Chapter 38: Pharmacology and Toxicity of Antineoplastic Drugs

• Knowledge of drug actions, clinical toxicities, pharmacokinetics, and drug interactions is essential for the safe and effective administration of cancer chemotherapy.

• Base treatment on evidence from clinical trials.

• Use established regimens and recheck doses.

• Choice of a particular drug treatment program should depend on the disease, histology, and stage of the disease and on an assessment of individual patient tolerance.

• High-dose chemotherapy programs used in autologous and allogeneic hematopoietic cell transplantation result in additional organ toxicities that are not seen at conventional doses.

• Chemotherapy often targets process of DNA replication.

• More recently, drugs have been introduced to target specific cellular processes, including receptor signaling, inhibition of oncoproteins, angiogenesis, and membrane cluster of differentiation antigens.

• Combination chemotherapy uses several drugs simultaneously based on certain empiric principles:

  — Each drug selected has demonstrable antitumor activity against the neoplasm for which it is used.

  — Each drug should have a different mechanism of action.

  — The drugs should not have a common mechanism of resistance.

  — Drug dose-limiting toxicities should not overlap.

  — Specific combinations chosen should be based on preclinical and clinical protocol-based evidence of synergistic activity.

• Cell cycle–specific agents, such as antimetabolites, kill cells as they traverse the DNA synthetic phase (S phase) of the cell cycle.

  — Diminished killing of resting cells occurs.

  — Prolonged exposure to drug is useful for minimizing effects of asynchronous cell division.

  — High-dose regimens are the most useful.

• Non–cell cycle–dependent agents do not require cells to be exposed during a specific phase of the cell cycle.

  — Total dose of drug is more important than duration of exposure.

  — Appropriate dose depends on cell cycle dependence, toxicity to marrow and other tissues, pharmacokinetic behavior, interaction with other drugs, and patient tolerance.

• The basis for drug resistance is spontaneous occurrence of resistant cancer cell mutants and selection of drug-resistant cells under pressure of chemotherapy (clonal selection).

• Mechanisms such as additional mutations in mismatched repair genes and genes that block apoptosis also operate to impair treatment efficacy.

• Use of multiple drugs not sharing resistance mechanisms should be more effective than single agents.

• Multiple agents should be used simultaneously, because the probability of double- or triple-resistant cells is the product of the probabilities of the independent drug-resistant mutations occurring simultaneously in the same cell.

Methotrexate

• Methotrexate is used for maintenance therapy of acute lymphocytic leukemia, combination chemotherapy of lymphomas, and treatment and prophylaxis of meningeal leukemia.

• This agent inhibits dihydrofolate reductase, which leads to depletion of cellular folate coenzymes and to inhibition of DNA synthesis and cessation of cell replication.

• Acquired resistance is a result of increased levels of dihydrofolate reductase via gene amplification, defective polyglutamylation, and impaired cellular uptake.

• Doses of 5 to 10 mg/m² are well absorbed orally, but doses of more than 25 mg/m² should be given intravenously.

• The agent is excreted primarily unchanged by the kidney.

• Renal impairment is a contradiction to methotrexate therapy.

• Dose-limiting toxicities are myelosuppression and gastrointestinal effects (mucositis, diarrhea, bleeding).

• Intrathecal methotrexate may result in acute arachnoiditis, delirium, motor deficits, seizures, and coma. Leucovorin cannot prevent or reverse central nervous system (CNS) toxicities.

• Leucovorin intravenously will reverse acute toxicity of methotrexate, except for CNS toxicity.

Cytarabine (Arabinosyl Cytosine, Ara-C)

• This agent is used primarily to treat acute myelogenous leukemia, in combination with an anthracycline antibiotic drug.

• Ara-C triphosphate (Ara-CTP) is formed intracellularly, inhibits DNA polymerase, and causes termination of strand elongation.

• Acquired resistance is a result of a loss of deoxycytidine kinase, the initial activating enzyme of Ara-C, decreased drug uptake, or increased deamination.

• Cytarabine is not active orally and must be given parenterally.

