Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Commonly used drugs in hematologic disorders ELISE ANDERES AND SUCHA NAND* Division of Hematology and Oncology, Department of Medicine, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
AGENTS USED TO TREAT BENIGN HEMATOLOGIC DISORDERS Replacement therapies ANEMIAS RESULTING FROM IRON AND VITAMIN DEFICIENCIES
Anemias are commonly encountered in medical practice and are often due to deficiencies of iron and vitamins such as cobalamin (vitamin B12), or folic acid. Iron deficiency is the most common cause of anemia in the US and worldwide (Umbreit, 2005). Iron deficiency can be treated orally, parenterally, or with blood transfusion. Oral iron is the simplest and least expensive option. Ferrous iron salts are preferred due to increased solubility at the pH of the duodenum and jejunum. Approximately 200 mg of elemental iron per day is required to replete iron stores. Each 325 mg tablet of ferrous sulfate contains 66 mg of elemental iron; therefore one tablet three times daily is the recommended replacement dose. The most common side-effects of oral iron sulfate include nausea, heartburn, constipation, or loose stools. Oral iron is best absorbed on an empty stomach, but is best tolerated with foods. The majority of patients will tolerate therapy without significant side-effects. Reducing the frequency of administration or taking iron supplements with meals can alleviate gastrointestinal complaints (Cook, 2005; Killip et al., 2007). Parenteral iron replacement is indicated in patients with iron malabsorption due to resection or disease of the stomach or bowel, conditions with high iron requirements such as chronic gastrointestinal blood loss or endstage renal disease, and failure of oral iron replacement due to poor tolerance or compliance (Cook, 2005). Parenteral replacement is best given intravenously, since the
intramuscular route has been associated with development of soft tissue sarcomas. Formulations available in the US include iron dextran, iron sucrose, and iron gluconate. All are associated with the risk of lifethreatening anaphylaxis, arthralgias, fever, and hypotension. Iron sucrose and iron gluconate have a lower incidence of anaphylaxis and are generally preferred, although they are more expensive (Silverstein, 2004). Headaches and dizziness are associated with intravenous iron preparations. Paresthesias and syncope have also been reported with iron gluconate infusions. Pleocytosis of the cerebrospinal fluid following a febrile reaction to iron dextran has been reported. The patient also developed a peripheral blood leukocytosis (Forristal and Witt, 1968). In another patient, meningismus without increased leukocytes in the spinal fluid but a high spinal fluid iron concentration was documented (Wallerstein, 1968). Iron sucrose and iron gluconate have a lower incidence of anaphylaxis and are generally preferred, although they are more expensive (Silverstein, 2004). Megaloblastic anemias most commonly result from deficiencies of cobalamin or folic acid. Folate deficiency can occur due to decreased intake secondary to poor nutrition, impaired absorption in the duodenum or jejunum due to tropical or nontropical sprue, or increased requirement due to pregnancy or hemolytic anemia. Various drug interactions can also lead to folate deficiency. Decreased dietary intake is the most common cause of folate deficiency and is often seen in alcoholics or elderly or poor patients. The recommended daily intake of dietary folate is 400 mg daily and inadequate consumption leads to anemia within several months. Folate deficient persons are treated with 1–5 mg daily of oral folate. Changes in mental status, sleep disturbances, irritability, and excitability have been reported with higher
*Correspondence to: Sucha A. Nand, MD, Loyola University Medical Center, Cancer Center, Room 345, 2160 S. First Avenue, Maywood, IL 60153, USA. E-mail: [email protected]
E. ANDERES AND S. NAND
doses of folate such as 15 mg/day (Hunter et al., 1970). Folic acid was also reported to exacerbate seizure activity in a young woman who started supplementation while attempting to become pregnant. She had a history of monthly seizures not controlled by medication, but her seizures became more frequent and more severe after starting folate 0.8 mg/day. Substitution of folinic acid 7.5 mg/day resulted in improvement of her seizure activity (Guidolin et al., 1998). Concomitant cobalamin deficiency should be excluded prior to beginning treatment with folate, as anemia may improve but neurologic symptoms due to cobalamin deficiency will progress. Folate replacement is inexpensive and effective even in persons with malabsorption (Krishnaswamy and Nair, 2001). Cobalamin deficiency is most commonly caused by impaired absorption secondary to pernicious anemia. Other causes include gastric or ileal resection, regional enteritis, intestinal lymphoma, bacterial overgrowth in blind intestinal loops, and vegan diet (Babior, 2006). Cobalamin deficiency can result in severe neuropsychiatric complications as well as anemia or pancytopenia. Cobalamin is usually given by intramuscular injections, which saturate tissue stores and compensate for daily losses. Oral and intranasal preparations are also available. In symptomatic patients or those with severe cytopenias, 1000 mg of cobalamin is typically given intramuscularly every day for 2 weeks, then weekly until cytopenias resolve, and then monthly indefinitely. For those with subclinical deficiency (cobalamin levels between 200 and 350 ng/L), replacement with daily injections for 1 week, followed by weekly injections for 4 weeks, then monthly injections indefinitely is acceptable. Oral replacement with 1000–2000 mg daily is equally effective in most cases of cobalamin deficiency (Oh and Brown, 2003), though patients should be monitored closely to ensure that laboratory parameters are correcting and the cobalamin levels are being repleted. For those who respond to oral replacement, lifelong therapy with 1000 mg daily is indicated. For nonresponders, parenteral replacement should be given. Excess cobalamin is excreted in the urine, so toxicity from excess vitamin replacement does not occur. Asthenia, dizziness, and headache have been reported after cobalamin injections in approximately 12% of patients. This may be related to the method of administration. A summary of the agents used to treat the various hematologic disorders discussed in this chapter is given in Table 76.1.
