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Clinical Journal of Oncology Nursing Volume 15, Number 1 Management of Outpatients Treated With Clofarabine E13

At a Glance

Clofarabine, a second-generation purine nucleoside analog, has shown promising safety and efficacy results in clinical trials of adult patients with acute leukemia.

Anorexia, nausea, vomiting, diarrhea, myelosuppression, hepatoxicity, and renal dysfunction are the most common toxicities associated with clofarabine treatment.

Although clofarabine usually is administered on an inpatient basis, with careful monitoring, support, and education, many patients can subsequently be treated as outpatients.

Amanda Dressel, RN, BSN, CCRC, is a clinical research nurse in the Leukemia Clinical Research Center at the University of Michigan Medical Center in Ann Arbor; Monica Kwari, RN, BSN, CCRP, is a research nurse supervisor in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston; and Ann M. McGreal, RN, OCN, is an oncology nurse clinician at Oncology Specialists, S.C., in Park Ridge, IL. Dressel and Kwari contributed equally as primary authors of this manuscript. The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. Medical writing and editing support were provided by Genzyme Corporation. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the editorial staff. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted October 2009. Revision submitted April 2010. Accepted for publication June 21, 2010.)Digital Object Identifier: 10.1188/11.CJON.E13-E23

A n estimated 43,050 adults were diagnosed with acute or chronic leukemia, and 21,840 died of the disease in 2010 (Jemal, Siegel, Xu, & Ward, 2010). Encouragingly, the overall relative five-year sur-vival rate for adults with leukemia has improved

from 35% in the mid-1970s to 54% in 2005 (Jemal et al., 2010). However, despite the fact that most patients with acute myelog-enous leukemia (AML) are older than age 60, the outcome for older patients with AML remains essentially unchanged since the mid-1980s (Burnett & Mohite, 2006). Older adults with good performance status can benefit from standard therapies, but many older patients cannot tolerate such therapies, respond poorly because of adverse cytogenetics, or face a higher risk

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Amanda Dressel, RN, BSN, CCRC, Monica Kwari, RN, BSN, CCRP, and Ann M. McGreal, RN, OCN

Despite improvements in treatment, the outcome for some adult patients with acute or chronic leukemias remains poor. Clofarabine, a second-generation purine nucleoside analog, received U.S. Food and Drug Administration approval in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia after at least two previous regimens. In addition, clinical studies have shown encouraging safety and efficacy results with clofarabine in the treatment of adult patients with various hematologic malignancies. Although most adult patients with leukemia receive the first course of clofarabine while hospitalized, many can be subsequently treated as outpatients with proper monitoring, support, and educa-tion. The most frequent side effects associated with clofarabine are gastrointestinal-related, myelosuppression, hepatotoxicity, renal dysfunction, and anorexia. Careful patient monitoring is essential to ensure early identification and prompt intervention. Younger patients and those of any age with no comorbid health issues, good performance status, and an adequate support network are more likely to tolerate outpatient clofarabine administration. Early identification and proactive pharmacologic and nonpharmacologic interventions may reduce the severity of these toxicities and prevent their progression. Patient education about strategies for prevention and management of symptoms also is essential.

Nursing Considerations for Optimal Outpatient Management of Adult Patients With Leukemia Treated With Clofarabine

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E14 February 2011 Volume 15, Number 1 Clinical Journal of Oncology Nursing

of toxicity because of comorbidities and impaired physical functioning (Appelbaum et al., 2006; Klepin & Balducci, 2009; Lancet & Giralt, 2008). This has stimulated the development of new drugs and therapeutic approaches. Among the newer drugs to reach the oncology-hematology clinic is clofarabine, a second-generation purine nucleoside analog that acts by in-hibiting DNA synthesis and repair and by inducing apoptosis (Genzyme, 2008; Montgomery, Shortnacy-Fowler, Clayton, Riordan, & Secrist, 1992; Parker et al., 1991). Clofarabine was initially approved in 2004 by the U.S. Food and Drug Adminis-tration for the treatment of pediatric patients aged 121 years with relapsed or refractory acute lymphocytic leukemia after at least two previous regimens (Genzyme, 2008). Clinical studies conducted after initial approval have shown encouraging results with clofarabine in the treatment of adult patients with various hematologic malignancies (Burnett et al., 2006; Burnett, Russell, Kell, Milligan, & Culligan, 2004; Faderl et al., 2005, 2006, 2008; Kantarjian et al., 2010; Kantarjian, Gandhi, Cortes, et al., 2003; Kantarjian, Gandhi, Kozuch, et al. 2003; Nabhan et al., 2010). In the absence of results from phase III studies, clofarabine has not been approved for the treatment of adult patients with leukemia. Based on phase II data, the National Comprehensive Cancer Net-work (2010) practice guidelines for AML include clofarabine as a category 2B intermediate intensity option for patients with AML who are 60 years or older. Phase III trials are ongoing.

