Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + BASIC PRINCIPLES OF CANCER CHEMOTHERAPY Download Section PDF Listen +++ ++ Knowledge of drug actions, pharmacokinetics, clinical toxicities, and drug interactions is essential for the proper and safe administration of cancer chemotherapy. 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 stem cell transplantation result in additional organ toxicities that are not seen at conventional doses. Chemotherapy usually 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 Download Section PDF Listen +++ ++ 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 KINETICS AND CANCER CHEMOTHERAPY Download Section PDF Listen +++ ++ 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. — 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 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. + DRUG RESISTANCE Download Section PDF Listen +++ ++ 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, as 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. + DRUGS USED TO TREAT HEMATOLOGIC MALIGNANCIES Download Section PDF Listen +++ +++ Cell Cycle–Active Agents +++ Methotrexate ++ Methotrexate is used for maintenance therapy of acute lymphocytic leukemia, combination chemotherapy of lymphomas, and treatment and prophylaxis of meningeal leukemia. 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. Is well absorbed orally in doses of 5 to 10 mg, but doses of more than 25 mg should be given intravenously. Excreted primarily unchanged by the kidney. Renal impairment is contradiction to methotrexate therapy. Dose-limiting toxicities are myelosuppression and gastrointestinal effects (mucositis, diarrhea, bleeding). Intrathecal methotrexate may produce acute arachnoiditis, dementia, motor deficits, seizures, and coma. Leucovorin cannot prevent or reverse CNS toxicities. Leucovorin intravenously will reverse acute toxicity of methotrexate, except for CNS toxicity. +++ Cytarabine (Cytosine Arabinoside, Ara-C) ++ 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 CSF concentration achieved (50% of plasma level). Cytarabine may be given intrathecally for meningeal leukemia. At usual doses (100 to 150 mg/m2, intravenously, q 12 h for 5 to 10 days), myelosuppression is dose-limiting toxicity. High-dose cytarabine therapy, 1 to 3 g/m2, intravenously, at q 12 h for 6 to 12 doses, 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 analogue 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. +++ 5-Azacytidine and Decitabine (5-aza-2′-deoxycytidine) ++ Cytidine analogues that display cytotoxic activity and that may induce differentiation at low doses. These drugs are used primarily in patients with myelodysplasia. Their differentiation actions result from their incorporation into DNA and subsequent covalent inactivation of DNA methyltransferase. The resulting inhibition of methylation of cytosine bases in DNA leads to enhanced transcription of otherwise silent genes. For example, the differentiating effects of 5-azacytidine are the basis for the induction of fetal hemoglobin synthesis in patients with sickle cell anemia and thalassemia. The usual doses of 5-azacytidine are 75 mg/m2 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. +++ Purine Analogues: 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 (HPRT). 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 decreased in 10 percent of persons of European descent. May need dose adjustment. Myelotoxic with peak neutropenia and thrombocytopenia at about 7 days; moderate nausea and vomiting; mild, usually reversible hepatotoxicity. +++ Fludarabine Phosphate ++ Fludarabine has outstanding activity in chronic lymphocytic leukemia (CLL). It is strongly immunosuppressive, like the other purine analogues, and is frequently used for this purpose in nonmyeloablative allogeneic hematopoietic stem cell transplantation and in the treatment of collagen vascular diseases. 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) ++ A purine analogue 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 percent of patients with hairy cell leukemia, and partial responses in the remainder. Administered intravenously and eliminated mainly by renal excretion. Cladribine is 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 analogue 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 percent. 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 analogue, nelarabine has relatively specific activity as a secondary agent for T-cell lymphoblastic lymphoma and acute T-cell leukemias. Its mode of action is similar to the other purine analogues, in that it becomes incorporated into DNA and terminates DNA synthesis. Its 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 analogue 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 preventing painful crisis and reducing hospitalization in patients with sickle cell disease and in patients with hemoglobin (Hgb) SC. Its anti-sickling activity results from induction of Hgb F through its activation of a specific promoter for the γ-globin gene. It may also exert anti-sickling 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 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. 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 percent of individuals cannot tolerate hydroxyurea due to gastrointestinal symptoms or skin ulcers. May increase probability of evolution to acute myelogenous leukemia transformation when used to treat chronic clonal myeloid diseases, although this is controversial. There has been no report of enhanced leukemogenesis in patients treated with hydroxyurea for sickle cell diseases, despite over 20 years of use. +++ 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 weekly or every 2 weeks during a cycle of therapy. Approximately 70 percent 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 percent decrease in dose is recommended for patients presenting with a bilirubin level of 1.5 to 3 mg/dL and a 75 percent reduction for levels greater than 3 mg/dL. Very useful in Hodgkin or non-Hodgkin lymphomas and acute lymphocytic leukemia. 