COAGULOPATHIES Fresh frozen plasma Fresh frozen plasma (FFP) is obtained from units of whole blood donation or from plasmapheresis of
Table 76.1 Commonly used drugs in hematologic disorders 1. Agents used to treat benign hematologic disorders A. Replacement therapies Anemias resulting from iron and vitamin deficiencies Coagulopathies B. Antifibrinolytic agents Lysine analogs C. Antiplatelet agents Cyclooxygenase inhibitors Adenosine diphosphate receptor inhibitors Glycoprotein IIb/IIIa antagonists Thromboxane synthase inhibitors D. Antithrombotic agents Unfractionated heparin Low molecular weight heparin Factor Xa inhibitors Warfarin Direct thrombin inhibitors 2. Management of hemorrhagic complications of anticoagulation A. Intracranial hemorrhages due to Warfarin Heparin Direct thrombin inhibitors Antiplatelet agents 3. Agents used to treat hematologic malignancies A. Chronic myeloproliferative disorders Hydroxyurea (hydroxycarbamide) Anagrelide BCR-ABL tyrosine kinase inhibitors B. Myelodysplasia DNA methyltransferase inhibitors C. Leukemias, lymphomas and multiple myeloma Chemotherapeutic agents Targeted therapies a. Monoclonal antibodies b. Radioimmunotherapy c. Immunomodulatory drugs d. Proteosome inhibitors
volunteer donors. FFP can be used for replacement of factors II, V, VII, IX, X, or XI, and protein S, since specific factor replacement are often not available. Thus, FFP is most commonly used in the treatment of multiple factor deficiencies, such as in patients with disseminated intravascular coagulation (DIC), patients on warfarin with significant bleeding, those with vitamin K deficiency requiring urgent correction of factor deficiencies, patients with bleeding associated with acute blood loss, or those requiring plasma exchange for treatment of thrombotic thrombocytopenic purpura (TTP) or hyperviscosity syndrome. A typical unit of plasma derived from a collection of whole blood has a volume of nearly 300 mL, and local and national guidelines for usage
COMMONLY USED DRUGS IN HEMATOLOGIC DISORDERS 1127 generally specify a dose of around 10–20 mL/kg anti-inflammatory drugs (NSAIDs), antihistamines, or (Stanworth, 2007). intravenous glucocorticoids may also be helpful (Reutter and Luger, 2004). Headache is the most comCryoprecipitate mon side-effect of IVIg therapy, with reported incidence ranging from 5–80%. Usually the headaches are mild Cryoprecipitate is a relatively concentrated preparation and can be alleviated by slowing the infusion rate and of procoagulant factors, including fibrinogen, factor giving analgesics or antihistamines. However, in some VIII, von Willebrand factor, factor XIII, and fibronecpatients IVIg therapy must be terminated because of tin. Cryoprecipitate is most commonly used for replacesevere headaches (Orbach et al., 2005). Other adverse ment of acquired or congenital hypofibrinogenemia. An effects associated with IVIg administration include renal adult dose of around 10 single bags of cryoprecipitate failure, arterial and venous thrombosis, and dermatoderived from units of whole blood typically raises the logic toxicity, such as urticaria, rash, and pruritus plasma fibrinogen level by up to 1 g/L (60–100 mg/dL) (Orbach et al., 2005). Thrombotic events occur in 1–13% (Stanworth, 2007). It can also be used in treatment of of patients, with arterial thromboses (stroke, myocardial von Willebrand disease or hemophilia, though specific infarction) being more common than venous (pulmonary replacement with von Willebrand factor or factors VIII embolism, deep venous thrombosis). Arterial events also and IX are usually preferred. Patients with DIC and low tend to occur earlier, with 50% of events occurring fibrinogen are probably best treated with a combination within 4 hours of the IVIg infusion. Older age and carof FFP and cryoprecipitate, to minimize the risk of inducdiovascular risk factors increase the risk of arterial ing thrombosis with transfusion of cryoprecipitate thromboses, while obesity and immobility increase the alone. Adequate transfusion should be given to maintain risk of venous thromboses (Paran et al., 2005). Premedithe fibrinogen level above 100 mg/dL. Cryoprecipitate cation with aspirin may decrease the risk of thromboses can also be used for treatment of qualitative platelet dysin patients with underlying risk factors. Hyperviscosity function in uremia. may also increase the risk of stroke, and a baseline viscosity should be checked in patients at risk for Immunoglobulin hyperviscosity (e.g., monoclonal gammopathy) (Marie Intravenous immunoglobulin (IVIg) is derived from et al., 2006). A significant proportion of patients who large pools of human plasma. Most of the immunoglobreceive IVIg develop a positive direct antigobulin test ulin in commercially available preparations of IVIg is (DAT, or direct Coombs test), due to the presence of IgG, with a subtype distribution of IgG1–IgG4 similar anti-A or anti-B derived from type O individuals in the to that in normal human plasma. Relatively small donor pools. Transient hemolysis has been reported amounts of IgA and IgM are also present. IVIg is used (Copelan et al., 1986). to treat a variety of hematologic disorders, including Aseptic meningitis is a rare complication of IVIg congenital or acquired immunodeficiency syndromes, treatment, occurring in about 1% of patients. Clinical immune thrombocytopenic purpura (ITP), autoimmune manifestations include acute severe headache with neck hemolytic anemia (AIHA), autoimmune neutropenia rigidity, fever, lethargy, photophobia, nausea, and (AIN), and recurrent bacterial infections occurring in vomiting. Cerebrospinal fluid (CSF) examination demassociation with chronic lymphocytic leukemia (CLL) onstrates pleocytosis with high protein content and negor multiple myeloma. IVIg is also used to treat a variety ative culture. Signs and symptoms usually begin 48 hours of autoimmune disorders. In patients with ITP and after the infusion and last for 3–5 days (Orbach et al., AIHA, IVIg is considered the best “emergency” inter2005). Infusing IVIg at a slow rate and ensuring adevention when a rapid, albeit transient, response is quate hydration may prevent or reduce the incidence required (Knezevic-Maramica and Druskall, 2003). of aseptic meningitis. In patients with a history of The neurologic indications for the use of IVIg include IVIg-induced aseptic meningitis, premedication with Guillain–Barre´ syndrome and myasthenia gravis, among acetaminophen or antihistamines may reduce the inciothers. dence of recurrence. Corticosteroid treatment is not conThe immediate adverse reactions following IVIg sidered beneficial in IVIg-induced aseptic meningitis administration are usually mild and transient flu-like (Redman et al., 2002). symptoms, and include headache, facial flushing, malaise, chest tightness, fever and chills, myalgia, fatigue, Transfusion reactions and risks dyspnea, nausea, vomiting, diarrhea, change in blood pressure, and tachycardia. These side-effects usually Transfusion of plasma and plasma fractions can lead to resolve if the infusion rate is decreased (Orbach et al., adverse reactions or events, of which immune-mediated 2005). Premedication with analgesics, nonsteroidal reactions are most common. These include allergic and
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anaphylactic reactions, transfusion-related acute lung injury (TRALI) and hemolysis, and can range in severity from mild to fatal. TRALI is a leading cause of transfusion-related morbidity and mortality. It is characterized by acute noncardiogenic pulmonary edema and respiratory compromise in the setting of transfusion. TRALI is caused by passive transfusion of antigranulocyte antibodies that interact with recipient neutrophils, resulting in activation and aggregation in pulmonary capillaries, release of local biologic response modifiers causing capillary leak, and lung injury (Triulzi, 2006). Signs and symptoms include hypoxemia, hypotension, dyspnea, fever, and bilateral infiltrates on chest radiograph. Fluid overload and citrate toxicity can occur after rapid or massive transfusion. In developed countries, microbial transmission rates are low because of donor selection and testing. The risk of viral transmission is very low because of the use of two independent viral inactivation steps. The risk of transmission of variant Creutzfeldt–Jakob disease in both plasma components and pooled plasma products is as yet unknown. The low titer of prion infectivity in the blood of an infected individual (approximately 10 infectious units/mL) would be massively diluted by the thousands of units of plasma in the pool, likely making the risk extremely low. Subsequent manufacturing processes also remove prions from the final product (MacLennan and Barbara, 2006).