Although most adult patients receive their first course of clofarabine as inpatients, many can continue subsequent treat-ment on an outpatient basis. The purpose of this article is to discuss nursing considerations for optimal outpatient manage-ment of patients with hematologic malignancies treated with clofarabine. The authors describe the clinical development of clofarabine and their clinical experiences with outpatient clo-farabine treatment, administration and monitoring guidelines, management of toxicities, and recommendations for patient education.

Clinical Evaluation of ClofarabineInitial phase I trials with clofarabine were conducted to deter-

mine the dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD) of clofarabine for the treatment of pediatric and adult patients with acute leukemias, chronic lymphoprolifera-tive disorders (LPDs), and solid tumors (Jeha et al., 2004; Kan-tarjian, Gandhi, Kozuch, et al., 2003). Based on results of phase II studies, the recommended pediatric dosage for clofarabine is 52 mg/m2 administered via IV two hours daily for five days (Genzyme, 2008; Jeha et al., 2004, 2006).

In a phase I study in adult patients with solid tumors, LPD, and acute leukemias, clofarabine was given as a one-hour infusion daily for five days (Kantarjian, Gandhi, Kozuch, et al., 2003). Among the patients with acute leukemias, the DLT was hepatox-icity and the MTD recommended for phase II trials was 40 mg/m2. Results of phase II studies with clofarabine monotherapy or combination therapy in adult patients with hematologic malignancies showed promising efficacy and a low mortality rate (Burnett et al., 2004, 2006; Faderl et al., 2005, 2006, 2008; Kantarjian et al., 2010; Kantarjian, Gandhi, Cortes, et al., 2003) (see Table 1).

Experience With Outpatient ClofarabineThe experience at the authors institutions has been that most

patients receive the first course of clofarabine monotherapy as inpatients and approximately 80% are then treated as outpa-tients for subsequent cycles. Data analysis from the Classic II study (Kantarjian et al., 2010) indicates that, among patients who received more than one cycle of clofarabine, at least 50% of consolidation cycles were administered on an outpatient basis. Most patients who are treated with clofarabine as outpatients have AML. In the authors collective experiences, patients treat-ed in the outpatient setting tend to be younger than age 50 or are any age and have an adequate Eastern Cooperative Oncology Group ([ECOG], 2006) performance status (2 or less), no serious comorbidities, and tolerance for previous chemotherapy (i.e., previous lines of treatment or first cycle of clofarabine). In the authors experiences, less than 50% of patients with a complete remission are readmitted while they continue with outpatient clofarabine treatment. After achieving complete remission, transfusion requirements and risk of infections usually are lower than during induction, given the shorter duration of myelosup-pression in subsequent cycles. Readmission is mostly needed when leukemia relapses and a new line of treatment is started.

Some patients may be treated as outpatients for one cycle and then require hospitalization for subsequent cycles because of serious toxicities experienced as outpatients and the need to be closely monitored during future treatment cycles. Although clofarabine may be used for outpatient therapy, understand-ing that the nature of acute leukemia and its treatment often requires patients to be admitted during therapy for treatment of life-threatening infections is important. Although patients frequently require transfusions during induction, transfusion requirements are generally low during consolidation.

Potential Benefits and Detriments

Potential benefits of outpatient treatment include reduced costs (if frequent readmissions are avoided), increased patient convenience, decreased potential for nosocomial infection, and improved quality of life. Patients generally thrive when given the freedom in a home environment with family. Outpatients often feel more empowered and participate more in their disease and treatment management.

