28 Pharmacology and Toxicity of Antineoplastic Drugs

Question 1

For bilirubin >1.5 mg/dL reduce initial dose by

Answer 1

50%

Question 2

For bilirubin >3.0 mg/dL reduce initial dose by

Answer 2

75%

Question 3

TRUE OR FALSE

Individual agents in a combination should have different mechanisms of action and should have nonoverlapping and should not have overlapping mechanisms of resistance.

Answer 3

TRUE

Individual agents in a combination should have different mechanisms of action and should have nonoverlapping and should not have overlapping mechanisms of resistance.

Question 4

While most chemotherapy agents have toxicity for marrow and epithelium, certain drugs, such as____________ are particularly valuable because their toxicities do not overlap with cytotoxics, which allows them to be used in combination at full doses.

Answer 4

Bleomycin, prednisone, and antibodies

Question 5

____________ and __________ are potent radiosensitizers and are often used with radiation therapy to improve local tumor control of the head and neck and gastrointestinal cancers.

Answer 5

5-fluorouracil and cisplatin

Question 6

The toxicity of radiation therapy to normal tissues such as skin, lung, heart, and brain is markedly enhanced by concurrent administration of _____________________

Answer 6

Anthracyclines, bleomycin, or gemcitabine

Question 7

Antimetabolites are analogues of normal metabolites kill cells most effectively during the DNA _____________________.

Answer 7

Synthetic phase (S-phase) of the cell cycle

For these agents, a prolonged period of tumor exposure to drug is essential so as to maximize the number of cells exposed during the vulnerable period of the cell cycle.

Question 8

_______________________ do not require cells to be exposed during a specific phase of the cell cycle, although like the antimetabolites, these drugs are generally more effective against actively proliferating cells as compared to resting cells.

Answer 8

Topoisomerase inhibitors and alkylating agents

Question 9

_________________ and ____________, are equally toxic to dividing and nondividing cells, and at the same time, deplete marrow stem cells.

Answer 9

Nitrosoureas and busulfan

Question 10

TRUE OR FALSE

In general, the toxicity of alkylating agents is determined by the total dose of drug, whereas the toxicity of the cell-cycle-specific drugs (such as MTX and cytarabine) depends upon both drug concentration and duration of exposure.

Answer 10

TRUE

In general, the toxicity of alkylating agents is determined by the total dose of drug, whereas the toxicity of the cell-cycle-specific drugs (such as MTX and cytarabine) depends upon both drug concentration and duration of exposure.

Question 11

For taxanes, which block mitosis, myelosuppression correlates best with the duration of exposure above a threshold plasma concentration, which is approximately _________nM for paclitaxel and_______ nM for docetaxel.

Answer 11

50–100 nM : Paclitaxel

200 nM: Docetaxel

Question 12

Cells are thus most vulnerable during periods of active DNA synthesis __________, and least affected during quiescent (_______) stages of their life cycle.

Answer 12

S-phase

G0

Question 13

Enters cells by active uptake process mediated by the reduced folate transporter and is actively effluxed from cells by the MRP class of exporters.

Answer 13

MTX

Question 14

TRUE OR FALSE

MTX is well absorbed orally at low doses (5–10 mg/m2), but at doses above 30 mg/m2 absorption is variable, requiring the MTX to be orally administered.

Answer 14

FALSE

MTX is well absorbed orally at low doses (5–10 mg/m2), but at doses above 30 mg/m2 absorption is variable, requiring the MTX to be parenterally administered.

Question 15

MTX is primarily cleared by excretion of unchanged drug through the _______________.

Answer 15

kidney

Question 16

Patients receiving HD-MTX can be rescued from drug toxicity by administering small doses of ________________, which replenishes the intracellular pool of reduced folates in a competitive manner with MTX.

Answer 16

N-10-formyltetrahydrofolate (leucovorin)

Question 17

Dose of leucovorin

Answer 17

10–25 mg/m2 at 6-hour intervals, starting 6–24 hours after the infusion of MTX

Question 18

Leucovorin continues until plasma levels of MTX fall below ______ μM.

Answer 18

1 μM

Question 19

The primary cause of decreased drug clearance and overwhelming toxicity during HD-MTX treatment.