Recombinant factor VIIa Recombinant factor VIIa (rfVIIa or NovoSeven®) is a procoagulant protein concentrate that was developed to “bypass” factor VIII or IX inhibitors in patients with hemophilia A or B. It is approved in these patients for the treatment of bleeding episodes, or for prophylaxis prior to invasive procedures or surgery. It is also approved in these settings in patients with congenital factor VII deficiency. RfVIIa is occasionally used off-label in patients with trauma and massive hemorrhage or in patients with platelet disorders or liver disease and uncontrolled bleeding. Recombinant factor VIIa binds directly to activated platelets and activates factor X, which in turn catalyzes the conversion of prothrombin to thrombin. Thrombin generation activates the intrinsic pathway and further promotes thrombin formation. Binding of rfVIIa to activated platelets localizes it to the site of bleeding and helps prevent thrombotic complications (Roberts et al., 2004). The incidence of serious adverse events, including myocardial infarction, stroke and venous thromboembolism, is about 1% in hemophiliacs (Abshire and Kenet, 2004). RfVIIa should be used cautiously in patients with a predisposition to thrombotic complications, such as obesity, cancer, or cardiovascular disease.
Prothrombin complex concentrates Prothrombin complex concentrates (PCCs) are a source of the vitamin K-dependent coagulation factors, including factors II, VII, IX and X and proteins C and S. They are isolated from the cryoprecipitate supernatant of large plasma pools after removal of antithrombin and factor XI. The PCCs are standardized according to their factor IX content. The concentrates are processed to inactivate the clotting factors and treated to inactivate transfusion-transmitted viruses. PCC administration is indicated for emergent reversal of oral anticoagulant therapy, for example in patients on warfarin with intracerebral hemorrhage. PCCs can also be used in the treatment of hemophilia B or congenital factor VII deficiency when specific factor concentrates are not available. Adverse events associated with PCC use include allergic reactions, heparininduced thrombocytopenia (when heparin is added to the PCC to inactivate clotting factors), and DIC (Hellstern, 1999).
Antifibrinolytic agents LYSINE ANALOGS Fibrinolysis occurs when plasmin that is generated by plasminogen activators digests fibrin clots. Both plasmin and plasminogen bind thrombin through lysine-binding sites. The synthetic lysine analogs Eaminocaproic acid (EACA, Amicar®) and tranexamic acid (AMCA) compete with plasmin and plasminogen activators at lysine binding sites. Binding of these agents inhibits fibrinolysis and stabilizes the clot. These agents can be administered orally, intravenously or topically, although optimal dosing has not been established in most clinical settings (Verstraete, 1985). They are used in the treatment of severe mucosal hemorrhage (e.g., upper gastrointestinal bleeding, menorrhagia) or other bleeding conditions associated with increased fibrinolysis. EACA and AMCA are also used to control bleeding in thrombocytopenic conditions such as ITP. Both agents are generally well tolerated, although nausea, vomiting, diarrhea, dizziness, malaise, fever, rash, and transient hypotension or cardiac arrhythmias may occur. EACA can also rarely cause rhabdomyolysis, particularly with prolonged use. Headache is a common side-effect of AMCA and can also occur with EACA. Both agents can cause or aggravate cerebral infarction when used in patients with subarachnoid hemorrhage. EACA and AMCA should not be used in patients with DIC, as excessive thrombosis can occur; they are also relatively contraindicated in patients with urologic bleeding conditions.
COMMONLY USED DRUGS IN HEMATOLOGIC DISORDERS
Antiplatelet agents CYCLOOXYGENASE INHIBITORS Aspirin is a nonselective inhibitor of cyclooxygenase (COX), the enzyme that regulates conversion of arachidonic acid to prostaglandins and thromboxane A2. Aspirin has an irreversible effect on COX-1 that results in inhibition of platelet aggregation and prevention of vasoconstriction. Aspirin has many therapeutic uses, including the prevention and treatment of arterial and venous thromboses. It is most commonly used to prevent or treat coronary or cerebral arterial thromboses. In hematology practice, aspirin is used as thrombosis prophylaxis in patients with primary bone marrow disorders such as multiple myeloma and myeloproliferative disorders. Aspirin can also alleviate microvascular symptoms such as headache, light-headedness, acral paresthesia and erythromelalgia in patients with polycythemia vera (PV) or essential thrombocythemia (ET) (McCarthy et al., 2002; Tefferi, 2003). In patients with arterial thrombophilias such as antiphospholipid antibody syndrome, aspirin is used for prevention of ischemic stroke (APASS Writing Committee, 2004; Albers et al., 2008) and recurrent pregnancy loss (Kutteh, 1996; Rai et al., 1997). The primary complication of aspirin use is bleeding. Bleeding can occur at any site but most commonly manifests as gastrointestinal bleeding or hemorrhagic stroke. Hypertension, older age and higher doses of aspirin appear to increase the risk of CNS hemorrhage. For most patients the benefits of aspirin in preventing cardiovascular, cerebrovascular, and ischemic events significantly outweigh the risk of a major hemorrhage (Gorelick and Weisman, 2005). Aspirin can also be nephrotoxic, causing acute renal failure from renal vasoconstriction or acute interstitial nephritis. Systemic vasoconstriction can cause exacerbation of congestive heart failure.
ADENOSINE DIPHOSPHATE RECEPTOR INHIBITORS Adenosine diphosphate (ADP) is a platelet agonist that is stored in platelet-dense granules. When a platelet is activated, ADP is released and binds to platelet surface receptors, thus recruiting additional platelets to form a platelet plug. ADP receptor inhibitors such as clopidogrel (Plavix®) and ticlopidine (Ticlid®) prevent platelet aggregation by selectively and irreversibly binding the platelet surface receptor P2Y12. Platelet aggregation is inhibited for the remainder of the platelet lifespan (7–10 days). Clopidogrel is indicated for treatment of acute ST and non-ST elevation myocardial infarction, peripheral arterial disease, arteriosclerotic vascular disease, and stroke. Ticlopidine is indicated after placement of coronary stents and after thromboembolic stroke (Varon and Spectre, 2009).
A noteworthy side-effect of ticlopidine and clopidogrel is thrombotic thrombocytopenic purpura (TTP). This was first reported with ticlopidine in the late 1990s, and incidence was estimated at 1 case per 1600–5000 patients treated (Bennett et al., 1998). Clopidogrel became the preferred antiplatelet agent after three phase III trials including more than 20 000 patients reported a more favorable safety profile, with less neutropenia, skin and gastrointestinal toxicities, and no cases of TTP. However, in the year 2000 a report of 11 patients who developed TTP while on clopidogrel was published (Bennett et al., 2000). Ten of 11 patients developed TTP within 2 weeks of starting the drug. The mechanism for development of TTP is not known, but is thought to be nonimmunologic given the short time to onset. Patients required a median of eight plasma exchanges (range, 1–30), and were prone to recurrence of TTP. One patient died shortly after the diagnosis of TTP. Treating physicians should be aware of this rare but serious side-effect of clopidogrel. The newest ADP receptor P2Y12 inhibitors include prasugrel and ticagrelor. Compared to clopidogrel, prasugrel has a more rapid onset of action and its inhibitory effect is stronger (Wallentin et al., 2008). In addition, prasugrel is not affected by genetic variations of cytochrome P450. The effect of prasugrel on platelets is irreversible and appears to be responsible for increased risk of bleeding with this agent (Wiviott et al., 2007). Ticagrelor is different in two respects: Its binding to the P2Y12 is stronger and faster than prasugrel but it is reversible. In a double blind randomized trial, comparing ticagrelor to prasugrel in patients with acute coronary syndromes, ticagrelor was superior in composite death rate, without increasing the risk of major bleeding (Schomig, 2009; Wallentin et al., 2009).