Detriments of outpatient treatment include the need for ur-gent evaluation and intervention with change in vital signs, the need for regular laboratory tests in patients at high risk for renal and hepatic issues, difficulties with patient access to transporta-tion (i.e., many do not feel well enough to bring themselves for frequent clinic visits), delays in detecting serious events (e.g., infection, renal insufficiency), and challenges for weekend sup-port when infusion centers are closed. In the outpatient setting, the family must be very involved and proactive on behalf of the patient.

Selection Criteria

Criteria used to determine whether a patient can be treated as an outpatient for the first course includes being younger than age 50 or any age with adequate ECOG performance status (2 or less), a history of tolerating previous chemotherapy (in patients with


relapsed or refractory disease), an absence of borderline renal or hepatic dysfunction, and an absence of significant comorbid disease or disorder (e.g., renal insufficiency, coronary artery disease) while undergoing previous treatment. The determining factor may be the nature and stage of the disease. For example, in the authors experiences, patients with chronic lymphocytic leukemia or lymphoma might be better candidates for outpatient clofarabine because these diseases usually are less myelosup-pressive than acute leukemias. In addition to clinical factors, a patients level of comprehension of self-care instructions and so-cial support should be considered when determining if a patient is suitable for outpatient treatment.

Patients with highly proliferative disease (e.g., white blood cell count of 20 X 109/L or higher, rapid doubling time of white blood cells), those who might require apheresis to reduce the white blood cell count, and patients who have signs of spontane-ous tumor lysis syndrome (TLS) would need to be admitted for inpatient treatment. Patients who present with elevated creati-nine without a history of renal insufficiency often are admitted to reverse the condition with IV hydration and allopurinol or rasburicase. Management of proliferative disease should be determined by the medical judgment of the treating physician and institution guidelines.

The decision to treat in the outpatient setting for subsequent cycles is based on considerations similar to those used in adminis-tering the first cycle. Patients with elevated creatinine or hepatic levels, despite discontinuing most or all other concomitant medi-cations, should receive subsequent cycles as inpatients at a re-duced dose or with a dose delay. Patients with elevated creatinine should be closely and carefully monitored for serious side effects.

Guidelines

Induction therapy with clofarabine is primarily administered as an inpatient regimen. However, subsequent cycles of clofara-bine can be administered to selected adult patients in outpatient settings with appropriate patient management, support, and education. The preferred route of administration is by periph-eral IV, which eliminates the need for insertion of a central line and associated increased risk of infection. A new peripheral IV line usually is used for each drug infusion, but for patients with difficult IV access, it may be preferable to keep the peripheral IV line as long as possible. In these cases, the peripheral IV should be checked daily during each infusion cycle for correct placement and signs of infection.

Table 1. Phase II Clinical Trials of Clofarabine Monotherapy or Combination Therapy for Adult Patients With Hematologic Malignancies

STUDY TREATMENT REGIMEN SAMPLE RESPONSE RATES MORTALITY RATES

Studies in newly diagnosed patients

Burnett et al., 2004

Clofarabine 30 mg/m2 daily for five days on a four-week cycle

28 patients with AML aged 60 years or older

Complete response was 59%. Not reported

Burnett et al., 2006

Clofarabine 30 mg/m2 for a maxi-mum of three cycles


Overall response was 48%, complete response was 29%, CRp was 15%, and partial response was 5%.

30 days, 21%

Faderl et al., 2006

Clofarabine 40 mg/m2 plus cytara-bine 1 g/m2 for five days on a four- to six-week cycle


Overall response was 60%, complete response was 52%, and CRp was 8%.