• High cerebrospinal fluid (CSF) concentration achieved (50% of plasma level).

• Cytarabine may be given intrathecally for meningeal leukemia.

• At standard doses (100–150 mg/m² per day for 5–10 days), myelosuppression is dose-limiting toxicity.

• High-dose cytarabine therapy, 1 to 3 g/m², intravenously, at q12h on days 1, 3, and 5, is especially effective in consolidation therapy of acute myelogenous leukemia.

• At the higher doses (g/m²), neurologic, hepatic, and gastrointestinal toxicities may occur. Patients older than 50 years of age may develop cerebellar toxicity (ataxia, slurred speech), which can progress to confusion, dementia, and death. Severe conjunctivitis may also occur but may be prevented or reduced by glucocorticoid eye drops.

Gemcitabine

• Although primarily used for solid tumors, gemcitabine, a 2′-2′-difluoro analog of deoxycytidine, has significant activity against Hodgkin lymphoma.

• Its mechanism of action is similar to cytarabine, in that, as a nucleotide, it competes with deoxycytidine triphosphate for incorporation into the elongating DNA strand, where it terminates DNA synthesis.

• Gemcitabine achieves higher nucleotide levels in tumor cells than does Ara-CTP and has a longer intracellular half-life. Standard schedules use 1000 mg/m² infused over 30 minutes.

Purine Analogs: 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG)

• Both 6-MP and 6-TG are converted to nucleotides by the enzyme hypoxanthine-guanine phosphoribosyl transferase. Cell death correlates with incorporation of the 6-MP or 6-TG nucleotides into DNA.

• Both 6-MP and 6-TG are given orally.

• Equivalent myelosuppression occurs with 6-MP or 6-TG.

• Metabolism of 6-MP is inhibited by allopurinol; 6-TG metabolism is not affected.

• Thiopurine inactivating enzyme activity is decreased in 10% of persons of European descent. Dose adjustment may be necessary.

• Drugs are myelotoxic with peak neutropenia and thrombocytopenia at about 7 days; moderate nausea and vomiting; and mild, usually reversible, hepatotoxicity.

Fludarabine Phosphate

• Fludarabine has outstanding activity in chronic lymphocytic leukemia (CLL). It is strongly immunosuppressive, like the other purine analogs, and is frequently used for this purpose in nonmyeloablative allogeneic hematopoietic cell transplantation.

• It is administered intravenously and eliminated mainly by renal excretion.

• The recommended oral dose is 40 mg/m² per day. In CLL, the recommended doses are 25 mg/m² per day for 5 days given as 2-hour infusions and repeated every 4 weeks. When administered at these doses, fludarabine causes only moderate myelosuppression.

• At recommended doses, moderate myelosuppression and opportunistic infection are major toxicities. Peripheral sensory and motor neuropathy may also occur.

• Tumor lysis syndrome may occur with treatment of patients with large tumor burdens. Thus, patients should be well hydrated and their urine alkalinized prior to beginning therapy.

Cladribine (2-Chlorodeoxyadenosine)

• This purine analog is active in hairy cell leukemia, low-grade lymphomas, and CLL. A single course of cladribine, typically 0.09 mg/kg per day for 7 days by continuous intravenous infusion, induces complete response in 80% of patients with hairy cell leukemia and partial responses in the remainder.

• Eliminated primarily (> 50%) by renal excretion. In a patient with renal failure, continuous flow hemodialysis effectively cleared the drug and prevented serious myelosuppression.

• Cladribine retains effectiveness in at least a fraction of hairy cell leukemia patients resistant to deoxycoformycin or fludarabine.

• Myelosuppression, fever, and opportunistic infection are major toxicities.

• Repeated doses may produce thrombocytopenia.

Clofarabine (2-Chloro-2′ Fluoro-Arabinosyladenine)

• This analog has halogen substitutions on both the purine ring and arabinose sugar, resulting in a ready uptake and activation to a highly stable intracellular triphosphate, which terminates DNA synthesis, inhibits ribonucleotide reductase, and induces apoptosis.

• As a single agent, the drug is well tolerated by elderly acute myelogenous leukemia (AML) patients in whom it produces remission rates of 30%.