Answer 19

Drug-induced renal dysfunction

Question 20

Serious toxicity from MTX can be prevented by vigorous pretreatment hydration of _______L/24 h during drug infusion and by raising the urine pH higher than _______ with intravenous sodium bicarbonate prior to and during therapy.

Answer 20

2.5 L/24 h

higher than 7

Question 21

A commercially available bacterial enzyme that instantly degrades extracellular antifolates and prevents further toxicity

Answer 21

Glucarpidase

Question 22

The dose-limiting toxicities of MTX are

Answer 22

Myelosuppression and gastrointestinal toxicity

Question 23

Most common hematologic side effect

Answer 23

Leukopenia

Question 24

An early indication of MTX toxicity to the gastrointestinal tract is

Answer 24

Oral mucositis

More severe toxicity may be manifested as diarrhea and gastrointestinal bleeding.

Question 25

_________ an inhibitor of protein synthesis, blocks cells from entering DNA synthesis and antagonizes the effects of MTX, when used before the antifolate.

Answer 25

L-Asparaginase

• MTX and 6-mercaptopurine (6-MP) are synergistic in their inhibition of purine biosynthesis.
• Nonsteroidal antiinflammatory drugs, which diminish renal blood flow, may reduce MTX clearance, as may proton pump inhibitors, which block the OAT3 MTX transporter in renal tubules

Question 26

An antimetabolite analogue of 2′-deoxycytidine
An inhibitor of DNA polymerase and is also incorporated into DNA, where it terminates strand elongation.

Mainstay in the induction of remission in patients with AM

Answer 26

CYTARABINE (CYTOSINE ARABINOSIDE, ARABINOSYL CYTOSINE, ARA-C)

Question 27

Cytratbine is **not orally bioavailable **because of its degradation by ___________________ , which is present in the gastrointestinal epithelium and liver.

Answer 27

Cytidine deaminase

Question 28

Ara-C confers particular benefit in patients with the ff cytogenetic abnormalities :

Answer 28

• AML: (t[8:21], inv[16], t[9:16], and del[16]) related to the core binding factor that regulates hematopoiesis
• AML: K-RAS mutations
• ALL: mixed lineage leukemia (MLL) gene translocations

Question 29

TRUE OR FALSE

Single-bolus injections and short infusions (30–60 minutes) at doses as high as 5 g/m2 produce little myelotoxicity because of the drug’s rapid clearance, whereas continuous intravenous infusion of only 1 g/m2 over 48 hours produces severe marrow toxicity.

Answer 29

TRUE

Single-bolus injections and short infusions (30–60 minutes) at doses as high as 5 g/m2 produce little myelotoxicity because of the drug’s rapid clearance, whereas continuous intravenous infusion of only 1 g/m2 over 48 hours produces severe marrow toxicity.

Question 30

Doseof cytrabine routinely used for consolidation therapy of AML

Answer 30

High-dose ara-C (3 g/m2 q12h for 3 days on days 1, 3, and 5)

Lower doses of 1 g/m2 or less should be used in patients older than 60 years to avoid CNS toxicity

Question 31

Dose of Ara-C used intrathecally to treat meningeal leukemia.

Answer 31

50–70 mg

Ara-C (50 mg given every 2 weeks) has been impregnated into a gel matrix, in a formulation called DepoCyt, for sustained release into the CSF, thus avoiding the need for repeated spinal taps.

Question 32

Form of Ara-C that provides a slow release form of drug and has been approved for AML therapy of elderly and high-risk patients.

Answer 32

Liposomal preparation containing a 5:1 ratio of ara-C to daunorubicin
(CPX-351)

Question 33

The dose-limiting toxicity for conventional dosing regimens of intravenous ara-C

Answer 33

Myelosuppression

Question 34

The nadir of the white count and platelet count occurs at about days _________ after the last dose of drug.

Answer 34

Days 7 to 10

Question 35

A 2′-2′-difluoro analogue of 2′-deoxycytidine, has significant activity against Hodgkin lymphoma

It competes with deoxycytidine triphosphate (dCTP) for incorporation into the elongating DNA strand
It inhibits ribonucleotide reductase, the rate-limiting enzyme that converts ribonucleotides into deoxyribonucleotides

Answer 35

GEMCITABINE

Question 36

Drug that upon incorporation into DNA, covalently inactivates DNA methyltransferase

Answer 36

AZACITIDINE AND DECITABINE

Question 37

Block the de novo synthesis of purines

Answer 37

6-MP and thioguanine (6-TG)

Question 38

TRUE OR FALSE

MTX and 6-MP are highly synergistic, possibly because MTX blocks the de novo synthesis of purines and enhances the activation of 6-MP from purine salvage pathways.