6 weeks, 7%

Faderl et al., 2008

Clofarabine 30 mg/m2 for five days for four to seven weeks versus clofarabine 30 mg/m2 for five days, with cytarabine 20 mg/m2 for 14 days, for four to seven weeks


Combination overall response was 67% (complete response of 63% and CRp of 4%) versus a clofarabine alone overall response of 31% (complete response of 31%)

Induction: com-bination, 19%; monotherapy, 31%

Kantarjian et al., 2010

Clofarabine 30 mg/m2 for induction and 20 mg/m2 during reinduction and consolidation for a maximum of six cycles

112 patients with AML aged 60 years or older with a 1 or higher adverse prog-nostic factor score


30 days, 10%

Studies in patients with relapsed or refractory disease

Faderl et al., 2005

Phase II dose: clofarabine 40 mg/m2

plus cytarabine 1 g/m2 for five days on a four- to six-week cycle

16 patients with AML, 3 pa-tients with high-risk MDS, and 1 patient with CMLBP


Induction, 5%

Kantarjian, Gandhi, Cortes, et al., 2003

Clofarabine 40 mg/m2 daily for five days on a three- to six-week cycle

31 patients with AML, 12 patients with ALL, 11 pa-tients with CMLBP, and 8 patients with MDS

Overall response was 48%, complete response was 32%, CRp was 15%, and partial response was 2%.

2 weeks, 3%; induction, 5%

ALLacute lymphocytic leukemia; AMLacute myelogenous leukemia; CMLBPchronic myeloid leukemia in blastic phase; CRpcomplete response with incomplete platelet recovery; MDSmyelodysplastic syndrome


In adult patients with acute leukemia, clofarabine is adminis-tered via a one-hour IV infusion at dosages ranging from 2040 mg/m2 (Burnett et al., 2004, 2006; Kantarjian et al., 2010; Kan-tarjian, Gandhi, Cortes, et al., 2003). Administration of clofara-bine should be performed under the supervision of a physician experienced with the use of antineoplastic agents. Table 2 lists general warning and monitoring precautions recommended for the administration of clofarabine (Genzyme, 2008). Because the administration of clofarabine to patients with liver or renal dysfunction has not been evaluated, it should be used cautiously for patients with hepatic or renal impairment.

General Supportive Care

Regular laboratory assessment (at least two to three times per week) of hematologic parameters as well as renal and hepatic function during and following clofarabine therapy is essential (Clofarabine, 2004; Genzyme, 2008). The frequency and specific nature of laboratory assessments should be determined by physician orders and specific institution guidelines. Trans-fusions of red blood cells or platelets are required by most pa-tients with hematologic malignancies receiving treatment with clofarabine. Physician orders and institution guidelines define hemoglobin and platelet levels that would prompt treatment with transfusions. Table 3 summarizes guidelines for delaying and modifying clofarabine doses.

Regular monitoring of vital signs and symptoms (i.e., tempera-ture, pulse, blood pressure, and respiratory rate) prior to, dur-ing, and following completion of the clofarabine administration is recommended to detect the development of symptoms such as dyspnea, chest pain, palpitation, fever, and hypotension. Physi-cians should be notified when patients present with or develop abnormal vital signs during infusions, such as systolic blood pressure of 90 mmHg or less, pulse of 50 beats per minute or less, or temperature of 38.1C (100.5F) or higher. Patients who experience complications during or immediately following the infusion should be considered for inpatient admission for addi-

tional monitoring; these patients would then receive subsequent treatments as inpatients.

The main criteria used to decide if a patient is ready for the next cycle of treatment are resolution of toxicities to baseline or maximum grade 1, ECOG performance status of 2 or less, and hematologic recovery (in general, an absolute neutrophil count of 1 x 109/L or higher and platelets of 100 x 109/L or higher). Other important concerns include how quickly a patient recov-ers from being myelosuppressed following clofarabine infusion and whether the patient experienced complications of myelo-suppression (e.g., severe infection, multiple infections) in the previous cycle. As blood counts recover, patients generally recover from infections quicker; recovery from infection and other toxicities may delay the next cycle.

Management of Toxicities During Outpatient Administration

Tables 4 and 5 list the most common toxicities observed in adult patients treated with single-agent clofarabine (Kantar-jian, Gandhi, Cortes, et al., 2003). Nurses play a key role in the prevention and early identification of toxicities and in the implementation of strategies for their management. To optimize telephone triage of patient issues and concerns, nurses should understand the side effects and risks associated with outpatient administration of clofarabine. Nurses must also be aware that many older adult patients do not want to bother the outpa-tient nurse and may not report side effects unless specifically asked. In addition, many older adult patients face the added responsibility of caring for ailing spouses or partners. Some of these patients may provide inaccurate reporting of side effects for fear of being admitted to the hospital for acute management.