• The usual adult dose of 52 mg/m² given as a 2-hour infusion daily for 5 days.

• The primary route of clofarabine clearance is through renal excretion, and dose adjustment according to creatinine clearance is recommended for patients with abnormal renal function.

• Toxicities include myelosuppression; uncommonly, fever, hypotension, and pulmonary edema, suggestive of capillary leak caused by cytokine release; hepatic transaminitis; hypokalemia; and hypophosphatemia.

Nelarabine (6-Methoxy-Arabinosylguanine)

• The only guanine nucleoside analog, nelarabine, has relatively specific activity as a secondary agent for T-cell lymphoblastic lymphoma and acute T-cell leukemias.

• Mode of action is similar to the other purine analogs, in that it becomes incorporated into DNA and terminates DNA synthesis.

• Selective action for T cells may relate to the ability of T cells to activate purine nucleosides and the lack of susceptibility of this drug to purine nucleoside phosphorylase, a degradative reaction.

• Usual doses are an intravenous 2-hour infusion of 1500 mg/m² for adults on days 1, 3, and 5, and a lower dose of 650 mg/m² per day for 5 days for children.

• The primary toxicities are myelosuppression and abnormal liver function tests, but the drug may cause a spectrum of neurologic abnormalities, including seizures, delirium, somnolence, and the Guillain-Barré syndrome of ascending paralysis.

Pentostatin (2′-Deoxycoformycin)

• A purine analog that inhibits adenosine deaminase, resulting in accumulation of intracellular adenosine and deoxyadenosine nucleotides, which are probably responsible for the cytotoxicity.

• Biweekly doses of 4 mg/m² are extremely effective in inducing pathologically confirmed complete responses in hairy cell leukemia.

• Severe depletion of T lymphocytes occurs and opportunistic infections are common.

• The drug is eliminated entirely by the kidney.

Hydroxyurea

• Hydroxyurea inhibits ribonucleotide reductase, which converts ribonucleotide diphosphates to deoxyribonucleotides.

• Hydroxyurea is used to treat polycythemia vera, essential thrombocythemia and primary myelofibrosis, the hyperleukocytic phase of chronic myelogenous leukemia (CML), and to reduce rapidly rising blast counts in the acute phase of CML or in hyperleukocytic AML.

• The drug has also become the standard agent for decreasing the frequency of painful crisis and reducing hospitalization in patients with sickle cell disease and in patients with hemoglobin (Hgb) SC.

• Its antisickling activity results from induction of Hgb F through its activation of a specific promoter for the γ-globin gene. It may also exert antisickling activity and decrease occlusion of small vessels through its generation of the vasodilator nitric oxide or through suppression of neutrophil production and expression of adhesion molecules, such as L-selectin.

• The dose of hydroxyurea is determined empirically; patients are usually started on 500 mg orally per day, and titrated upward to balance disease control and gastrointestinal toxicity in patients with myeloproliferative diseases, and to the limit of mild neutropenia in patients with sickle cell disease.

• Resistance occurs as a result of increases in ribonucleotide reductase activity or from development of a mutant enzyme that binds the drug less avidly.

• The drug is well absorbed when administered orally.

• Renal excretion is major source of elimination.

• Major toxicities are leukopenia and induction of megaloblastic changes in marrow blood cells. Approxi­mately 30% of individuals cannot tolerate hydroxyurea due to gastrointestinal symptoms or skin ulcers.

Vinca Alkaloids (Vincristine and Vinblastine)

• Vinca alkaloids bind to microtubules and inhibit mitotic spindle formation.

• Resistance occurs by acquisition of multidrug resistance phenotype or development of microtubules with decreased vinca alkaloid binding.

• Vincristine and vinblastine are both administered intravenously. The average single dose of vincristine is 1.4 mg/m² and that of vinblastine 8 to 9 mg/m². Sequential doses of the drugs are usually given at 1- or 2-week intervals during a cycle of therapy.