Answer 38

TRUE

MTX and 6-MP are highly synergistic, possibly because MTX blocks the de novo synthesis of purines and enhances the activation of 6-MP from purine salvage pathways.

6-MP blocks warfarin anticoagulation in some patients, leading to a requirement for higher doses of warfarin in patients receiving chronic 6-MP therapy for immunosuppression.

Question 39

Dose of both 6-TG and 6-MP

Answer 39

Given orally at doses of 50–100 mg/m2 per day

Oral absorption of 6-MP is erratic, as only 16% to 50% of an oral dose is systemically available.

Question 40

Drug that inhibits the metabolic inactivation of 6-MP, but not of 6-TG

Answer 40

Allopurinol

Therefore, it is recommended that dosages of orally administered 6-MP be reduced by 75% in patients receiving allopurinol.

Question 41

Both 6-TG and 6-MP are myelotoxic, producing nadirs of white blood cells and platelets at ________ days after treatment.

Answer 41

7–10 days

Question 42

TRUE OR FALSE

Patients may experience mild but rapidly reversible hepatotoxicity after treatment with either compound.

Answer 42

TRUE

Patients may experience mild but rapidly reversible hepatotoxicity after treatment with either compound.

TPMT (thiopurine- S-methyltransferase), which inactivates 6-thiopurines, is found in polymorphic forms that fail to metabolize the analogues.

Question 43

An an inhibitor of DNA synthesis and ribonucleotide reductase

Has outstanding activity in chronic lymphocytic leukemia (CLL)
Strongly immunosuppressive, like the other purine analogues, and is frequently used for this purpose in low-intensity allogeneic marrow transplantation, and for preparation for chimeric antigen-receptor T-cell (CAR-T) therapy

Answer 43

FLUDARABINE PHOSPHATE

Question 44

Fludarabine

Intravenous dose:
Oral dose:

Answer 44

Intravenous dose: 25 mg/m2 daily for 5 days
Oral dose: 40 mg/m2 daily for 5 days

Question 45

Drug that was originally identified as an adenosine deaminase (ADA) inhibitor

Has potent activity in hairy cell leukemia

Answer 45

CLADRIBINE (2-CHLORODEOXYADENOSINE, 2-CDA)

Question 46

Dose of Cladribine

IV:
SQ:

Answer 46

IV: 0.1 mg/kg per day for 7 days
SQ: 3.4 mg/m2 per day × 7 days, or by 2-hour intravenous infusion of 0.12 mg/kg daily for 5 days

Question 47

A guanine nucleoside analogue that has useful activity as a secondary agent for T-cell lymphoblastic lymphoma and acute T-cell leukemias.

Answer 47

NELARABINE (6-METHOXY-ARABINOSYLGUANINE)

Question 48

A ribonucleotide reductase inhibitor that quenches the free radical action of RNR by chelating iron, an essential cofactor in the reduction of the ribose to a deoxyribose

Answer 48

Hydroxyurea (HU)

Question 49

Uses of HU:

Answer 49

• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Lowering the myeloblast count in patients presenting with AML or blastic crisis of CML
• Preventing painful crisis and reducing hospitalization in patients with sickle cell disease
• Thalassemia patients with hemoglobin (Hb) C/SS

• Its antisickling activity results from induction of HbF through its activation of a specific promoter for the γ-globin gene.
• It may also prevent occlusion of small vessels in sickle cell patients through its generation of nitric oxide, a vasodilator, and through decreased expression of adhesion molecules such as L-selectin, on neutrophils

Question 50

The major toxicities of HU

Answer 50

Leukopenia and thrombocytopenia

The leukocyte nadir occurs 3–5 days after a single dose of drug, and the leukocyte count recovers rapidly.