Tumor Lysis Syndrome

Patients undergoing clofarabine treatment should be evalu-ated and monitored for signs and symptoms of TLS (Genzyme,

Table 2. General Warnings and Precautions for the Administration of Clofarabine

WARNING PRECAUTION INTERVENTIONS

Hematologic toxicity Monitor complete blood count and plate-lets.

Anticipate suppression of bone marrow function.

Hepatic and renal impairment

Monitor laboratory tests for liver and renal function.

Clofarabine has not been studied in patients with hepatic or renal dysfunction.Use clofarabine with great caution in these patients.

Hyperuricemia (tumor lysis syndrome)

Monitor for signs and symptoms of hyper-uricemia.

Provide IV fluids during five days of infusion to minimize the effects of tumor lysis and other toxicities.

Administer hyperuricemic medication such as allopurinol or rasburicase if hy-peruricemia is anticipated.

Infection Monitor for signs and symptoms of infection. Treat promptly.

Systemic inflammatory response syndrome and capillary leak syndrome

Evaluate and monitor for signs and symp-toms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema).

Prophylactic steroids may help prevent signs and symptoms of cytokine release.Immediately discontinue clofarabine if clinically significant signs or symptoms

emerge.Consider use of steroids, diuretics, and albumin.When patient is stable, treat with a 25% reduced dose of clofarabine.

Note. Based on information from Genzyme, 2008.


2008) (see Table 6) in the presence of active disease, which can lead to hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia (McGraw, 2008). Clinical signs of TLS range from nausea, vomiting, diarrhea, anorexia, lethargy, edema, and muscle cramps to congestive heart failure, cardiac dysrhyth-mias, and even sudden death (Coiffier, Altman, Pui, Younes, & Cairo, 2008; McGraw, 2008). Symptoms usually occur during the 1272 hours following the start of chemotherapy (Coiffier et al., 2008). Nurses should be thoroughly familiar with the signs and symptoms of TLS to not only evaluate and monitor patients, but also to educate them and their caregivers to identify the first signs of incipient TLS.

Infusion Reactions

Infusion reactions are uncommon in adults with single-agent clofarabine, but nurses should be aware of the symptoms during patient monitoring. Infusion reactions usually occur during the first few minutes following the start of clofarabine infusion and include wheezing, bronchospasm, cough, stridor, congestion, sneezing, runny nose, urticaria, rash, edema, pruritus, nausea, diarrhea, hypotension, chest discomfort, dizziness, syncope, headache, arthralgia or myalgia, diaphoresis, fever, rigors, chills, and occasional cardiac events (Genzyme, 2008). Education about possible signs and symptoms of an infusion reaction also is essential. Patients should be encouraged to inform nursing

staff if they notice any symptoms potentially indicative of an infusion reaction.

Clofarabine may induce cytokine release and capil-lary leak syndrome, which cause signs and symptoms such as tachypnea, hypotension, and tachycardia (Genzyme, 2008). Discontinuation of blood product transfusions or other medications prior to initiation of clofarabine therapy is advisable because these interven-tions could provoke signs and symptoms that might be confused with a true clofarabine infusion reaction. If patients require treatment with clofarabine and red blood cell or platelet transfusion, clofarabine should be administered prior to the transfusion. A reaction kit may be placed at each chemotherapy station, and an emergency crash cart should be readily available in the outpatient clinic or office.

Management of infusion reactions must be rapid. Clo-farabine infusion should be discontinued at the first sign of a reaction (Genzyme, 2008). Following discontinua-tion of the infusion, treatment options include use of antihistamines, corticosteroids, epinephrine, oxygen, and bronchodilators. Vital signs should be monitored every five minutes until the patient is stable; airway, breathing, circulation, and orientation should be as-sessed immediately and monitored.

Patients who experience an infusion reaction can continue clofarabine treatment, but may benefit from prophylactic administration of corticosteroids or a dose reduction for subsequent infusions (Genzyme, 2008). Nursing staff must recognize that infusion reactions are potentially lethal but preventable. Vigilant patient monitoring during each infusion is critically important to prevent severe reactions or death.