GLYCOPROTEIN IIB/IIIA ANTAGONISTS The primary use of these agents is in the cardiac catheterization laboratory. The representative agents of this group are abciximab, eptifibatide, and tirofiban. The published trial suggests a 9% reduction in death rate at 30 days in patients with acute coronary syndromes. Oral GPIIb/IIIa blockers (xemilofiban, orbofiban, sibrafiban, and lotrafiban) have been disappointing as they have been shown to be no more effective than aspirin and may even increase the risk of mortality (Chew et al., 2001).
THROMBOXANE SYNTHASE INHIBITORS A brief mention also must be made of dipyridamole, which inhibits thromboxane synthase. This results in lower uptake of thromboxane A2 and lowered cellular uptake of adenosine. It acts as an antiplatelet agent
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and is also a vasodilator. Dipyridamole has been studied extensively, frequently in combination with aspirin. A review of over 25 trials suggests that while its effects in coronary syndromes are modest at best, it may reduce the risk of stroke (Diener et al., 1996). Newer formulation of dipyridamole with better bioavailability may confirm such an advantage of this old drug.
Antithrombotic agents UNFRACTIONATED HEPARIN Unfractionated heparin is a glycosaminoglycan composed of polysaccharide chains with molecular weights ranging from 5000 to 30 000 kDa (Hirsh et al., 2001). It exerts its anticoagulant effect by binding to antithrombin (AT), causing a conformational change that accelerates the inhibition of thrombin and factor Xa. Inhibition of thrombin and factor Xa prevents the conversion of fibrinogen to fibrin and the activation of other clotting factors, thus minimizing clot formation. Heparin is effective and indicated for the prevention of venous thromboembolism; for the treatment of venous thrombosis and pulmonary embolism (PE); for the early treatment of patients with unstable angina and acute myocardial infarction (MI); for patients who undergo cardiac surgery using cardiac bypass, vascular surgery, and coronary angioplasty; in patients with coronary stents; and in selected patients with disseminated intravascular coagulation. Heparin can cause hyperkalemia, osteoporosis after long-term use, and nonimmune-mediated thrombocytopenia due to platelet agglutination. Heparin can cause bleeding at any site, reported to occur in 5–10% of patients receiving heparin (Kelton and Hirsh, 1980). Epidural or spinal hematomas can occur in patients receiving unfractionated or low molecular weight heparin, particularly in patients who undergo lumbar puncture or epidural catheter placement for analgesia. Careful timing of heparin administration, attention to heparin dose, and avoidance of other medications that can cause bleeding are essential to minimize the risk of epidural or spinal hematomas (Wysowski et al., 1998). Heparin can be inactivated by protamine sulfate to prevent or minimize bleeding complications. The most feared complication of heparin is heparininducted thrombocytopenia and thrombosis (HITT), which occurs in about 1% of patients receiving unfractionated heparin. HITT is caused by antibodies directed against heparin-platelet factor 4 complexes, which activate platelets and stimulate thrombin generation. Onset typically occurs 7–10 days after heparin exposure, unless patients have had prior heparin exposure within the past 3 months, in which case onset can occur within 1–2 days. Patients have a drop in platelet count of 50% and about
half of patients develop venous or arterial thrombosis. Thrombosis can occur even after heparin is discontinued, so patients should be placed on anticoagulation with a direct thrombin inhibitor and eventually transitioned to warfarin for a minimum of 2–3 months (longer if thrombosis occurred). Patients presenting with acute thrombosis 1–2 weeks after heparin exposure should be evaluated for HITT (Hirsh et al., 2001).
LOW MOLECULAR WEIGHT HEPARIN Low molecular weight heparin (LMWH) is derived from depolymerization of unfractionated heparin. It has an average molecular weight of 5000 kDa, with a range of 1000–10 000. The majority of these heparin chains are too short to bind ATIII and thrombin, and the anticoagulant effect is primarily the result of ATIIImediated inactivation of factor Xa. LMWH has a more predictable pharmacokinetic profile than unfractionated heparin and monitoring is usually not necessary. Antifactor Xa levels can be measured if anticoagulant monitoring is desired, since LMWH does not reliably prolong the aPTT. LMWH is primarily cleared by the kidneys and it should be used with caution in patients with renal insufficiency. It is prudent to check factor Xa levels periodically in this patient population, though there are few guidelines for dose modifications. Similarly, there are no guidelines for dose adjustments in morbidly obese patients, and factor Xa levels should be checked a few days after therapy is initiated (Hirsh et al., 2001). LMWH is indicated for prevention of venous thromboembolism (VTE), for treatment of venous thrombosis, for treatment of acute PE, and for the early treatment of patients with unstable angina. Like unfractionated heparin, bleeding can occur with LMWH but is less common. Spinal and epidural hematomas have been reported (see section on unfractionated heparin). HITT can occur with LMWH but the incidence is very low. LMWH is only partially neutralized by protamine sulfate.
FACTOR XA INHIBITORS Fondaparinux is an indirect factor Xa inhibitor, which acts by catalyzing factor Xa inhibition by antithrombin. It is a synthetic analog of the antithrombin-binding pentasaccharide found in heparin or LMWH (Weitz et al., 2008). Fondaparinux is currently approved for treatment of DVT or PE, and VTE prophylaxis after major orthopedic surgery or abdominal surgery. It was shown to be as effective as LMWH in the treatment of acute DVT (Buller et al., 2004), and as effective as intravenous unfractionated heparin in the treatment of acute PE (Buller et al., 2003). The main complication of therapy is bleeding, and protamine sulfate is not effective at neutralizing fondaparinux (Rosenberg, 2001). As with other
COMMONLY USED DRUGS IN HEMATOLOGIC DISORDERS heparinoids, spinal and epidural hematomas have been reported. Isolated cases of HITT have also been reported (Warkentin et al., 2007).
WARFARIN Warfarin (4-hydroxycoumarin) inhibits the synthesis of vitamin K-dependent coagulation factors, including factors II, VII, IX, and X, as well as proteins C and S. It is commonly used for prevention and treatment of VTE, prevention of stroke in atrial fibrillation, anticoagulation for mechanical prosthetic heart valves, and myocardial infarction prevention in coronary artery disease. Hemorrhage is the most common side-effect of anticoagulation with warfarin and can occur at any site. Cases of acute femoral neuropathy have been reported with therapeutic use of warfarin and are secondary to retroperitoneal bleeding (Butterfield et al., 1972). FFP can rapidly, albeit temporarily, reverse the anticoagulant effect in patients with life-threatening bleeding. Otherwise, oral vitamin K should be used to correct the coagulopathy. Warfarin is extensively metabolized by the hepatic cytochrome P450 system and polymorphisms in these enzymes contribute to interpatient variations in dosing (Francis, 2008). Warfarin also interacts with a variety of medications, which can lead to sub- or supratherapeutic INR values in a given patient. Similarly, variations in intake in vitamin K-containing foods can affect warfarin dosing. Warfarin is a teratogen and should not be given to women of child bearing age who may become pregnant. Warfarininduced skin necrosis and venous gangrene can occur in patients with protein C or S deficiency who start warfarin without prior alternate anticoagulation. Anticoagulation with another medication prior to starting warfarin prevents this rare but serious complication of therapy, but is not uniformly required (Brandjes et al., 1992).