Question 51

Mitotic inhibitors that derived from extracts of the vinca rosea or periwinkle plant

Bind to tubulin, a structural protein found in the cytoplasm of cells, and interrupt the formation of tubulin polymers (microtubules), the spindle along which the chromosomes migrate during mitosis

Answer 51

Vinblastine
Vincristine

Vinblastine: testicular cancer and Hodgkin lymphomas
Vincristine:non- Hodgkin lymphomas and ALL and in pediatric sarcomas

Question 52

The average single dose of:

Vinblastine
Vincristine

Answer 52

Vinblastine: 8 to 9 mg/m2
Vincristine: 1.4 mg/m2

Sequential doses of the drugs are usually given at 1–2-week intervals.

Vinca drugs have long half-lives of 20–85 hours in plasma, as they undergo metabolism by the cytochrome P450 (CYP) system in the liver.

*Both drugs cause severe pain and local toxicity if extravasated.
Do not give either drug intrathecally. *

Question 53

The dose-limiting side effect of vincristine

Answer 53

Neurotoxicity

• Usually occurs when the total dose received exceeds 6 mg/m2.
• The initial signs of neurotoxicity are paresthesia of the fingers and lower extremities and loss of deep tendon reflexes.

Question 54

TRUE OR FALSE

While marrow suppression is not common with vincristine administration, myelosuppression may be noted in patients with impaired marrow function as a consequence of prior treatment with other drugs. Platelet counts are relatively unaffected.

Answer 54

TRUE

While marrow suppression is not common with vincristine administration, myelosuppression may be noted in patients with impaired marrow function as a consequence of prior treatment with other drugs. Platelet counts are relatively unaffected.

Question 55

The primary toxicity of vinblastine

Answer 55

Leukopenia

The white count reaches a nadir at day 5–7 and reverses rapidly.

Question 56

A unique class of natural products that intercalate the DNA double helix and inhibit topoisomerase II (Topo II), an enzyme important in DNA strand passage allowing the untangling of DNA prior to replication or repair

Answer 56

ANTHRACYCLINE ANTIBIOTICS

Doxorubicin, daunorubicin, idarubicin, and epirubicin
Mitoxantrone

The anthracyclines are produced by a Streptomyces species, whereas mitoxantrone is a synthetic compound.

Question 57

Uses of Antracyclines:

Doxorubicin:
Daunorubicin, idarubicin, and mitoxantrone:
Epirubicin:

Answer 57

Doxorubicin: Hodgkin lymphoma (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]) and aggressive non-Hodgkin lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)

Daunorubicin, idarubicin, and mitoxantrone: AML

Epirubicin: solid tumors

Liposome-encapsulated doxorubicin (Doxil) is employed primarily for relapsed ovarian cancer and Kaposi sarcoma

Vyxeos, a liposome incorporating both ara-C and daunorubicin in fixed dose ratios, is approved for treatment of therapy-related AML.

Question 58

The only anthracycline amenable to oral administration

Answer 58

Idarubicin

Has a bioavailability of 20% for the parent drug and 40% for the parent drug plus idarubicinol, the primary active metabolite

Unlike other anthracycline, eliminated primarily by renal excretion. No dose adjustment for hepatic dysfunction is indicated.

Question 59

The anthracycline of choice in the treatment of adult AML

Answer 59

Daunorubicin

• The daunorubicin dosage (45–60 mg/m2 for adults younger than 60 years) is given daily for 3 days
• In people older than 65 years, a lower dose of 30 mg/m2 daily for 3 days is typically used in combination therapy.

Question 60

The primary acute toxicity of anthracycline

Answer 60

Myelosuppression

Nadir occurring 7–10 days after single-dose administration and recovery by 2 weeks.

Question 61

The major late toxic effect of anthracyclines, resulting from free radical formation catalyzed by the anthracycline’s quinone moiety.

Answer 61

Cardiotoxicity

Monitoring ejection fraction is required during anthracycline treatment and discloses reductions of 15% or greater from baseline, or an absolute ejection fraction less than 40%

Clinical risk factors include age younger than 4 years, prior chest irradiation, patients of African descent, female gender, and a history of cardiac disease.

In patients with normal cardiac function prior to treatment, the subsequent rate of doxorubicin-induced CHF reaches less than 1% at total doses of 400 mg/m2, but climbs steeply thereafter to 7% to 20% at total doses of 550 mg/m2.

Early institution of angiotensin-converting enzyme inhibitors and β blockers appears to forestall the development of CHF, and cardiac resynchronization may add benefit.

