
  • High-dose leucovorin per institutional guidelines (increase because is a folate analogue and can also be cleaved by glucarpidase)
  • Glucarpidase (CPDG2) 50units/kg IV x 1-3 doses
59
Q

Important interaction with allopurinol? Why? What is result? How to manage?

A
  • Mercaptopurine
  • Bioavailability of MP is limited by extensive first-pass metabolism by xanthine oxidase in the liver and intestinal mucosa. Allopurinol is an inhibitor of xanthine oxidase, which is the enzyme responsible for the catabolism (breakdown) of MP. Inhibition of first-pass metabolism of oral MP
  • Results in 5X increase in bioavailability of oral MP (NOT IV)
  • Management: Reduction of oral MP dose by 75%
60
Q

Interactions with methotrexate?

A
  • Competitors for renal tubular secretion: salicylates, penicillin, NSAIDs, ciprofloxacin (Decreased MTX excretion)
  • Pharmacodynamic interaction with sulfa drugs (bactrim)
  • L-asparaginase: Capizzi: MTX prior to L-asparaginase results in synergistic cytotoxicity - 1974
61
Q

What do topoisomerases do?

A
  • orchestrate the topology of DNA and are required for replication, transcription, recombination and repair
  • create and re-ligate DNA strand breaks to allow uncoiling or strand passage
62
Q

Single strand breaks = topoisomerase __.

Double strand breaks = topoisomerase ___.

A

I

II

63
Q

What do topoisomerase inhibitors do?

A

Block re-ligation leading to strand breaks

64
Q

The only topoisomerase I inhibitors we use in pediatric oncology are the ______. 2 examples.

A
  • Camptothecins

- Topotecan, irinotecan

65
Q

Examples of topoisomerase II inhibitors?

A
  • Anthracyclines: Doxorubicin, daunomycin, idarubicin
  • Epipodophyllotoxins: Etoposide, teniposide
  • Antracenedione: Mitoxantrone
  • Phenoxazone: Dactinomycin
66
Q

Which topoisomerase inhibitors are anti-tumour antibiotics?

A
  • Anthracyclines
  • Dactinomycin
  • Mitoxantrone
67
Q

Which topoisomerase inhibitors are plant products?

A

Epipodophyllotoxins, camptothecins

68
Q

Irinotecan is a _____ that is metabolized to ____ which is ____ more cytotoxic.

A
  • Prodrug
  • SN-38
  • 1000X
69
Q

SN-38 is glucuronidated to increase _______ by _____ for biliary excretion via the GI traact.

A
  • water solubility

- UGT1A1

70
Q

______ are enzymes produced by normal gut bacteria that cleave _____ from SN-38, causing diarrhea.

A
  • Glucuronidases

- glucuronide

71
Q

When does hyper-acute diarrhea secondary to irinotecan occur? Mechanism? Intervention?

A
  • Within hours (<8h)
  • Cholinergic
  • Atropine
72
Q

When does acute diarrhea secondary to irinotecan occur? Mechanism? Intervention?

A
  • > 8h
  • SN-38
  • Loperamide, octreotide
73
Q

Prophylaxis for irinotecan associated diarrhea?

A

Cefixime or similar to decrease glucuronidase producing bacteria in the gut

74
Q

Mechanism of cytotoxicty of tubulin bnding agents?

A
  • Microtubules function by having a dynamic equilibrium between polymerization and depolymerization
  • Inhibition of micrtubule function by: inhibiting tubulin polymerization, inhibiting depolymerization = stabilizing tubuliln
  • Impacts mitosis, cell structure, intracellular transport, membrane signaling, nuclear transport fo p53
  • Inhibitino of mitotic spindle formation results in metaphase arrest
  • Effects are schedule/cell-cycle dependent
75
Q

Tubulin binding agent examples, class and mechanism?

A
  • Inhibition of polymerization: Vina alkaloids: vincristine, vinblastine, vinorelbine
  • Inhibition of depolymerization (stabilize): Taxanes: paclitaxel, docetaxel
  • Both: Eribulin
76
Q

Types of vincristine neurotoxicity?

A
  • Peripheral neuropathy:
  • -Sensory (numbness, paresthesia, pain)
  • -Motor (fine motor, loss of DTRs)
  • Cranial nerve involvement:
  • -Diplopia, ptosis, hoarseness
  • Autonomic neuropathy
  • -Constipation, abdominal pain, paralytic ileus
  • -Orthostatic hypotension
  • -Urinary retention

-SIADH

77
Q

Treatment of hypersensitivity related to paclitaxel and docetaxel (secondary to vehicle).

A
  • Corticosteroids
  • H1 and H2 blockers
  • Prolong infusion
78
Q

CYP3A4 inhibitors ______ the clearance of vinca alkaloids and taxanes? CYP3A4 inducers ____ clearance of vinca alkaloids and taxanes?

A
  • reduce

- enhance

79
Q

Mechanism of action of corticosteroids?