• Approximately 70% of vincristine is metabolized in the liver. The site of vinblastine metabolism is unidentified. Liver disease, but not renal disease, requires a reduction in dose. In general, although specific guidelines for dose reduction have not been developed, a 50% decrease in dose is recommended for patients presenting with a bilirubin level of 1.5 to 3 mg/dL and a 75% reduction for levels greater than 3 mg/dL.

• These alkaloids are very useful in Hodgkin or non-Hodgkin lymphomas and acute lymphocytic leukemia (ALL).

• The dose-limiting toxicity of vincristine is neurotoxicity, which may begin with paresthesias of fingers and lower legs and loss of deep-tendon reflexes. Constipation is common. Other severe neurologic effects can occur.

• Severe weakness of extensor muscles of hands and feet may occur with continued use.

• Marrow suppression is not a common side effect of vincristine, but a primary toxicity of vinblastine is leukopenia.

• Both vincristine and vinblastine are potent vesicants on extravasation during administration.

• Neither vincristine nor vinblastine can be given intrathecally.

Taxanes (Paclitaxel and Docetaxel)

• These are antimitotic drugs that bind to microtubules, although the taxanes differ in their mechanism and toxicity profile from the vinca alkaloids.

• These agents have modest activity in lymphoma.

• Both drugs are cleared primarily by hepatic CYP metabolism, although by different isoenzymes (paclitaxel predominantly by CYP 2B6 and docetaxel by CYP 3A4) and are thus cleared more rapidly in patients treated with phenytoin (Dilantin) and other CYP-inducing drugs such as ketoconazole.

• They are formulated in lipid-based solvents that can cause hypersensitivity reactions; therefore, both are administered after pretreatment with antihistamines and glucocorticoids to decrease risk of allergic reaction.

• Principal toxicities are leukopenia, thrombocytopenia, and mucositis.

• Peripheral neuropathy, cardiac arrhythmias, and fluid retention can occur.

Campothecins (Irinotecan and Topotecan)

• These agents target topoisomerase I, preventing resealing of single-strand DNA breaks.

• Irinotecan has activity against some lymphomas.

• Irinotecan, 125 mg/m², is administered intravenously once each week for 4 weeks every 42 days.

• Irinotecan should be used with caution in patients with hepatic dysfunction.

• Topotecan, 1.5 mg/m² per day for 5 days, may be useful in oligoblastic leukemia, especially subacute myelomonocytic leukemia.

• Topotecan dose should be reduced if renal or hepatic impairment, including patients with Gilbert syndrome.

• Topotecan toxicity is principally myelosuppression and mucositis.

Anthracycline Antibiotics

• Anthracycline antibiotics act by forming a complex with both DNA and the DNA repair enzyme topoisomerase II, resulting in double-stranded DNA breaks.

• Doxorubicin is a mainstay of treatment for Hodgkin disease, and non-Hodgkin lymphoma, in combination with a number of other agents (eg, Adriamycin/bleomycin/vinblastine/dacarbazine [ABVD] and cyclophosphamide/hydroxy-daunorubicin (doxorubicin)/Oncovin/prednisone [CHOP], respectively).

• Daunorubicin and idarubicin are used in combination with cytarabine for AML.

• Mitoxantrone is used for AML.

• The anthracyclines are usually given every 3 to 4 weeks. Schedules that avoid high-peak plasma levels may reduce cardiac toxicity.

• Idarubicin is the only anthracycline that has reasonable oral bioavailability.

• Doxorubicin and daunorubicin are metabolized in the liver. It is wise to begin therapy of patients with elevated serum bilirubin levels at 50% doses of doxorubicin or daunorubicin and adjust according to tolerance.

• Myelosuppression is the major acute toxicity from anthracyclines. Nausea and vomiting may occur.

• Anthracyclines generate intracellular oxygen free radicals, which may cause cardiac toxicity.

• Doxorubicin may produce mucositis.

• All these drugs can produce reaction in previously irradiated tissues.

• All can produce tissue necrosis if extravasated.

• Dose-related chronic cardiac toxicity is a major side effect of doxorubicin and daunorubicin.

• Acute cardiac effects are arrhythmias, conduction disturbances, and pericarditis-myocarditis syndrome.