Question 62

The incidence of cardiotoxicity is decreased by coadministering _________________, an iron chelator, during chemotherapy.

Answer 62

Dexrazoxane

Fortunately, dexrazoxane does not cause any apparent diminution of antitumor activity.

Should be added only in patients who have received a total dose of at least 300 mg/m2 doxorubicin.

Dexrazoxane injected subcutaneously lessens tissue damage after extravasation.

Question 63

Treatment with Topo II inhibitors, including anthracyclines, mitoxantrone, and the epipodophyllotoxins , increases the risk of AML.

Usually can give rise to balanced chromosomal translocations involving the _______________________ genes, which contain apparent “hot spots” for Topo II breaks

Answer 63

MLL or PML (promyelocytic leukemia) genes

Question 64

Major toxicities of Alkylating agents:

Answer 64

• Myelosuppression and mucositis- primary acute toxicities
• Delayed pulmonary fibrosis (busulfan and the nitrosoureas)
• Late secondary leukemias

These secondary leukemias often arise after a period of myelodysplasia, are usually highly drug-resistant AML, and carry defects in chromosome 5 or 7.

Busulfan, bischloroethylnitrosourea (BCNU), or cyclophosphamide are most likely to cause vascular endothelial damage (hepatic venoocclusive disease) when used in high doses.

Question 65

TRUE OR FALSE

Platinum analogues are not true alkylating agents in that they form metal adducts rather than carbon adducts with DNA, RNA, and protein

Answer 65

TRUE

Platinum analogues are not true alkylating agents in that they form metal adducts rather than carbon adducts with DNA, RNA, and protein

Their range of toxicities and mechanisms of resistance have much in common with the classical alkylators.

They have few indications in hematologic malignancy, aside from carboplatin and its role in high-dose chemotherapy for lymphomas.

Question 66

The oxic metabolite of cyclophosphamide and ifosfamide

Answer 66

Acrolein

To counteract toxicity of acrolein to kidneys and bladder, the mercaptoethane sulfonate (mesna) disulfide becomes a sulfhydryl in acid urine and inactivates acrolein.

Question 67

A structural congener of DTIC, spontaneously activates to a methylating intermediate, and has become the preferred drug for treating glioblastomas

Answer 67

Temozolomide

Question 68

A highly reactive compound in its parent form, and thus can be administered topically for treatment of skin cancers and cutaneous lymphoma

Answer 68

Nitrogen mustard (mechlorethamine)

Question 69

The dose-limiting toxicity of DTIC is _______________ rather than marrow suppression.

Answer 69

Nausea and vomiting

Other adverse effects:
* Carboplatin causes an acute thrombocytopenia, neutropenia, and a more chronic sensory neuropathy.
* Nitrosoureas cause nephrotoxicity
* Cyclophosphamide and ifosfamide cause chronic bladder toxicity, hematuria, and, in rare cases, bladder carcinomas

Question 70

The most frequently used conditioning regimen for autologous stem transplantation for lymphomas

Answer 70

(BEAM) includes BCNU, etoposide, ara-C, and melphalan

Question 71

Dose-Limiting Extramedullary Toxicities of Single-Agent High-Dose Chemotherapy:

• Cyclophosphamide
• Ifosfamide
• Thiotepa
• Melphalan
• Busulfan
• BCNU
• Cisplatin
• Carboplatin
• Etoposide
• Cytarabine

Answer 71

• Cyclophosphamide:Cardiac
• Ifosfamide: Renal, CNS
• Thiotepa: GI, CNS
• Melphalan: GI
• Busulfan: GI, hepatic
• BCNU: Lung, hepatic
• Cisplatin: Renal, neuropathy
• Carboplatin: Hepatic, renal
• Etoposide: GI
• Cytarabine: Neurologic, mucositis

Question 72

Primary toxicities of Bleomycin

Answer 72

Pulmonary fibrosis and skin changes

The clinical risk of pulmonary toxicity is related to the cumulative dose of BIP administered, with the risk increasing to 10% in patients given more than 450 mg over the patient’s lifetime.

Early symptoms of BIP include cough and dyspnea.

Baseline pulmonary function tests are not recommended, except for patients with known pulmonary disease.