Myelosuppression

Neutropenia, thrombocytopenia, and anemia are common toxicities associated with clofarabine (Genzyme, 2008). Most complications associated with myelosuppression are linked to infections, which can result in early death. The onset of myelo-suppression is rapid with blood counts reported to decrease after the second day of infusion. Hematologic laboratory tests are generally performed two to three times per week during outpatient administration of clofarabine. Prophylactic antibiot-ics may be administered to patients as per institution guidelines and may include antibacterial agents such as levofloxacin, sul-famethoxazole and trimethoprim, and amoxicillin clavulanate; antiviral agents such as valacyclovir hydrochloride and acyclo-vir; and antifungal agents such as itraconazole, fluconazole, and voriconazole. However, whenever possible, hepatotoxic and nephrotoxic antibiotics, particularly of the -azole family, should be discontinued during the administration of clofarabine to avoid exacerbation of potential liver and renal toxicity.

Human hematopoietic growth factors may be used in the set-ting of life-threatening infections to reduce febrile neutropenia according to guidelines from the American Society for Clinical Oncology (Smith et al., 2006). Growth factors also may be ad-ministered to patients who do not experience recovery of abso-lute neutrophil count in a timely manner and should continue to be used in subsequent clofarabine treatment cycles. Patients

Table 3. Dose Delays and Modifications With Clofarabine Treatment

TOXICITY ACTION

Hematologic

Grade 4 neutropenia (absolute neutrophil count of less than 0.5 x 109/L) lasting four weeks or longer

Reduce clofarabine dose by 25% for next cycle.

Nonhematologic

Hypotension during five days of clofara-bine therapy

Discontinue clofarabine.

Clinically significant infection Withhold clofarabine until infection is clinically controlled, then restart at full dose.

Grade 3 noninfectious toxicity (excluding transient elevations in serum transami-nases or serum bilirubin, or nausea and vomiting controlled by antiemetic therapy)

Withhold clofarabine. Restart at 25% dose reduction when toxicity resolves or returns to baseline.

Grade 4 noninfectious toxicity Discontinue clofarabine.

Early signs or symptoms of systemic inflammatory response syndrome or capil-lary leak (e.g., hypotension, tachycardia, tachypnea, pulmonary edema)

Discontinue clofarabine and provide appropriate supportive measures.

Grade 3 or higher increases in creatinine or bilirubin

Discontinue clofarabine and provide appropriate supportive measures. Restart usually with a 25% dose reduction when patient is stable and organ function returns to baseline.

Note. Based on information from Genzyme, 2008.


who require growth factors should be monitored daily for white blood cell counts and circulating blasts.

Patients with febrile neutropenia require hospitalization along with chest radiographs and urine and blood cultures to identify the underlying cause of the infection. Administration of acetaminophen for relief of the fever should be delayed until all necessary cultures are obtained. Antibiotic treatment should be initiated promptly.

Patient education about infection prevention measures and steps to take if significant fevers are noted (i.e., 100.5F or higher) is extremely important. In addition, because corticoste-roids and acetaminophen can mask fever, these agents should be used with caution; patients should be instructed not to use these medications to treat fevers until they are evaluated by a healthcare provider. Patients also should be advised regarding optimal hygiene practices (e.g., frequent hand washing, avoid-ing exposure to crowds and ill individuals) to prevent infec-tions. Patients with infections or febrile neutropenia should contact their medical team immediately and be admitted for medical evaluation and close monitoring.

Hepatic Toxicity

Clofarabine may cause transient elevations of hepatic en-zymes and bilirubin, necessitating regular monitoring of liver function during all treatment cycles (Genzyme, 2008). Onset of hepatotoxicity usually occurs during the first or second week of clofarabine therapy, with most patients experiencing a return to baseline liver function one to two weeks following clofara-bine administration. Suggested tests for hepatotoxicity include alanine transaminase, aspartate transaminase, alkaline phospha-tase, and direct and total bilirubin, with the frequency of testing determined by physician orders and institution standards. For outpatients, laboratory studies usually are obtained at least two to three times per week for the first cycle and at least every week until count recovery for subsequent cycles. Discontinuation of known hepatotoxic agents (e.g., prophylactic antibiotics) dur-ing the five days of clofarabine administration is recommended.

