3. Methotrexate
Mechanism of action:
Inhibition of Dihydrofolate reductase (DHFR) resulting in depletion of reduced folates leading
to inhibition of DNA synthesis.
Elimination:
Main route of elimination is renal excretion.
Dose reduction is needed in patients with renal insufficiency.
Third Spacing:
Exits slowly from third space fluid collection (ascites, pleural effusion).
Half life is prolonged leading to increased toxicities.
Fluids should be drained prior to methotrexate therapy.
Route of administration:
Can be given oral, IV, and intrathecally (IT).
IT MTX may result in myelosuppression or mucositis as therapeutic blood level can be achieved.
4. Methotrexate and CNS lymphoma/leukemia
High-dose MTX:
(2-8 grams/m2 IV) results in therapeutic concentration of the drug in CSF.
cornerstone of therapy in primary or secondary CNS lymphoma/leukemia
Aggressive hydration:
should be started 12 hours before to ensure that the urine pH is more than 7
to avoid methotrexate-induced nephropathy by keeping urine alkaline
IVF should be continued and PH be maintained > 7 for 24-48h after MTX infusion
MTX level monitoring:
every 24 hr starting at 24 hr after completion of MTX infusion until level is down to <50nM
Leucovorin Rescue:
administered starting 24 hour after start of MTX and continued until the MTX level is <50nM
5. Cytarabine (ara-C)
Standard agent in combination with anthracyclines for AML (7+3).
Cytarabine (ara-C): inhibits DNA synthesis and function
Usually administered by continuous IV infusion to circumvent rapid
metabolism and short half life
May be used intrathecally for therapy of meningeal leukemia
High-dose cytarabine
can cause severe myelosuppression
Mucositis
Cerebral, cerebellar dysfunction: slurred speech, ataxia, confusion and coma
Conjunctivitis: drug is excreted in tears, give hydrocortisone eye drops
6. Fludarabine
Significant activity against lymphoid malignancies: CLL and NHL
Inhibits DNA synthesis.
Fludarabine can cause:
Myelosuppression:
Neutropenia, thrombocytopenia,
autoimmune hemolytic anemia and thrombocytopenia
Nausea, vomiting, fever, tumor lysis syndrome
Immunosuppression:
increased incidence of opportunistic infections: herpes, fungus, PCP pneumonia.
patient should be placed on Bactrim prophylaxis.
recovery of CD4 cells may take up to a year after completion of chemotherapy.
7. Cladribine
Inhibition of DNA synthesis
Main activity is in the treatment of hairy cell leukemia
Usual dose is single 0.09 mg/kg/day IV continuous infusion for 7 days
leading to complete remission in 85% of patients.
Cladribine can cause:
Myelosuppression, thrombocytopenia and neutropenia, fever
Immunosuppression:
increased incidence of opportunistic infections: herpes, fungus, PCP pneumonia.
patient should be placed on Bactrim prophylaxis.
recovery of CD4 cells may take up to a year after completion of chemotherapy.
9. Cyclophosphamide
Clinical pharmacology
Well absorbed orally (90% bioavailability)
Metabolized by liver, excreted in urine (adjustment in renal dysfunction)
drug-drug interaction with coumadin, PT/INR must be closely monitored
Toxicity
Myelosupression, nausea, vomiting, SIADH (hyponatremia)
Hemorrhagic cystitis, late sequelae contracture and bladder cancer
Uroprotection with MESNA and IVF decreases the risk
Increased risk of secondary malignancies: AML and bladder cancer
Ifosfamide is used only IV (clinical pharmacology and toxicity same)
11. Vinka Alkaloids
Clinical pharmacology
Metabolized in the liver and excreted in the bile
Dose adjustment needed for hepatic disease
Renal excretion is only 10-15%
Toxicity
Peripheral neuropathy: dose limiting with vincristine, rare with vinblastine
Ileus
SIADH (hyponatremia)
Potent Vesicant
Myelosupression (dose limiting with vinblastine)
13. Anthracyclines
Clinical pharmacology
Primarily metabolized in the liver, about 50% excreted in the bile (dose
adjustment needed in liver dysfunction)
Renal clearance is minor (<10%)
Toxicity
Myelosupression, mucositis, alopecia, reddish urine
Cardiotoxicity: dilated cardiomyopathy, dose dependent,
risk 10% with cumulative dose of >450mg/m2 of doxorubicin, low risk
<350mg/m2
High risk group: age >70, HTN, prior CAD, prior radiation to the mediastinum
Potent Vesicant
14. Immunotherapy
Rituximab
CD20+ve lymphoma and leukemias
Ofatumumab
CD20+ve lymphoma and leukemias, works in rituximab resistant cases
Daratumumab
CD38 monoclonal antibody used for treatment of refractory multiple myeloma
alone or in combination with iMID or PI
Has single agent activity in multiple myeloma
Elotuzumab
Anti-CS1 monoclonal antibody used for treatment of refractory multiple myeloma
Does not have single agent acitivity
Needs to be used in combination with iMID or PI.