DIRECT THROMBIN INHIBITORS Direct thrombin inhibitors inactivate thrombin in an antithrombin-independent fashion. Unlike heparin, they can inactivate thrombin that is bound to fibrin. Examples include hirudin (lepirudin), bivalirudin, and argatroban. These agents do not bind to plasma proteins, and therefore have a more predictable anticoagulant response than unfractionated heparin (Bauer, 2006). Also, they do not cause HITT and all three drugs are approved as treatment of patients with HITT. Argatroban does not require dose adjustment in patients with renal failure, but does for patients with liver disease. Lepirudin is renally excreted and should be dose-reduced in patients with decreased glomerular filtration rates. All three agents are given by continuous intravenous infusion and are monitored using the aPTT. Argatroban can also elevate the PT, making the transition to warfarin more
complicated. All direct thrombin inhibitors can cause bleeding, including intracranial hemorrhage. Dabigatran (Pradaxa ®) is a reversible oral thrombin inhibitor. Its absorption is pH sensitive and is decreased by approximately 30% in the presence of proton pump inhibitors. Unlike warfarin, its metabolism is not dependent on cytochrome P450 enzymes and there are fewer drug interactions. Dabigatran can accumulate in patients with renal failure. A recent phase III trial of anticoagulation in patients with atrial fibrillation demonstrated rates of stroke and systemic embolism similar to those observed with warfarin, but lower rates of major hemorrhage (Connolly et al., 2009). Another trial (Schulman et al., 2009) shows that dabigatran is as effective as warfarin in the management of acute venous thromboembolism. This drug was recently FDA approved for use in patients with atrial fibrillation. Bleeding is the most common side-effect of dabigatran, including intracranial hemorrhage in 0.3% of patients (Connolly et al., 2009).
MANAGEMENT OF HEMORRHAGIC COMPLICATIONS OFANTICOAGULATION (Table 76.2)
Intracranial hemorrhages WARFARIN Warfarin use accounts for 10–15% of intracranial hemorrhages (ICH) (SPIRIT Study Group, 1997). The frequency of events is increasing as more elderly patients receive anticoagulation. Warfarin increases the risk of Table 76.2 Management of coagulopathic intracranial hemorrhage Anticoagulant
FFP or PCC and Vitamin K Protamine sulfate
15 mL/kg 15–30 U/kg 10 mg
Heparin (unfractionated or low molecular weight) Direct thrombin inhibitors Antiplatelet agents
No antidote available Platelet transfusion and/or desmopressin (DDAVP)
1 mg per 100 U of heparin or 1 mg of enoxaparin
Transfuse to > 100 000 platelets 0.3 mg/kg
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ICH two to five times, with the risk of bleeding being proportional to the intensity of anticoagulation (Aguilar et al., 2007). There are no randomized trials addressing management of warfarin-induced ICH. Prompt, emergent reversal of anticoagulation is indicated and should be initiated prior to obtaining results of coagulation studies (Rincon et al., 2007). Reversal is usually accomplished with vitamin K and FFP; however, this takes several hours to accomplish. The volume of FFP required to reverse the INR can be > 2 liters, which is problematic in older patient populations. PCCs normalize the INR more rapidly and can be given in smaller volumes than FFP; however, they carry an increased risk of thrombosis and DIC in patients with severe brain injury. There are few data on PCCs in ICH, and different PCCs vary in their coagulation factor components, making comparison between trials difficult. Dosing is dependent on the specific PCC available, but the goal of treatment is reduction of the INR to < 1.2 (Aguilar et al., 2007). Vitamin K should also be administered. Recombinant FVIIa has been used off-label to reverse anticoagulation in patients with ICH on warfarin. RFVIIa can reverse the INR within minutes, though the effect only lasts several hours and vitamin K and FFP should also be administered (Freeman et al., 2004). The FAST trial investigated two different doses of rFVIIa in ICH. Although rFVIIa reduced growth of the hematoma, there was no survival benefit or improvement in functional outcome at 90 days for either dose compared to placebo. Additionally, treatment increased the frequency of arterial thromboembolic serious adverse events in the high dose arm as compared to placebo (Mayer et al., 2008). Though this trial does not specifically address patients on warfarin with ICH, it does provide safety information and dosing guidelines. RFVIIa is currently not approved for treatment of ICH. Restarting anticoagulation in patients with atrial fibrillation or mechanical prosthetic valves poses a therapeutic dilemma. There are no large randomized trials, and recommendations in the literature for holding anticoagulation vary from 1–6 weeks. The risk of embolic stroke occurring within 7–14 days after stopping warfarin appears to be low. If the INR is reversed with PCCs, subcutaneous heparin can be considered to reduce the risk of thrombosis. In most patients, warfarin can safely be restarted 7–14 days after the ICH (Aguilar et al., 2007).
UNFRACTIONATED AND LOW MOLECULAR WEIGHT HEPARIN
The anticoagulant effect of unfractionated heparin can be reversed with protamine sulfate. Protamine can partially reverse the effect of low molecular weight heparin.
The recommended dose of protamine is 1 mg per 100 U of heparin, or 1 mg of enoxaparin. Side-effects include flushing, bradycardia, and hypotension.
DIRECT THROMBIN INHIBITORS The direct thrombin inhibitors lipirudin, argatroban, and bivalirudin directly inhibit thrombin. Unfortunately no direct antidote is available for their reversal.
ANTIPLATELET AGENTS Aspirin, nonsteroidal anti-inflammatory agents, and ADP receptor inhibitors irreversibly inhibit platelet function. Treatment of hemorrhage associated with these agents involves stopping the drugs and transfusing platelets. Platelet levels should be maintained above 100 000/mL. Desmopressin (DDAVP) 0.3 mg/kg can be considered. This treatment promotes release of von Willebrand factor and enhances platelet function. However, there are few data to support this approach (Rincon et al., 2007).
AGENTS USED TO TREAT HEMATOLOGIC MALIGNANCIES Chronic myeloproliferative neoplasms The classic myeloproliferative neoplasms include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and chronic myeloid leukemia (CML). They are characterized by clonal bone marrow expansion of the myeloid series, with clinical features of hepatosplenomegaly, hypercatabolism, and increased numbers of circulating mature blood cells. The focus of treatment is to reduce cell proliferation and prevent sequelae of thrombosis and hemorrhage. In CML, small molecule tyrosine kinases target the disease defining genetic abnormality, the t(9;22)(q34;q11).