Renal Toxicity

The effect of clofarabine on patients with renal dysfunction has not been evaluated, and this patient population should be closely monitored (Genzyme, 2008). Newly diagnosed patients with AML often present with or develop renal dysfunction prior to and during treatment that is related to spontaneous or chemo-therapy-induced TLS and dehydration. Adequate hydration is es-sential to prevent additional exacerbation of renal impairment. In addition, avoiding the use of nephrotoxic medications can reduce the risk of new or additional impairment. Discontinua-tion or delayed administration of medications known to impair renal function is recommended for patients during the five days of clofarabine administration.

The median time to peripheral blood blast clearance for patients treated with clofarabine is about five days; during this time, patients are at significantly increased risk for TLS which also may cause renal impairment (Kantarjian et al., 2010). Patients with high white blood cell counts and who are at risk for TLS should be treated prophylactically with hyperuricemic agents such as allopurinol and rasburicase. They also can be treated with ambulatory pump IV hydration or admitted for close monitoring and care. Patients who fail to regain good renal function despite these interventions may not be eligible for continued treatment with clofarabine.

Optimal oral hydration prior to and during administration of clofarabine is essential to support renal function throughout the course of every treatment cycle. Although IV hydration during outpatient infusion of clofarabine is not standard at most institu-tions, patients should be encouraged to drink adequate amounts of fluids daily, monitor their urine output, and report any signs of edema or weight gain that might be attributed to fluid reten-tion. Monitoring changes in weight, edema, and fluid input and output at each outpatient appointment can identify patients

Table 4. Most Common Side Effects Associated With Clofarabine Monotherapy in Previously Untreated Adult Patientsa With AML

TOXICITYALL GRADES

(%)GRADE 3

(%)GRADE 4

(%)

Nausea 63 4 Febrile neutropenia 40 38 3Vomiting 40 Diarrhea 34 2 Rash 30 2 Fatigue 20 3 Headache 15 Pyrexia 14 2 Anorexia 13 3 Mucosal inflammation 12 3 Pruritus 12 1

a Aged 60 years or olderAMLacute myelogenous leukemiaNote. Based on information from Kantarjian et al., 2010.

Table 5. Most Common Side Effects Associated With Clofarabine Administered as a Single Agent in Adult Patients With Relapsed or Refractory Acute Leukemias

TOXICITYGRADES 12

(%)GRADES 34

(%)

Documented infections 50Diarrhea 21 Febrile episodes 81Fever of unknown origin 31Liver dysfunction Elevatedbilirubin 35 15 Elevatedtransaminases 50 24Mucositis 15 Nausea and vomiting 65 3Palmoplantar erythrodysesthesia

(hand-foot syndrome)8 11

Skin rashes 37 10

Note. From Phase 2 Clinical and Pharmacologic Study of Clofarabine in Patients With Refractory or Relapsed Acute Leukemia, by H.M. Kantar-jian, V. Gandhi, J. Cortes, S. Verstovsek, S., M. Du, G. Garcia-Manero . . . E.J. Freireich, 2003, Blood, 102, p. 2383. Copyright 2003 by Ameri-can Society of Hematology. Adapted with permission.


who are in the early stages of renal impairment, fluid overload, or dehydration. Hydration level and fluid retention are a balanc-ing act in an older population, and fine-tuned assessment skills are essential for outpatient therapy.

Suggested tests to monitor changes in renal function include serum creatinine and blood urea nitrogen, with the frequency of testing determined by physician orders and institution stan-dards. These tests are performed at least two to three times per week during the first cycle and at least every week during subse-quent cycles of outpatient administration of clofarabine. If renal dysfunction occurs, treatment with clofarabine is discontinued until normal renal function is regained and then restarted as recommended (Genzyme, 2008).