• Chronic cardiac effects are diminished ejection fraction and clinical congestive heart failure with high mortality.

• Children receiving anthracyclines may show abnormal cardiac development and late congestive heart failure as teenagers.

• Resistance to anthracyclines occurs with increased activity of the MRP protein and the P-glycoprotein transport system, and with altered topoisomerase II activity.

Epipodophyllotoxins

• Two semisynthetic derivatives of podophyllotoxin, VP-16 (etoposide) and VM-26 (teniposide), inhibit topoisomerase II and have significant clinical activity in hematologic malignancies.

• Etoposide is used in combination regimens for Hodgkin lymphoma, large cell lymphomas, leukemias, and various solid tumors, and is a frequent component of high-dose chemotherapy regimens.

• The agents bind to DNA and induce double-stranded breaks.

• Resistance is a result of expression of multidrug resistance phenotype or diminished drug binding.

• They may be given orally or intravenously.

• Clinical activity is schedule dependent. Single conventional doses are ineffective; daily doses for 3 to 5 days are required.

• Hypotension may occur with rapid intravenous administration.

• Major toxicity is leukopenia; thrombocytopenia is less common.

• In high-dose protocols, mucositis is common and hepatic damage may occur.

• Etoposide may induce secondary AML.

Alkylating Drugs

• These are used as single agents or in combination with other drugs to treat hematologic neoplasms.

• All form covalent bonds with electron-rich sites on DNA.

• Myelosuppression and mucositis are the major acute toxicities.

• Pulmonary fibrosis and secondary leukemias are the major delayed toxicities.

• Clinical basis of resistance to alkylating drugs is not fully understood.

• These agents are rapidly eliminated by chemical conjugation to sulfhydryl groups or by oxidative metabolism.

• Cyclophosphamide and ifosfamide produce a toxic metabolite (acrolein) that is excreted in the urine and can cause hemorrhagic cystitis. Acrolein may be detoxified by sodium 2-mercaptoethane sulfonate (mesna) given simultaneously.

• Nitrogen mustard is a potent vesicant.

• Marrow toxicity is cumulative and is a function of the total dose.

• The incidence of secondary leukemias is related to the total dose administered and to the drugs used. Procarbazine is especially potent in inducing secondary leukemia.

• Dose-limiting toxicity of dacarbazine is nausea and vomiting.

• Nitrosoureas produce delayed myelosuppression, with nadir of blood counts 4 to 6 weeks after the dose, and can also cause nephrotoxicity.

• All alkylating agents can produce pulmonary fibrosis. Busulfan and nitrosoureas are the most likely to do so.

High-Dose Alkylating Agent Therapy

• High-dose chemotherapy programs use one or several alkylating agents because of the strong relationship between dose and cytotoxicity of these drugs.

• With autologous or allogeneic hematopoietic stem cell infusions, doses of alkylating agents can be increased 2- to 18-fold until extramedullary toxicities become limiting.

Bleomycin

• Bleomycin is used in combination chemotherapy programs for Hodgkin lymphoma, aggressive lymphomas, or germ cell tumors.

• Antitumor activity is caused by formation of single- and double-stranded DNA breaks.

• Resistance is a result of accelerated drug inactivation, enhanced DNA repair capacity, or decreased drug accumulation.

• The drug is administered intravenously or intramuscularly for systemic effects and may be instilled intrapleurally or intraperitoneally to control malignant effusions.

• It is eliminated largely by renal excretion and may need dose reduction with renal dysfunction.

• It has little effect on normal marrow.

• A major toxicity is pulmonary fibrosis, which is dose related and is usually irreversible.

• Skin changes, also a major toxicity, are dose related, and include erythema, hyperpigmentation, hyperkeratosis, and ulceration.

• Fever and malaise commonly occur.

l-Asparaginase

• l-Asparaginase is used in the treatment of lymphoid neoplasms.

• Neoplastic lymphoid cells require exogenous l-asparagine for growth. l-Asparaginase destroys this essential nutrient.

• l-Asparaginase is given either intravenously or intramuscularly.