15. Rituximab
Mechanism of action: Chimeric MAB that targets CD20 antigen
present in the surface of B cell NHL and lymphoid leukemias
Clinical Pharmacology
Metabolized and eliminated by reticuloendothelial system
Toxicity
Infusion related reaction (black-box warning): fever, hives, angioedema,
bronchospasm, anaphylaxis can be fatal
Tumor lysis syndrome (black-box warning)
Progressive Multifocal Leukoencephalopathy (PML):Black-box warning
Hepatitis B reactivation
Increased risk of infections
16. Targeted Therapy
BCR/ABL tyrosine kinase inhibitors for CML
First generation: Imatinib,
Second generation: dasatinib and nilotinib
Third generation: busitinib, ponatinib
Bruton’s tyrosine kinase inhibitor for CLL and B cell NHL
Ibrutinib
Immunomodulatory agents (iMIDs) for multiple myeloma
Thalidomide, lenalidomide, pomalidomide
Proteasome inhibitors (Pis) for multiple myeloma
First generation: Bortezomib, Second generation: carfilzomib,
Newer generation: ixazomib (oral)
17. Imatinib
Mechanism of action
BCR/ABL tyrosine kinase inhibitor, useful in Ph+ CML and ALL
Clinical pharmacology
Oral bioavailability almost 100%
Metabolized in the liver and excreted in feces
Use with caution in patients with coumadin, monitor PT/INR closely,
Use with caution in patients on phenytoin, phenobarbital and St Jones wort
as these drugs enhance metabolism of imatinib
Toxicity
Mild nausea, vomiting, myelosuppression, myalgia, fluid retention e.g ankle
edema, periorabital edema, very rarely CHF
18. MCQs
Which one of the following is unlikely to have caused the tissue
damage ?
a. Doxorubicin
b. Vincristine
c. Mitoxantrone
d. Etoposide
Correct answer is d.
Anthracycline and vinka alkaloids are
potent vesicant; need central line to administer these agents
19. Pleural effusion needs to be drained before
administration of which one of the drugs?
a. Doxorubicin
b. Vinblastin
c. Cytarabine
d. Methotrexate (MTX)
Correct answer is d.
MTX exits slowly from third space fluid collection (ascites, pleural effusion), half
life is prolonged leading to increased toxicities; fluids should be drained prior to
methotrexate therapy.
20. Treatment with which one of the following
agents may have caused the rash?
a. Lenalidomide
b. Bortezomib
c. Rituximab
d. Vincristine
Correct anser is b.
Reactivation of herpes zoster can occur while getting treated with proteasome inhibitors (Pis) e.g.
boretezomib, carfilzomib, ixazomib. Low dose acyclovir or valaciclovir prophylaxis is very
effective.
21. Which one of the drugs need to be used with
caution with Coumadin?
a. Imatinib
b. Cyclophosphamide
c. Iphosphamide
d. Dasatinib
e. All of the above
Correct answer is d.
all of the above drugs can increase PT/INR, recommend close
monitoring of PT/INR after initiation of these agents
22. Dose adjustment in renal insufficiency is
needed for?
a. Methotrexate
b. Vincristine
c. Doxorubicin
d. Rituximab
e. All of the above
Correct answer is a.
vinka alkaloids and anthracyclines are cleared in the bile (feces) but
methotrexate is cleared by kidneys
23. Which one of the following agents is unlikely
to cause the side effect shown?
a. Methotreate (MTX)
b. Cytarabine (Ara-C)
c. Doxorubicin
d. Bortezomib
Correct anser is d.
Mucositis (painful oral sores and diarrhea) can be caused by MTX,
Ara-C and anthracyclines, boretezomib does not cause mucositis.
24. Which one of the agents is unlikely to have
caused the reaction shown?
a. Rituximab
b. Ofatumumab
c. Elotuzumab
d. Daratumumab
e. Vincristine
Answer is e.
All monoclonal antibodies can cause infusion reaction (rash, hives,
bronchospasm, fever, rarely angioedema and anaphylaxis