A

Glucocorticoids bind intracellular glucocorticoid receptors, the complexes are translocated to the nucleus, dimerize and bind DNA response elements and modulate gene expression, inducing apoptosis

80
Q

_____ is a orodrug, requiring hepatic activation to ______ but not impacted by hepatic dysfunction.

A

Prednisone, prenisolone

81
Q

_______ is not bound to transcortin, _______ is tightly bound to transcortin, may contribute to lower rate of meningeal relapse in children with ALL treated with ______.

A
  • Dexamethasone
  • Prenisoloone
  • Dexamethasone
82
Q

Toxicities of corticosteroids?

A
  • Centripedal obesity
  • Growth failure
  • Immunosuppression
  • Myopathy
  • Avascular necrosis of bone
  • Gastric ulcers
  • Pancreatitis
  • Diabetes
  • Psychiatric disorders
  • Hypertension
  • Impaired wound healing
83
Q

Mechanism of action of asparginase?

A

Childhood leukemic blasts are deficient in asparagine synthase and sensitive to asparagine depletion. Depletion of asparagine is associated with improved survival in children with ALL. Asparaginase is a bacterial enzyme that depletes extracellular asparagine.

84
Q

Toxicities associated with asparaginase?

A
  • Hypersensitivity (incidence varies by type)
  • Coagulopathy
  • Pancreatitis
  • Hepatic/hyperbilirubinemia
  • Neurotoxicity
85
Q

Mechanism of action of bleomycin?

A
  • Mixture of low molecular weight glycopeptides
  • Chelates divalent transition metals such as iron, copper, zinc and nickel
  • Bleomycin-iron complexes are the active form and bind DNA producing double and single strand breaks
86
Q

Toxicity from bleomycin?

A
  • Interstitial pneumonitis
  • Linear hyperpigmentation of skin and nails
  • Alopecia
  • Hypersensitivity reactions
  • Raynaud phenomenon
  • Not myelosuppressive
87
Q

Objective, Endpoint, Subjects and Duration for Phase 1, 2 and 3 clinical trials?

A

Phase 1:

  • Objective: Dose, Toxicity Profile, Pharmacology
  • Endpoint: Toxicity, PK/PD parameters
  • Subjects: Relapsed cancer (<25)
  • Duration: 12-24 months

Phase 2:

  • Objective: Activity
  • Endpoint: Response
  • Subjects: Relapsed cancer (10-20 per tumour)
  • Duration: 24 months

Phase 3:

  • Objective: Efficacy (benefit)
  • Endpoint: Survival
  • Subjects: Untreated cancer (100s-1000s)
  • Duration: 5-10 years
88
Q

Mechanism of action and toxicities of arsenic trixoide (ATO, As2O3)?

A
  • Mechanism of action: apoptosis and differentiation of PML-RARA
  • Toxicities:
  • -Prolonged QTc
  • -Leukocytosis, APL differentiation syndrome
  • -Elevated hepatic transaminases
  • -Dermatitis
  • -Low Mg, Ca, hyperglycemia
89
Q

Mechanism of action and toxicities of all-trans retinoic acid (ATRA)?

A
  • Mechanism of action: Bind transcription factor (Retinoic acid receptor (RAR))
  • Toxicities:
  • -Retinoid acid (APL differentiation) Syndrome (25%)
  • -Chelitis
  • -Headache, pseudotumour cerebri
  • -Bone and joint pain
  • -Hypertriglyceridemia
  • -Venous thrombosis
90
Q

Mechanism of action and side effects of 13-cis Retinoic acid (isotretinoin)?

A

-Mechanism of Action: Can induce the differentiation of neuroblastoma cell lines and decrease cell proliferation
-Side effects:
Common:
–Dermatologic changes (dry skin, chelitis, photosensitivity)
–Headache
–Hypertriglyceridemia
–Hypercalcemia

Severe:

  • -Epiphyseal changes
  • -Pseudotumour cerebri
  • -Visual change
  • -Psychiatric effects
91
Q

Patients with which mutation should not receive a TKI and go on to receive transplant in CML?

A

T3151

92
Q

Toxicities from TKIs?

A
  • Skin rash
  • Diarrhea
  • Hypertension
  • Hypothyroidism
  • Proteinuria
  • Skin/Hair depigmentation
  • Hemorrhage
  • Thromboembolism
  • Hepatic
  • Hyperglycemia
93
Q

Toxicities with ALK inhibitors? Ones that have CNS penetration?

A
  • Mild neutropenia, hepatotoxicity, AKI

- CNS: mental status changes, seizures, neurocognitivie dysfunction

94
Q

Cancers with NTRK fusion oncoproteins?

A
  • Frequently (<90%): Congenital mesoblastic nephroma, infantile fibrosarcoma, secretory breast carcinoma
  • Occasionally (5-25%): Papillary thyroid cancer, some gliomas, GIST
  • Rarely (<5%): Adenocarcinoma, soft tissue sarcoma, leukemia
95
Q

Dose-limiting toxicities of NTRK inhibiors?