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 upon extravasation during administration. Neither vincristine nor vinblastine can be given intrathecally. +++ Taxanes (Paclitaxel and Docetaxel) ++ Antimitotic drugs that bind to microtubules, although the taxanes differ in their mechanism and toxicity profile from the vinca alkaloids. 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. 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. Toxicities principally leukopenia, thrombocytopenia, and mucositis. Peripheral neuropathy, cardiac arrhythmias, and fluid retention can occur. +++ Campothecins (Irinotecan, Topotecan) ++ Targets 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 with repetition at 6-week intervals. 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 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 (e.g., adriamycin/bleomycin/vinblastine/dacarbazine [ABVD] and cyclophosphamide/hydroxydaunorubicin (doxorubicin)/oncovin/prednisone [CHOP], respectively). Daunorubicin and idarubicin are used in combination with Ara-C for acute myelogenous leukemia. Mitoxantrone is used for acute myelogenous leukemia. 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 percent 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. Binds to DNA and induces double-stranded breaks. Resistance is a result of expression of multidrug resistance phenotype or diminished drug binding. 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 (>30 minutes) 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 acute myelogenous leukemias. +++ Bleomycin ++ Bleomycin is used in combination chemotherapy programs for Hodgkin disease, 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. Administered intravenously or intramuscularly for systemic effects, and may be instilled intrapleurally or intraperitoneally to control malignant effusions. Eliminated largely by renal excretion. May need dose reduction with renal dysfunction. 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. +++ Non–Cell Cycle–Active Agents +++ Alkylating Drugs ++ 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. 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. +++ Thalidomide and Lenalidomide ++ Thalidomide and lenalidomide have established value in treating myeloma refractory to first-line chemotherapy and are now being considered for use as first-line therapy in combination with other biological agents (e.g., proteasome inhibitors). When used in doses of 25 mg/day for 21 of 28 days, lenalidomide is dramatically effective in normalizing hematologic parameters in the subset of patients with myelodysplasia who have a 5q–deletion on cytogenetics. 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. In CLL, the drug is equally effective in patients with poor prognostic cytogenetics (chromosomes 11 and 17 deletions). To avoid acute tumor responses, lenalidomide should be used in low doses (beginning at 2.5 to 5 mg/day and escalating thereafter). The mechanism of action of thalidomide and the newer analogue, lenalidomide, acts through a number of different mechanisms, including a prominent antiangiogenic effect against tumors, immune modulation, and inhibition of cytokine (e.g., tumor necrosis factor) secretion. The dose of thalidomide is 50 to 400 mg. There is no evidence for induction of metabolism on a daily dosing regimen. The major pathways for elimination including spontaneous hydrolysis of the imide esters, and further CYP-mediated metabolism by the liver. Less than 1 percent of the drug is excreted unchanged in the urine. Lenalidomide is well absorbed orally in doses up to 400 mg. Approximately 70 percent of administered drug is excreted unchanged by the renal route. Dose adjustments are recommended for patients in moderate (10 mg/day for creatinine clearance of 30–50 mL/min) or severe (10 mg every other day for creatinine clearance < 30 mL/min) renal failure. Lenalidomide causes much less sedation, constipation, and neurotoxicity than thalidomide, but it does cause prominent myelosuppression in 20 percent of patients. +++ Cell-Maturing (Terminal-Differentiating) Agents All-Trans-Retinoic Acid and Arsenic Trioxide ++ Chemical agents, such as carotenes, retinoids, vitamin D, and some cytotoxic drugs, can cause maturation of human neoplastic granulocytic cells. 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. ATRA used without an accompanying anthracycline antibiotic is associated with relapse. 