Question 73

Catalyzes the hydrolysis of asparagine to aspartic acid and ammonia, rapidly depletes l-asparagine from plasma and induces an asparagine deficiency in lymphoid malignant cells

Answer 73

L-Asparaginase

Question 74

TRUE OR FALSE

Hyperdiploid ALL cells are particularly sensitive to l-asparaginase, whereas lymphoid leukemia cells containing the BCR-ABL translocation are more resistant

Answer 74

TRUE

Hyperdiploid ALL cells are particularly sensitive to l-asparaginase, whereas lymphoid leukemia cells containing the BCR-ABL translocation are more resistant

Question 75

Preparations that have long plasma half-lives, are less likely to cause hypersensitivity, and are used for first-time therapy and for patients hypersensitive to the unmodified enzyme

Answer 75

Pegaspargase and calaspargase

DOSE:
* E. coli enzyme-derived: 6000–10,000 IU intramuscularly every third day for 3–4 weeks
* Pegaspargase: 2500 IU/m2 intramuscularly every 2 weeks
* Calaspargase: 2500 IU doses every 3 weeks

Question 76

TRUE OR FALSE

Anaphylaxis is less likely when E. coli l-asparaginase is given intramuscularly than when it is administered intravenously.

Answer 76

TRUE

Anaphylaxis is less likely when E. coli l-asparaginase is given intramuscularly than when it is administered intravenously.

The other major toxic effects of l-asparaginase are a consequence of the ability of this drug to inhibit protein synthesis in normal tissues, resulting in hypoalbuminemia, a decrease in clotting factors, a decrease in serum lipoproteins, and a marked increase in plasma triglycerides, which predisposes to pancreatitis.

Question 77

Induces myeloid differentiation physiologically through binding to dimers formed by the retinoic acid receptor-α (RARα) and various partners such as the retinoid X receptor

Answer 77

ALL-TRANS RETINOIC ACID

For induction of remission, ATRA is administered to APL patients in oral doses of 25–45 mg/m2 per day until complete remission is achieved.

Question 78

ATRA side effects that causes hyperleukocytosis, fever, altered mental status, pleural and pericardial effusions, and respiratory failure.

Answer 78

Differentiation syndrome

Glucocorticoids and HU are effective in reversing this syndrome.

Question 79

It promotes ubiquitination and degradation of the PML-RARα fusion protein, and upregulates p53 and proapoptotic proteins.

Part of the preferred all-oral regimen for induction and consolidation therapy of low-risk and intermediate-risk APL

Answer 79

ARSENIC TRIOXIDE

For induction, patients typically receive ATRA orally and a 2-hour intravenous infusion of ATO, 0.15 mg/kg day for up to 60 days, or until marrow remission is achieved, with further ATRA/ATO consolidation therapy beginning 3 weeks after remission

To avoid the inconvenience of daily infusions of ATO, oral formulations of both micronized ATO (15 mg/day) and arsenic Realgar-Indigo naturalis formula (RIF) (0.15 mg/kg per day) have been employed

Question 80

Side effects of ATO:

Answer 80

• Hyperglycemia
• Elevated liver enzymes
• Depletes serum potassium and magnesium
• Prolongs the cardiac QT interval
• Atrial or ventricular arrhythmias (uncommon)

It is important to monitor the QT (< 500 msec), adjust serum potassium to above 4 mEq/L, and serum Mg2+ above 1.8 mEq/L prior to drug administration, and to avoid other drugs that prolong the QT interval (macrolide antibiotics, methadone, or quinidine).

Question 81

Demythelating agents that incorporated into DNA, substituting for cytosine bases, and form a suicide covalent bond with DNMT

Answer 81

Azacitidine and decitabine

• Decitabine is phosphorylated by dCK whereas azacitidine is activated by cytidine kinase.
• Decitabine nucleotide is incorporated only into DNA, whereas azacitidine is found in both RNA and DNA.

Question 82

TRUE OR FALSE

A metaanalysis showed a significant overall survival benefit versus supportive care only for azacitidine.

Answer 82

TRUE

A metaanalysis showed a significant overall survival benefit versus supportive care only for azacitidine.

A retrospective review found no significant difference in efficacy for MDS treatment between the 2 compounds except in patients older than 65 years, for whom azacitidine resulted in improved survival and a more favorable toxicity profile.