A
  • Larotrectinib: Increased ALT

- Entrectinib: Pulmonary edema, fatigue, dysguesia, elevated creatinine, weight gain, ataxia, bone fractures

96
Q

Mechanism of action of azacitidine? Toxicity?

A
  • Inhibitor of DNA methylation
  • pyrimidine nucleoside analogue of cytidine
  • incorporates into DNA reversibly inhibiting DNA methyltransferase and blocking DNA methylation
  • incorporates into RNA and disrupts normal RNA function and impairs tRNA cytosine-5-methyltransferase activity

-Toxicity: nausea, vomiting, fevers, diarrhea, bruising, petechiae, rigors, weakness, hypokalemia, constipation

97
Q

Mechanism of action of tazometostat? Toxicity?

A
  • Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (e.g. mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation
  • Toxicity: Anorexia, muscle spasms, nausea, vomiting
98
Q

Examples and specific toxicities of histone deacetylase (HDAC) inhibitors?

A
  • Valproic acid: somnolence, intratumour hemorrhage, pancreatitis
  • Vorinostat: thrombocytopenia, fatigue, nausea, diarrhea, anemia and vomiting
  • Etinostat: fatigue, vomiting, diarrhea, thrombocytopenia, neutropenia
99
Q

PDL1/PD1 inhibitors are an example of _______. How do they work?

A
  • Immune checkpoint inhibitors
  • PD-L1/PD1 binding inhibits T-cell killing of tumour cell
  • Blocking PD-L1 or PD-1 allows T cell killing of tumour cell
100
Q

Immune-related adverse effects (irAEs) are more frequent for ______ alone or in combination with ______ therapy. They occur ______ in the course of therapy and result in _________.

A
  • Anti-CTLA-4
  • PD-1/PD-L1
  • Early (40 days for each alone, 14 days in combination)
  • Rapid deterioration
101
Q

Immune related adverse events that resulted in fatalities in adults?

A
  • Colitis
  • Pneumonitis
  • Hepatitis
  • Myocarditis* highest fatalitty rate with 40% of reported cases resulting in death*
  • Neurologic
  • Nephritis
  • Multiorgan failure
102
Q

Effective management of immune related adverse effects?

A
  • Early recognition

- Prompt intervention with immune suppression (methylprednisolone) and/or immunomodulatory strategies

103
Q

What is bevacizumab? Mechanism of action? Tumours? Toxicity?

A
  • Humanized antibody targeting VEGF1/2/3
  • Mechanism: Blocks angiogenesis
  • Tumours: Brain tumours in children
  • Toxicity: Hypertension, rash, proteinuria, growth plate changes, fatigue
104
Q

What is rituximab? Mechanism? Tumours? Toxicity?

A
  • Chimeric antibody targeting CD20
  • Mechanism: depletes normal B-cells and antibody
  • Tumours: B-cell lymphoma, PTLD
  • Toxicity: -Infusion reactions (fever, chills, flu-like symptoms), bronchospasm, hypotension, angioedema; Lymphopenia (recovery 9-10 months); hypogammaglobulinemia/opporttunistic infections
105
Q

What is dinutuximab/dinutuximab beta? Mechanism? Tumours? Toxicity?

A
  • Chimeric/cloned in cell lines anti-GD2 antibody
  • Mechanism: Antibody dependent cell mediated cytotoxicity (ADCC)
  • Tumours: Neuroblastoma
  • Toxicity: Neuropathic pain, capillary leak, hypersensittivity, rare transverse myelitis
106
Q

What is gemtuzumab ozogamicin? Mechanism? Tumours? Toxicity?

A
  • Humanized antibody drug conjugate targeting CD33 with N-acetyl calicheamicin (ozogamicin) attached
  • Mechanism: Calicheamicin is internalized and binds DNA creating double strand breaks
  • Tumours: AML
  • Toxicity: Infusion, related reactions, myelosuppression, serious infections
107
Q

What is inotuzumab ozogamicin? Mechanism? Tumours? Toxicity?

A
  • Humanized antibody drug conjugate targeting CD20 with N-acetyl calicheamicin (ozogamicin) attached
  • Mechanism: Ozogamicin is internalized and binds DNA creating double stranded breaks
  • Tumours: B-cell malignancies
  • Toxicity: Infusion reactions: myelosuppression, infection, hepatotoxicity, post-transplant SOS
108
Q

What is brentuximab vendotin? Mechanism? Tumours? Toxicity?

A
  • Chimeric antibody drug conjugate targeting CD30 with monomethyl auristatin E (MMAE) attached
  • Mechanism: Tubulin binding agent
  • Tumours: Hodgkin lymphoma, ALCL
  • Toxicity: Neutropenia, neuropathy, fatigue, fever, anorexia, nausea, vomiting, infusion reaction, rare leukoencephalopathy

ASPHO Lectures 2021 (10 decks)

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