Pharmacology II Malignant Hematology Therapeutics

1. MALIGNANT HEMATOLOGY
PHARMACOLOGY
Rapid Integration Course
September 30, 2017
Chakra P Chaulagain, MD, FACP

2. Antimetabolites
 Methotraxate
 Cytarabine (ara-C)
 Fludarabine
 Cladribine

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.

8. Alkylating Agents
 Cyclophophamide: ALL, CLL and Non-Hodgkins lymphoma (CHOP) and
multiple myeloma
 Ifosphamide: salvage regimen in NHL (ICE)

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)

10. Vinka Alkaloids
 Vincristine
 ALL,
 NHL
 Vinblastin
 HL

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)

12. Anthracyclines
 Doxorubicin:
 Lymphoma, ALL
 Mitoxantron, daunorubicin and idarubicin
 AML

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