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 induces apoptosis of leukemic cells in APL. Its mechanism of action probably stems from its ability to promote free radical production. Useful in refractory APL for reinduction of remission. +++ 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. The most recent addition to the list of differentiating agents approved for clinical use against hematologic malignancies is vorinostat, or SAHA (suberoylanilide hydroxamic acid). Vorinostat causes partial or complete responses in 30 percent of patients with refractory cutaneous T cell lymphoma (CTCL). The drug causes minimal toxicity: mild to moderate fatigue, diarrhea, anemia, and minor decreases in the platelet count. Clinically significant thrombocytopenia occurs in 6 percent. + SMALL MOLECULES WITH SPECIFIC MOLECULAR TARGETS Download Section PDF Listen +++ +++ c-ABL 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. Like imatinib, nilotinib and dasatinib are also inhibitors of the BCR-ABL kinase, as well as the c-KIT kinase and the platelet-derived growth factor receptor kinase. Dasatinib also inhibits the Src family kinases, an important secondary target in CML. Both dasatinib and nilotinib are more potent than imatinib. Nilotinib has been modified to overcome 32 of the 33 point mutations in the ABL portion of BCR-ABL that can cause resistance to imatinib. Dasatinib is unique in that it is able to bind BCR-ABL in both the open and closed configuration, which may be one of the mechanisms that allows it to overcome resistance. The BCR-ABL kinase inhibitors are all well absorbed by the oral route and subject to clearance by hepatic CYP 3A4 metabolism. Dasatinib's absorption is pH dependent and may be affected by the use of H2-blockers or proton pump inhibitors. Imatinib, dasatinib, and nilotinib have modest toxicity, including gastrointestinal distress (diarrhea, nausea, and vomiting), fluid retention (edema and pleural effusions). Nilotinib causes a unique prolongation of the QT interval. All three drugs can induce neutropenia and anemia and hepatotoxicity. +++ Bortezomib ++ 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 play 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. + THERAPEUTIC MONOCLONAL ANTIBODIES AND OTHER IMMUNOLOGICALLY BASED AGENTS Download Section PDF Listen +++ ++ Monoclonal antibodies used alone can block access to important growth promoting cell surface molecules; induce apoptosis upon binding; promote antibody dependent cellular cytotoxicity; and when coupled to toxic moieties, target cells for enhanced concentrations of the appended molecule. +++ 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 percent of B-cell neoplasms. Rituximab induces programmed cell death upon binding to CD20. While initially approved for use as a single agent in indolent non-Hodgkin lymphoma, rituximab is now a component of multi-agent chemotherapy for a wide range of lymphomas and other B-cell neoplasms. Rituximab is infused intravenously both as a single agent and in combination with chemotherapy at a dose of 375 mg/m2. As a single agent, it is given weekly for 4 weeks with maintenance doses every 3 to 6 months. Rarely, rituximab infusion leads to severe mucocutaneous skin reactions (Stevens-Johnson syndrome). Pretreatment with antihistamines, acetaminophen, and glucocorticoids have 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. +++ 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. The most concerning side effects are acute infusion reactions and depletion of normal neutrophils and T cells. +++ Denileukin Diftitox ++ Denileukin diftitox (Ontak, DAB389 IL-2) combines IL-2 and the catalytically active fragment of diphtheria toxin. The toxin fragment crosses into the target cell, carried in with its fusion partner which binds with high affinity to the human IL-2 receptor. Malignant T- and B-cell tumors express the high affinity form of the IL-2R, which is not expressed on normal resting T cells but is upregulated by antigen activation. The limited tissue expression of the high-affinity IL-2R makes this a selective target for cancer treatments. Denileukin diftitox causes hypersensitivity reactions, a vascular leak syndrome, and constitutional toxicities including fever, chills, and fatigue; glucocorticoid premedication significantly decreases toxicity. +++ Gemtuzumab Ozogamicin ++ Gemtuzumab ozogamicin (Mylotarg), a humanized mouse antibody covalently linked to a potent chemical toxin, calicheamicin. The antibody recognizes CD33, an antigen expressed by more than 90 percent of AML cells but not expressed on normal marrow hematopoietic stem cells (although it is expressed on myeloid progenitor cells). The antibody conjugate produced a 30 percent complete response rate in relapsed AML, when administered at a dose of 9 mg/m2 for up to three doses at 2-week intervals. Most patients require two to three doses to achieve remission. The drug is currently approved for use in older adults (>60 years) with acute myelogenous leukemia in first relapse. Its primary toxicities include myelosuppression in all patients treated, and hepatocellular damage in 30 to 40 percent of patients, manifested by hyperbilirubinemia and enzyme elevations. Patients may manifest a syndrome that resembles hepatic venoocclusive disease when they subsequently undergo myeloablative therapy, or when gemtuzumab ozogamicin follows high-dose chemotherapy. +++ Radioimmunoconjugates Tositumomab and 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, and 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. Murine anti-CD20 antibodies with either 131I (tositumomab or Bexxar) or 90Y (ibritumomab tiuxetan or Zevalin) have impressive responses rates of 65 to 80 percent in relapsed lymphomas. The administration of either ibritumomab tiuxetan or tositumomab requires two steps: first, a test dose to determine biodistribution and allow dose calculation, and a second step of actual therapeutic dosing. In each step, unlabeled antibody is first administered to saturate non-tumor binding sites. Use of these agents requires careful coordination between oncologist and a nuclear medicine specialist. ++ For a more detailed discussion, see Bruce A. Chabner, Jeffrey Barnes, James Cleary, Andrew Lane, Constantine Mitsiades, and Paul Richardson: Pharmacology and Toxicity of Antineoplastic Agents. Chap. 20, p. 283 in Williams Hematology, 8th ed.