Question 83

Dosing

Azacitidine:
Decitabine:

Answer 83

Azacitidine: 75 mg/m2/day for 7 days every 28 days
Decitabine: 20 mg/m2 intravenously daily for 5 days every 4 weeks

Azacitidine is initially phosphorylated by a different kinase (uridine-cytidine kinase) than decitabine; thus, decitabine may benefit patients unresponsive to azacytidine.

Question 84

Directly deacetylate and activate many nonhistone proteins, including p53 and members of the DNA repair complex

Effective in relapsed or refractory multiple myeloma, T-cell lymphomas

Answer 84

HISTONE DEACETYLASE INHIBITORS

Question 85

The most potent pan-HDAC inhibitor, is approved in combination with bortezomib and dexamethasone, for relapsed or refractory multiple myeloma.

Answer 85

Panobinostat

t has notable, but preliminary activity in angioimmunoblastic T-cell lymphoma, either alone or in combination with oral 21 day azacitidine.

Question 86

Other HDACs (disease targeted)

Vorinostat and romidepsin:
Romidepsin and belinostat:

Answer 86

Vorinostat and romidepsin: Cutaneous T-cell lymphoma
Romidepsin and belinostat Peripheral T-cell lymphoma

Question 87

An inhibitor of ABL tyrosine kinase activity and is particularly efficacious against the mutant ABL characteristic of the BCR-ABL fusion protein

Answer 87

BCR-ABL TYROSINE KINASE INHIBITORS

Question 88

Other gene targets of TKI:

Answer 88

• c-KIT kinase: gastrointestinal stromal tumor and mastocytosis
• PDGFR: hypereosinophilia syndrome,chronic monomyelocytic leukemia, MDS with PDGFR rearrangement, and dermatofibrosarcoma protuberans

Dasatinib and ponatinib also inhibit the Src family kinases, an important secondary target in CML.

Question 89

The only agent with significant activity against the most common resistance mutation T315I

Answer 89

Ponatinib

Question 90

All BCR-ABL inhibitors can promote fluid retention resulting in peripheral edema and pleural effusions; ____________ being the most significant offender

Answer 90

Dasatinib

Question 91

Example of JAK inhibitors

Answer 91

Ruxolitinib (Jakafi)
Fedratinib (Inrebic)

• Ruxolitinib inhibits all JAK kinases independent of their mutational status and to similar degree independent from the disease subtype
• Fedratinib is a selective JAK2 inhibitor with activity against wild-type and mutant JAK2 as well as FLT3, but significantly less activity against JAK1, JAK3, and TYK2.

Question 92

TRUE OR FALSE

Ruxolitinib improves constitutional symptoms and splenomegaly, but does not have disease-modifying activity.

Answer 92

TRUE

Ruxolitinib improves constitutional symptoms and splenomegaly, but does not have disease-modifying activity.

Question 93

Fedratinib carries this boxed warning

Answer 93

Fatal Wernicke encephalopathy

Thiamine levels should be checked before and throughout fedratinib treatment

Question 94

The most common activating FLT3 mutation

Answer 94

Internal tandem duplication (ITD) variant,

• Found in approximately 25% of patients with AML
• Confer an adverse overall prognosis

Question 95

Type of FLT3 inhibitors

Answer 95

• Sorafenib- only FLT3-ITD
• Midostaurin
• Gilteritinib

Question 96

Isocitrate Dehydrogenase Inhibitor Therapies

IDH1:
IDH2:

Answer 96

IDH1: Ivosidenib
IDH2:Enasidenib

Question 97

BTK inhibitors

Answer 97

• Ibrutinib
• Acalabrutinib
• Zanubrutinib

Uses: CLL, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and chronic graft-versus-host disease

Ibrutinib is administered orally once daily, while acalabrutinib and zanubrutinib are administered orally twice daily.

Question 98

Blocks the binding and inactivation of BH3 proapoptotic peptides to BCL-2

Answer 98

Venetoclax

Venetoclax is given in a dose escalation of 100 mg on day 1, increasing to 200 mg on day 2, 400 mg on days 3–28, with further increase in dose to 600 mg on day 4 when given with low-dose ara-C.

Antifungal drugs (posaconazole and voriconazole) strongly inhibit its clearance and necessitate a 75% reduction in dose.

Question 99

PHOSPHOINOSITOL 3 KINASE DELTA INHIBITORS:

Answer 99

• IDELALISIB
• COPANLISIB
• DUVELISIB
• UMBRALISIB

Idelalisib and duvelisib are isoform-selective, whereas copanlisib is a multitargeted pan-class I PI3K inhibitor.