HYDROXYUREA Hydroxyurea (Hydrea; hydroxycarbamide) is classified as an antimetabolite. It is thought to be cell cycle-specific for the S phase of cell division. Hydrea inhibits the enzyme ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides, critical precursors for de novo DNA biosynthesis and DNA repair. There does not appear to be an effect on synthesis of RNA or protein (Chu and DeVita, 2009). In PV and ET, hydroxyurea is used as cytoreductive therapy in patients over the age of 60 years or those with a prior thrombotic event. Treatment with hydroxyurea reduces platelet counts as well as the thrombosis rate in these patients (Cortelazzo et al., 1995; Fruchtman et al., 1997). The most common side-effect is myelosuppression. Mucocutaneous and skin ulcers, usually in the lower
COMMONLY USED DRUGS IN HEMATOLOGIC DISORDERS extremities, have been reported. Peripheral neuropathy has been reported in HIV-infected patients who receive hydroxyurea in combination with the antiretroviral agents didanosine (ddI) and stavudine (d4T). ddI and d4T are well known to cause neuropathy, but the addition of hydroxyurea to these medications significantly increases the risk of developing neuropathy. In this setting, hydroxyurea is used to potentiate the effect of these drugs (Moore et al., 2000). The most concerning potential side-effect of hydrea is development of secondary leukemia or myelodysplasia; however, data are not conclusive. Hydrea is teratogenic and is not given to women of child bearing potential. Interferon-a is used in place of hydroxyurea in this patient population.
ANAGRELIDE Anagrelide is thought to reduce platelet production by decreasing megakaryocyte hypermaturation. It is used as a second-line agent in patients with ET who are intolerant of hydroxyurea. Anagrelide can cause arterial thrombosis including myocardial infarction, stroke, and transient ischemic attack (TIA). Serious hemorrhage, cardiomyopathy, and edema can also occur. Headache is a common side-effect and can lead to drug discontinuation (Harrison et al., 2005). There are no controlled studies on anagrelide in pregnant women, therefore its use is not recommended in this patient population.
BCR-ABL TYROSINE KINASE INHIBITORS This class of drugs was rationally designed to target the disease-defining genetic abnormality that defines CML: the t(9;22)(q34;q11) or Philadelphia chromosome and its molecular equivalent, the bcr-abl fusion tyrosine kinase. Imatinib mesylate (Gleevec™) was the first drug in this class and is approved for front-line therapy in patients with CML. Imatinib binds to the ATP pocket of the bcr-abl protein and inhibits substrate phosphorylation, thereby inducing apoptosis (Chu and DeVita, 2009). Imatinib also inhibits other receptor tyrosine kinases such as platelet-derived growth factor receptors (PDGFR), stem cell factor (SCF) and c-kit. It is well tolerated and common side-effects include edema and fluid retention, fatigue, rash, nausea and vomiting, diarrhea, myelosuppression, and cough. Congestive heart failure is the most serious reported side-effect. Headaches, insomnia, paresthesias, dizziness and asthenia have been reported in up to approximately 10–20% of patients. Second-generation bcr-abl tyrosine kinase inhibitors have been developed to overcome resistance to imatinib. These agents were recently approved for first-line treatment of CML and are also used to treat accelerated or blast phase CML. Dasatinib (Sprycel®) is a potent
inhibitor of the bcr-abl kinase as well as the SRC family of kinases, c-kit, and PDGFR-b. It binds to both the active and inactive conformations of the abl kinase domain, thereby overcoming imatinib resistance resulting from bcr-abl mutations (Chu and DeVita, 2009). Common side-effects include fluid retention, rash, hypocalcemia, and hypophosphatemia, diarrhea, nausea and vomiting, headache, dyspnea, and fatigue. Serious side-effects include myelosuppression, pleural effusions, QT prolongation, and hemorrhage (gastrointestinal and cerebral) secondary to platelet dysfunction. Nilotinib (Tasigna®) is another second-generation bcr-abl kinase inhibitor, which also inhibits c-kit and PDGFR-b kinases. Nilotinib has a higher binding affinity and selectivity for the abl kinase domain when compared to imatinib, and is able to overcome imatinib resistance resulting from bcr-abl mutations (Chu and DeVita, 2009). Common side-effects include edema, pruritis, rash, constipation or diarrhea, myelosuppression, headache, nausea, fatigue, electrolyte disturbances, and elevations in serum lipase. QT prolongation and sudden death have been reported. Imatinib is predominantly metabolized in the liver by the cytochrome P450 enzymes CYP3A4 and CYP3A5, while dasatinib and nilotinib are primarily metabolized in the liver by CYP3A4. Drug interactions are common and should be considered when caring for a patient on these medications.
Myelodysplasia DNA METHYLTRANSFERASE INHIBITORS AND NUCLEOSIDE ANALOGS
5-azacitidine (Vidaza®) and 5-aza-20 -deoxycitidine (decitabine) are hypomethylating agents that inhibit DNA meythltransferase by incorporation of either azacitidine triphosphate or decitabine triphosphate into DNA. This leads to a loss of DNA methylation and reactivation of aberrantly silenced genes. They are cell cycle-specific with activity in the S phase. Azacitidine triphosphate is also incorporated into RNA, resulting in inhibition of RNA processing and function. A phase III trial demonstrated a survival advantage for azacitidine over conventional care, and established it as the preferred therapy for patients with high-risk myelodysplasia (MDS) (Fenaux et al., 2009). A similar trial conducted with decitabine did not demonstrate a survival advantage (WijerMans et al., 2008), though many feel the drugs are clinically equivalent and biologically similar. Common side-effects of these agents include myelosuppression, fatigue and anorexia, nausea, vomiting, constipation and abdominal pain, and peripheral edema. Azacitidine can cause renal toxicity with elevations in serum creatinine, renal tubular acidosis and
1134 E. ANDERES AND S. NAND hypokalemia, while decitabine can cause hyperbilirubiincludes dose-limiting myelosuppression, immunosupnemia. Both medications can also cause dizziness and pression, pulmonary toxicity, and severe neurotoxicity, headache (Chu and DeVita, 2009). CNS toxicity includalthough this complication has occurred primarily at siging coma was reported in a small number of patients on a nificantly greater doses than currently recommended for clinical trial who were treated with doses of azacitidine clinical use. Cladribine can cause a dose-dependent that are higher than those used in current clinical practice delayed sensorimotor peripheral neuropathy character(Saiki et al., 1981). Similarly, acute CNS toxicity with ized by axonal degeneration and secondary demyelinsevere myalgias and altered mental status was reported ation (Vahdat et al., 1994). Irreversible paraparesis and in a child receiving high doses of azacitidine (Weisman quadraparesis were reported in patients with refractory et al., 1985). acute leukemia and non-Hodgkin lymphoma who were treated with high doses of cladribine (Beutler et al., Leukemias, lymphomas, and 1991). High doses of fludarabine and pentostatin are also multiple myeloma neurotoxic (Cheson et al., 1994). At standard doses of fludarabine, somnolence and peripheral neuropathy CHEMOTHERAPEUTIC AGENTS have been reported (Cheson et al., 1994). Chemotherapeutic agents are classified according to The 6-thiopurines are primarily used in treatment of their mechanism of action. Broad categories include acute leukemia, while fludarabine, cladribine and penalkylating agents, platinum agents, antimetabolites, tostatin are active in both leukemias and lymphomas. topoisomerase inhibitors, antimicrotubule agents, and Pyrimidine analogs include cytarabine, gemcitabine, antibiotics. 