• Hypersensitivity reactions vary from urticaria to anaphylaxis. Skin testing with drug may help confirm hypersensitivity. Intramuscular administration may result in fewer hypersensitivity reactions. Patients should be observed carefully after dosing, and epinephrine should be available to reverse acute hypersensitivity reaction.

• Hypoalbuminemia may result from inhibition of hepatic protein synthesis.

• Decreased antithrombin, protein C, and protein S levels may result in arterial or venous thrombosis. Preexisting clotting abnormalities, such as antiphospholipid antibodies or factor V Leiden, may predispose to thromboembolic complications.

• Decreased levels of fibrinogen and factors II, VII, IX, and X may result in bleeding.

• Inhibition of insulin production may result in hyperglycemia.

• High doses of l-asparaginase may cause cerebral dysfunction manifested by confusion, stupor, and coma, and may also cause nonhemorrhagic pancreatitis.

• l-Asparaginase can be used to prevent marrow suppression if given after high-dose methotrexate.

Thalidomide, Lenalidomide, and Pomalidomide

• Thalidomide, and its analogs lenalidomide and pomalidomide, have established value in treating myeloma.

• Lenalidomide is highly active in first-line combination therapy for myeloma and is also approved for treatment of myelodysplasia with the 5q– variant.

• Lenalidomide produces dramatic tumor responses in patients with CLL, including a tumor flare and tumor lysis syndrome, a potentially fatal complication, even in patients with disease refractory to conventional agents. It is equally effective in patients with poor prognostic cytogenetics (chromosomes 11 and 17 deletions).

• The mechanism of actions include a prominent antiangiogenic effect against tumors, immune modulation, inhibition of cytokine (eg, tumor necrosis factor) secretion, and degradation of cereblon.

• The typical oral dose of thalidomide is 50 to 200 mg daily. The major pathways for elimination include spontaneous hydrolysis of the imide esters and further CYP-mediated metabolism by the liver. Less than 1% of the drug is excreted unchanged in the urine.

• Lenalidomide is typically used at oral doses of up to 25 mg/d for 21 of 28 days. It causes much less sedation, constipation, and neurotoxicity than thalidomide, but it does cause prominent myelosuppression in 20% of patients.

• Pomalidomide is given orally in doses up to 4 mg per day. It is eliminated by CYP-mediated metabolism in the liver with minimal renal clearance. Pomalidomide’s prominent toxicity is neutropenia in 50% to 60% of patients and thrombocytopenia in 25%. It has little sedating effects. It is highly active in relapsed, refractory myeloma, particularly in combination with dexamethasone and proteasome inhibitors.

Retinoids

• All-trans-retinoic acid (ATRA) may induce a complete response in acute promyelocytic leukemia (APL) by causing maturation and apoptosis of leukemic promyelocytes.

• ATRA is given orally in doses of 25 to 45 mg/m² per day in patients with APL.

• ATRA used with an anthracycline antibiotic has increased remission rates and duration of remission in APL.

• Toxicities of ATRA include dry skin, cheilitis, mild but reversible hepatic dysfunction, bone tenderness, hyperostosis on x-ray, and, occasionally, pseudotumor cerebri.

• The “retinoic acid syndrome” may occur, with respiratory failure, pleural and pericardial effusions, and peripheral edema usually associated with a rapid increase in the number of blood neutrophilic cells induced to mature from leukemic promyelocytes. High-dose glucocorticoid therapy may reverse the syndrome if the white blood cell count is rising rapidly. Otherwise, prompt administration of cytotoxic chemotherapy may prevent the syndrome.

Arsenic Trioxide

• Arsenic trioxide induces apoptosis of leukemic cells in APL. Its mechanism of action probably stems from its ability to promote free radical production.

• It can induce a remission and be curative when combined with ATRA in patients with lower-risk APL (diagnostic white blood cell count < 10 × 10⁹/L)

• It is useful in refractory APL for reinduction of remission.

Demethylating Agents

• Two DNA demethylating agents, azacitidine and decitabine, are approved for treatment of myelodysplastic syndrome and are useful in AML, particularly in older patients and those with comorbidities who cannot tolerate standard induction chemotherapy.