Umbralisib, in addition to having selective PIK3δ inhibition, inhibits casein-kinase-1ε, an important new target for therapy of inflammatory bowel disease.

Question 100

Approved for approved for R/R CLL/SLL or follicular lymphoma

Answer 100

• Idelalisib : 150 mg orally twice daily
• Duvelisib: 25 mg orally twice daily

Question 101

THERAPEUTIC MONOCLONAL ANTIBODIES

Answer 101

• Rituximab - anti CD-20
• Ofatumumab - anti CD-20
• Obinutuzumab- anti CD-20
• Alemtuzumab - anti CD-52
• Brentuximab Vedotin - anti-CD30

Question 102

The main toxicity of Brentuximab Vedotin

Answer 102

Peripheral neuropathy

Question 103

ANTILEUKEMIC ANTIBODIES:

Answer 103

• Gemtuzumab Ozogamicin - anti-CD33
• Inotuzumab Ozogamicin - anti-CD22
• Blinatumomab - concurrently binding CD3 on T cells and CD-19 on leukemic cells

Question 104

Hepatic damage with Gemtuzumab Ozogamicin likely results from calicheamicin injury to sinusoidal cells causes

Answer 104

Hepatic sinusoidal obstructive syndrome (SOS)

Also with Inotuzumab ozogamicin

Defibrotide may play a therapeutic role in preventing severe hepatic injury in patients receiving a stem cell transplantation following GO.

Question 105

ANTIMYELOMA ANTIBODIES

Answer 105

• Daratumumab - anti-CD38
• Isatuximab- anti-CD38
• Elotuzumab- anti-SLAMF7

Question 106

IMMUNOTOXINS

Immunotoxins combine immune proteins such as antibodies, antibody Fab fragments, or interleukins with toxins

Answer 106

• Moxetumomab Pasudotox : Pseudomonas exotoxin A+ CD22 (hairy cell leukemia)
• Denileukin diftitox: diphtheria toxin + IL-2 (non-Hodgkin lymphoma)
• Tagraxofusp: diphtheria toxin + CD123 (IL-3 receptor α) (blastic plasmacytoid dendritic cell neoplasm)

Question 107

The most common side effects of Moxetumomab Pasudotox :

Answer 107

Capillary leak syndrome and hemolytic uremic syndrome

Question 108

PROTEASOME INHIBITORS

Targets the ubiquitin–proteasome pathway

Answer 108

• Bortezomib
• Carfilzomib
• Ixazomib
• Marizomib
• Oprozomib

The novel beta-lactone proteasome inhibitor, marizomib, has emerged as the most potent inhibitor, blocking the β1, β2, and β5 subunits of the proteosome, and displaying synergy with IMiDs preclinically.

Bortezomib has potent clinical activity against myeloma, and other plasma cell dyscrasias, including amyloidosis and Waldenström macroglobulinemia, and is also active in mantle cell lymphoma

Question 109

Main dose-limiting toxicity of Bortezomib

Answer 109

Sensory peripheral neuropathy

Question 110

SELECTIVE INHIBITOR OF NUCLEAR PROTEIN EXPORT

Answer 110

Selinexor

Selinexor is FDA approved in combination with dexamethasone for adult patients with R/R multiple myeloma who have received at least 4 prior therapies and have become refractory to at least 2 proteasome inhibitors, at least 2 IMiDs, and an anti-CD38 monoclonal antibody

Question 111

IMMUNOMODULATORY DRUGS

Answer 111

• THALIDOMIDE
• LENALIDOMIDE
• POMALIDOMIDE

Pomalidomide, the newest IMiD, is the most potent and least toxic

Question 112

IMID highly active in first-line combination therapy with dexamethasone, and also with bortezomib for myeloma, and is approved for the treatment of myelodysplasia in patients with the 5q− variant of this syndrome.

Answer 112

Lenalidomide

Lenalidomide produces a dramatic tumor swelling (tumor flare reaction) and tumor lysis in patients with CLL, a potentially fatal complication, even in patients with disease refractory to conventional agents.

In CLL, it is equally effective in patients with poor prognostic cytogenetics (chromosomes 11 and 17 deletions).