5-fluorouracil and capecitabine. Cytarabine is critical Alkylating agents form covalent bonds with DNA in the treatment of acute myeloid leukemia (AML). It bases. Bifunctional alkylators interact with two strands is also used in treatment of acute lymphoblastic leukeof DNA and form a “cross-link” that covalently links mia (ALL) and lymphomas, including primary central the two strands of the DNA double helix. This prevents nervous system lymphoma. At high doses, cytarabine the cell from replicating effectively. Common sidecrosses the blood–brain barrier and can be effective as effects of alkylating agents include myelosuppression, prophylaxis for CNS leukemia. High-dose cytarabine is nausea and vomiting, and alopecia. They are teratogenic neurotoxic and can cause seizures, cerebral and cerebeland leukemogenic, with secondary myelodysplasia and lar dysfunction, peripheral neuropathy, bilateral rectus acute leukemia occurring 7–10 years after therapy muscle palsy, optic neuritis, aphasia, and parkinsonian (Colvin and Friedman, 2005). Examples of alkylating symptoms. Cerebral dysfunction manifests as generalagents used in hematologic malignancies include cycloized encephalopathy, with somnolence, confusion, disphosphamide, ifosfamide, melphalan, and chlorambucil. orientation, memory loss, cognitive dysfunction, Ifosfamide can cause CNS toxicity including confusion, psychosis, and frontal lobe release signs. Rapid infusion somnolence and hallucinations, as well as encephalopaof high doses of cytarabine increases the risk of cerebral thy and seizures. toxicity (Baker et al., 1991). Clinical signs of cerebellar Platinum agents interact with guanine and adenine dysfunction occur in up to 15% of patients within 8 days residues to form DNA adducts and cross-link DNA of treatment and include dysarthria, dysdiadochokinestrands. If the DNA damage is not repaired or tolerated, sia, dysmetria, and ataxia. EEG will often demonstrate apoptosis occurs (Johnson and O’Dwyer, 2005). Examdiffuse slow wave activity. Even when therapy is ples of platinum agents include cisplatin, carboplatin, discontinued, up to 30% of patients with cerebellar and oxaliplatin. Carboplatin is used for second-line treattoxicity do not fully recover. Peripheral neuropathy ment of leukemia and lymphoma. Cisplatin can cause is a rare complication of cytarabine therapy, occurring peripheral neuropathy and ototoxicity. Oxaliplatin comin < 1% of patients. The severity of symptoms monly causes both acute and delayed sensory neuropaincreases with higher cumulative doses of cytarabine thy. Less commonly, it can cause pharyngolaryngeal and can range from a pure sensory neuropathy to a rapdysesthesia and Lhermitte’s sign. idly progressive ascending polyneuropathy (Baker et al., Antimetabolites can be subclassified as purine ana1991). Neurotoxicity can be reduced by increasing logs, pyrimidine analogs, and antifolates. They are cell the duration of the infusion to more than 3 hours. cycle-specific and are therefore active on replicating Patients older than age 50 and those with elevated cells. Antimetabolites interfere with DNA production serum creatinine are particularly susceptible to neuroand replication, causing apoptosis. Purine analogs logic toxicity from high-dose cytarabine (Kummar include the 6-thiopurines 6-mercaptopurine and 6et al., 2005). Prior to each dose, patients are evaluated thioguanine, fludarabine, 2-chlorodeoxyadenosine (2for neurotoxicity and doses are held or adjusted as necCdA or cladribine) and pentostatin. Their toxicity profile essary to minimize toxicity.
COMMONLY USED DRUGS IN HEMATOLOGIC DISORDERS Cytarabine is also given intrathecally for prophylaxis of CNS leukemia in patients with acute lymphoblastic leukemia (ALL), and to treat leptomeningeal disease in both leukemias and solid tumors. A depot formulation, in which the cytarabine is encapsulated in multivesicular liposomes for sustained release in the CSF, is also available. Doses can be administered through an Ommaya reservoir or via lumbar puncture. For treatment of CNS leukemia, doses are typically given twice weekly until the leukemia is no longer detectable in the CSF. This is followed by weekly doses for 4 weeks, and monthly doses for up to 1 year. The depot formulation is typically given every 2 weeks. Dose-limiting toxicities include headache and arachnoiditis and are more common with the depot formulation. Myelopathy, paraplegia, papilledema, and seizures can also occur (Baker et al., 1991). Occasionally systemic toxicities such as nausea and myelosuppression, are seen with intrathecal cytarabine (Kummar et al., 2005). Antifolate analogs include methotrexate, raltitrexed and pemetrexed. Methotrexate inhibits dihydrofolate reductase and prevents de novo thymidylate and purine nucleotide biosynthesis (Kummar et al., 2005). High dose methotrexate, often used in CNS lymphoma, is occasionally associated with an acute, transient cerebral dysfunction manifesting as paresis, aphasia, and behavioral abnormalities. Seizures have been described in 4– 15% of patients who receive high-dose methotrexate. Symptoms generally occur within 6 days of treatment and completely resolve within 48–72 hours. Chronic neurotoxicity with encephalopathy, dementia and motor paresis can occur 2–3 months after administration of high-dose methotrexate (Kummar et al., 2005). Intrathecal methotrexate is used for CNS prophylaxis in ALL, as well as treatment of CNS leukemia and leptomeningeal involvement by solid tumors. There are three distinct neurotoxic syndromes associated with intrathecal methotrexate (Walker et al., 1984). Acute chemical arachnoiditis can occur immediately after administration and is the most common toxicity. This syndrome is characterized by severe headaches, nuchal rigidity, vomiting, fever, and an inflammatory cell infiltrate in the CSF. A subacute form of neurotoxicity is seen in approximately 10% of patients and usually occurs after the third or fourth course of intrathecal therapy. This most commonly occurs in patients with active meningeal leukemia and consists of motor paralysis, cranial nerve palsies, seizures, and/or coma. Continued intrathecal therapy with methotrexate can result in death, therefore a change in therapy is mandatory. The third syndrome is a chronic demyelinating encephalopathy, which typically occurs in children several months to years after treatment. Patients present with dementia, limb spasticity, and in advanced cases, coma. Ventricular