• They are incorporated into DNA with subsequent covalent inactivation of DNA methyltransferase. The resulting inhibition of methylation of cytosine bases in DNA leads to enhanced transcription of otherwise silent genes.

• The usual dose of azacytidine is 75 mg/m² subcutaneously or intravenously per day for 7 days, repeated every 28 days, whereas decitabine is used in doses of 20 mg intravenously every day for 5 days every 4 weeks.

• Responses become apparent in patients with myelodysplasia after two to five courses.

• Their principal clinical toxicities are reversible myelosuppression, severe nausea and vomiting, hepatic dysfunction, myalgias, fever, and rash.

Histone Deacetylase Inhibitors

• This family of enzymes removes acetyl groups from amino groups of the lysines found in chromatin, thus promoting the compacting of chromatin and DNA and preventing gene expression.

• Three inhibitors are approved for clinical use: vorinostat, romidepsin, and panobinostat.

• Vorinostat is approved to treat cutaneous T-cell lymphoma, romidepsin is approved to treat cutaneous and peripheral T-cell lymphoma, and panobinostat is approved in combination therapy for treatment of relapsed multiple myeloma.

BCR-ABL Tyrosine Kinase Inhibitors

• The first molecularly targeted drug to make a major impact on cancer treatment was imatinib mesylate (Gleevec), an inhibitor of ABL tyrosine kinase activity and notably the mutant ABL characteristic of the BCR-ABL fusion protein in CML.

• The drug has been impressively successful in inducing remission in chronic phase CML, and to lesser degrees in accelerated and blast crisis phases of the disease. However, many patients ultimately develop resistance to imatinib.

• Second-generation agents dasatinib, nilotinib and bosutinib, as well as the third-generation agent ponatinib, are approved for imatinib-refractory or intolerant patients. Targets, unique pharmacokinetics, mechanism of clearance, half-life, dosing, drug interactions, and toxicity are shown in Table 38–1.

• The BCR-ABL kinase inhibitors are all well absorbed by the oral route and subject to clearance by hepatic CYP 3A4 metabolism.

Janus Kinase Inhibitors (Ruxolitinib)

• The majority of BCR-ABL-negative myeloproliferative neoplasms carry a mutation in the Janus-type tyrosine kinase (JAK) gene.

• The substitution mutation JAK2^V617F is the most common gain-of-function alteration, and occurs in virtually all cases of polycythemia vera (PV) and approximately 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF).

• Expression of this mutation results in ligand independent growth or increased sensitivity to the cytokine/growth factor.

• The first specific JAK inhibitor, ruxolitinib, is approved for treatment of PV, ET, and PMF. It inhibits all JAK kinases independent of mutational status.

• Ruxolitinib is orally administered, reduces spleen volume and improve symptom control, but may cause anemia and thrombocytopenia.

Selective Bruton Tyrosine Kinase Inhibitor (Ibrutinib)

• Bruton tyrosine kinase (BTK), a downstream mediator of the B-cell receptor, is critical for B-cell activation, proliferation, and survival.

• Ibrutinib, a selective BTK inhibitor, is highly active in high-risk relapsed CLL and is also approved for patients with mantle cell lymphoma.

• Ibrutinib is orally administered once daily and metabolized by the liver.

• Side effects are typically mild; although 15% of patients develop grades 3 to 4 neutropenia, dose reductions allow drug continuation.

Proteasome Inhibitors (Bortezomib, Carfilzomib)

• Bortezomib inhibits the chymotryptic-like activity of the 20S subunit of the proteasome, thereby altering the balance of intracellular expression of regulators of proliferation and survival in a manner conducive to rapid and irreversible commitment of susceptible cells to their death.

• The drug is highly effective as a single agent in myeloma, due to multiple mechanisms including the induced accumulation of IκB, a proteasomal substrate, and the ensuing IκB inhibition of nuclear factor-κB, which plays an important role in myeloma cell survival.

• Bortezomib has now become a key component of many regimens in which it is combined with other agents, such as prednisone, melphalan, lenalidomide, or thalidomide.