enlargement, cortical thinning, and diffuse intracerebral calcifications are noted on computed tomographic (CT) scan (Kummar et al., 2005). Inhibitors of topoisomerase I and II include irinotecan, topotecan, etoposide, and anthracyclines. DNA topoisomerases modify the tertiary structure of DNA without altering the primary nucleotide sequence. Topoisomerase inhibitors generate single and double strand breaks in DNA, resulting in apoptosis and cell death. They are cell cycle-specific. Etoposide and anthracyclines are used in treatment of acute leukemia and lymphomas. Antimicrotubule agents include the vinca alkaloids (vincristine, vinblastine, vindesine) and the taxanes (paclitaxel and docetaxel). These agents interfere with microtubule function, particularly within the mitotic spindle apparatus. Vinca alkaloids are used in the treatment of ALL and lymphomas. Vincristine is particularly known for causing neurotoxicity, which is characterized by a symmetric, mixed sensorimotor and autonomic polyneuropathy. Pathologically, vincristine interferes with axonal microtubule function and causes axonal degeneration and decreased axonal transport. Symptoms start with a distal symmetric sensory impairment. With continued treatment, neuritic pain and loss of deep tendon reflexes can develop. This may be followed by foot drop, wrist drop, motor dysfunction, ataxia, and paralysis. Cranial nerves are rarely affected, but can manifest as hoarseness, diplopia, jaw pain, and facial palsies. Central toxicity from vincristine is also very rare because of minimal uptake in the CNS. Central effects can include confusion, mental status changes, hallucinations, insomnia, seizures, and coma. Acute, severe autonomic toxicity may be seen with high doses (greater than 2 mg/m2) or in patients with altered hepatic function. Autonomic toxicities can include constipation and abdominal cramps, ileus, urinary retention, and orthostatic hypotension. In adults, neurotoxicity can occur after treatment with cumulative doses of 5–6 mg, and toxicity can become severe after 15–20 mg. In routine treatment for lymphoma, adult patients receive 2 mg per treatment, with cumulative doses of 12–16 mg being given over 4–6 months. Children appear to be less sensitive, and older patients are particularly susceptible. Patients with preexisting neurologic disorders and hepatic dysfunction are at especially increased risk. The only treatment for vincristine neurotoxicity is discontinuation of the drug. Vinblastine and vindesine rarely cause neurotoxicity (Rowinsky and Tolcher, 2005). Taxanes, particularly paclitaxel, can also cause neurotoxicity. This is most commonly a peripheral sensory neuropathy in a symmetric stocking-glove distribution. Neurologic examination reveals sensory loss and loss of deep tendon reflexes. Most patients experience mild
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to moderate effects, but patients with pre-existing neuropathy are more prone to development of taxaneinduced neuropathy. Symptoms usually begin after several courses of standard-dose therapy, but can occur as early as 24–72 hours after the first treatment. Motor and autonomic neuropathy has also been reported with paclitaxel. Transient myalgia and arthralgia are also observed and most commonly occur within 24–48 hours after treatment. Treatment with prednisone can reduce myalgia and arthralgia. Taxanes are commonly used in the treatment of solid tumors.
TARGETED THERAPIES Monoclonal antibodies Rituximab (Rituxan®) is a chimeric (murine/human) monoclonal antibody against CD20, which is expressed on B lymphocytes. It is used in combination with chemotherapy to treat chronic lymphocytic leukemia, and can be given as a single agent or with chemotherapy to treat CD20 expressing non-Hodgkin’s lymphomas. Rituxan is also approved for use in rheumatoid arthritis, and is sometimes used off label to treat autoimmune cytopenias and other autoimmune diseases. Rituxan causes cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Common side-effects include infusion reactions (hypotension, bronchospasm, rigors, angioedema), fatigue, and myelosuppression. Tumor lysis syndrome can occur in patients with significant tumor burden. Patients with prior hepatitis B infection can have reactivation of the virus, and should be screened for prior infection before the drug is administered. Similarly, reactivation of the JC virus can cause progressive multifocal leukoencephalopathy (PML) in patients who receive Rituxan in combination with chemotherapy, immunosuppression, or stem cell transplant. The largest series reported 57 HIVnegative patients with hematologic malignancies and autoimmune disorders (Carson et al., 2009). Patients commonly presented with confusion/disorientation, motor weakness or hemiparesis, poor motor coordination, and changes in speech or vision. Symptoms progressed over weeks to months. The diagnosis was primarily confirmed by magnetic resonance imaging and JC virus detection in the CSF, or by brain biopsy or autopsy. Mortality was very high: all patients diagnosed with PML within 3 months of the last rituximab dose died, compared with 84% of patients who were diagnosed more than 3 months after the last rituximab dose. There is no standard effective therapy for this condition. Gemtuzumab ozogamicin (GO or Mylotarg®) is a recombinant humanized IgG4 k antibody that is conjugated with calicheamicin, a cytotoxic antitumor
antibiotic. The antibody portion of GO targets CD33, which is commonly expressed on leukemic blasts. After the antibody binds, a complex is formed and internalized, calicheamicin is released within the myeloid cell lysosomes, and the cell dies. GO is approved for treatment of relapsed leukemia. Common side-effects include infusion reactions, myelosuppression, and hepatotoxicity. Radioimmunotherapy Radioimmunotherapy allows the targeted delivery of ionizing radiation to the tumor site, while minimizing toxicity on normal tissue. This is accomplished by conjugating radioactive isotopes to monoclonal antibodies that target tumor cells. Currently, two products are approved for treatment of relapsed and refractory non-Hodgkin lymphoma. Tositumomab (Bexxar®) and ibritumomab (Zevalin®) are monoclonal antibodies to CD20 that are conjugated with the radionuclides iodine-131 (I-131) and yttrium-90 (Y-90), respectively. Side-effects include infusion reactions, asthenia and fatigue, and myelosuppression. There is also a risk of myelodysplasia and/or acute leukemia (Davies, 2007). Immunomodulatory drugs Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) primarily used in the treatment of multiple myeloma. Lenalidomide is also being studied for treatment of relapsed lymphomas. They have direct cytotoxic effects and induce apoptosis or growth arrest of myeloma cells. They also have potent antiangiogenic and anti-inflammatory effects that appear to inhibit cell growth (Kumar and Rajkumar, 2006). In the 1950s thalidomide was used to treat morning sickness in pregnant women. Several years later it was identified as a teratogen and was not used again until the 1990s, when it was investigated in cancer patients. Common sideeffects include constipation, drowsiness and somnolence, neutropenia, and VTE when used in combination with steroids or chemotherapy. Thalidomide also causes a debilitating peripheral neuropathy as well as orthostatic hypotension and dizziness. Lenalidomide, a second-generation IMiD, is much better tolerated, with myelosuppression being the most common side-effect. Lenalidomide can also cause VTE when used in combination with steroids or chemotherapy, but it is not associated with peripheral neuropathy. Proteosome inhibitors Bortezomib (Velcade®) is a small molecule that inhibits the activity of the 26S proteasome, which degrades
COMMONLY USED DRUGS IN HEMATOLOGIC DISORDERS ubiquitinated proteins. The ubiquitin-proteasome pathway is critical for regulating concentrations of intracellular proteins and maintaining intracellular homeostasis. Inhibition of the proteasome prevents this targeted proteolysis and can affect multiple signaling cascades within the cell. Disruption of the normal homeostatic mechanisms can lead to cell death. Bortezomib is active in multiple myeloma as well as non-Hodgkin lymphomas. Common side-effects include constipation or diarrhea, nausea and vomiting, myelosuppression, dyspnea and cough, and peripheral neuropathy. The neuropathy is predominantly sensory, but motor neuropathy has also been reported.
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