• The standard schedule of bortezomib administration is an intravenous injection at a maximum tolerated dose of 1.3 mg/m² administered twice weekly with a 10-day rest period (days 1, 4, 8, 11, 22, 25, 29, and 32).

• The most common side effects are thrombocytopenia and painful sensory neuropathy.

• Monoclonal antibodies are an important class of drugs used to treat hematologic malignancies.

• Used alone, they can block access to important growth promoting cell surface molecules; induce apoptosis on binding; promote antibody-dependent cellular cytotoxicity (ADCC); and when coupled to toxic moieties, target cells for enhanced concentrations of the appended molecule.

• See Table 38–2 for approved drugs, mechanisms, doses and schedules, and major toxicities.

Rituximab

• Rituximab was the first monoclonal to receive approval by the US Food and Drug Administration.

• It is a chimeric antibody containing the human immunoglobulin G1 and κ constant regions with murine variable regions that target the B-cell antigen CD20 expressed on the surface of normal B cells and on more than 90% of B-cell neoplasms.

• Rituximab is a component of multiagent chemotherapy for a wide range of lymphomas and other B-cell neoplasms.

• Rarely, rituximab infusion leads to severe mucocutaneous skin reactions (Stevens-Johnson syndrome). Pretreatment with antihistamines, acetaminophen, and glucocorticoids has become a standard measure to modulate infusion reactions.

• Rituximab, as a result of immune suppression, may reactivate hepatitis B infection; patients should be screened for hepatitis B infection prior to initiation of therapy. It may also lead to progressive and fatal multifocal leukoencephalopathy caused by Jacob-Creutzfeldt virus. Hypogammaglobulinemia and delayed neutropenia may appear 1 to 5 months after administration.

• Resistance to rituximab may occur by down regulation of CD20, impaired ADCC, decreased complement activation, limited effects on signaling and induction of apoptosis, or inadequate blood levels.

Ofatumumab

• Ofatumumab is a fully human immunoglobulin G1 kappa monoclonal antibody, which targets a unique CD20 antigen epitope. It has increased affinity for CD20 compared to rituximab.

• Ofatumumab is used to treat CLL refractory to fludarabine and alemtuzumab.

Obinutuzumab

• Obinutuzumab is a glycoengineered type 2 antibody that targets the CD20 antigen.

• Ofatumumab is approved in combination with chlorambucil in the treatment of patients with previously untreated CLL.

Alemtuzumab

• Alemtuzumab (Campath) is a humanized monoclonal antibody targeted against the CD52 antigen present on the surface of normal neutrophils and lymphocytes as well as most B- and T-cell lymphomas.

• The drug can induce tumor cell death through ADCC and complement-dependent cytotoxicity. The antibody is most useful in treating low-grade lymphomas and CLL, particularly in patients with disease refractory to fludarabine.

Brentuximab Vedotin

• Brentuximab vedotin is an antibody drug conjugate comprising an anti-CD30 monoclonal antibody conjugated to the potent antimicrotubule agent monomethylauristatin E.

• When brentuximab vedotin binds to CD-30 expressing cells, it is internalized with proteolytic cleavage of the linker, resulting in release of monomethylauristatin E, disrupting the microtubule network and inducing apoptotic cell death.

• It is approved for the treatment of Hodgkin lymphoma after the failure of at least two prior multiagent chemotherapy agents, following failure of an autologous hematopoietic cell transplant, and as maintenance therapy for high-risk patients postautologous transplant.

⁹⁰Y-Ibritumomab Tiuxetan

• The beta-emitter ⁹⁰yttrium (⁹⁰Y) has emerged as an attractive alternative to ¹³¹I coupled monoclonal antibodies, based on its higher energy and longer path length as well as its effectiveness in larger tumors. It also has a short half-life and remains tightly conjugated to antibody, even after endocytosis, providing a safer profile for outpatient use.

• ⁹⁰Y-ibritumomab tiuxetan has responses rates of 65% to 80% in relapsed lymphomas. The major toxicity is hematologic.