Nausea and Vomiting

The frequency of nausea and vomiting is relatively low with clofarabine treatment (Faderl et al., 2008). These toxicities, which are most likely to occur during rather than after infusion, can be treated in most patients by prophylactic administration of IV or oral serotonin (5-HT3) antagonists such as ondansetron or prochlorperazine (Genzyme, 2008). These antiemetics usually are administered 30 minutes before initiation of the clofarabine infusion. Dexamethasone also may be used as a premedication for nausea and to prevent infusion reactions. Persistent nausea and vomiting after oral premedication can be managed as needed with additional doses of ondansetron, prochlorperazine, or granisetron.

Diarrhea

Onset of diarrhea associated with clofarabine usually occurs during days 710 following treatment. Key interventions include patient education regarding increased oral hydration to main-tain optimal electrolyte balance and the use of a daily diary to record the number and consistency of diarrhea episodes. One

authors institution obtains elec-trolyte laboratory tests every other day for outpatients experiencing persistent diarrhea. Depending on institution policies, when patients experience a diarrhea episode, a stool culture for Clostridium dif-ficile toxin may be obtained prior to starting antidiarrheal measures. Use of high-dose loperamide (4 mg every 24 hours until 12 hours have elapsed since the last episode of diarrhea) is an effective treatment for patients who experience mild-to-moderate diarrhea. Combination treatment with diphenoxylate and atropine or loperamide is effective for outpatient treatment of diarrhea with the usual dose for adults of one tablet (22.5 mg) after each stool up to a maximum of eight per day. More severe cases of diarrhea may require hospitalization for IV fluid and electrolyte replacement.

Cutaneous Reactions

Cutaneous reactions usually presenting as a maculopapular rash or a sunburn-like rash were observed in about 33%50% of patients treated with single-agent clofarabine (Faderl et al., 2008; Genzyme, 2008; Kantarjian, Gandhi, Cortes, et al., 2003; Kantarjian, Gandhi, Kozuch, et al., 2003). Mild rashes can be managed with careful monitoring and symptom relief. Triamcin-olone cream or Aquaphor (Eucerin) are effective moisturizers that can be applied by patients to the affected areas. Steroids such as hydrocortisone and antihistamines such as hydroxyzine and diphenhydramine provide good symptom relief and can be administered prior to initiation of each clofarabine infusion. Patients treated with steroids for cutaneous reactions require monitoring for signs and symptoms of infection, including blood cultures, because steroids can mask infections.

In addition, patients should be advised to implement pro-phylactic measures such as the use of physical sun blocks (i.e., hats, long-sleeved clothing, and umbrellas), mild soaps for skin cleansing, and gloves to protect hands when washing dishes or cleaning. Patients also should be instructed to avoid exposure to cold and wind, as well as to avoid using sunscreens (most contain chemicals which may irritate and worsen the rash), agents that dry the skin (e.g., alcohol-based products, including acne products; household cleaning agents), and other chemical products. These measures might help decrease the incidence, symptoms, and severity of cutaneous reactions to clofarabine.

Interventions by nurses may be necessary for patients who experience more severe rashes that are characterized by blis-tering of the skin, pain, and pruritus. The severity of symptoms usually is associated with dose and combination of cytotoxic medications. Patients should be warned that cutaneous reac-tions can persist even after clofarabine is discontinued and that they should continue prophylactic measures to prevent or minimize the severity of these reactions.

Table 6. Signs and Symptoms of Tumor Lysis Syndrome

SIGNLABORATORY

FINDINGS PHYSICAL SYMPTOMSa

Hyperkalemia Higher than 5.5 mEq/L

Cardiac: irregular heart arrhythmias, hypotension (at greater than 5.3 mEq/L), and electrocardiogram changes (i.e., tall T waves, flattened P waves, prolonged PR intervals, widened QRS complexes, and depressed ST segments)

Gastrointestinal: nausea, vomiting, diarrhea, anorexia, abdomi-nal cramping, and pain

Neuromuscular: neuromuscular irritability, muscle weakness, paralysis, seizures, and tetany

Hyperphosphatemia Higher than 4.5 mg/dl

Gastrointestinal: nausea, vomiting, and diarrheaNeuromuscular: lethargy and seizures

Hyperuricemia Higher than 6 mg/dl

Renal: flank pain, gross hematuria, cloudy urine, oliguria, leth-argy, nausea, vomiting, weight gain, and edema

Hypocalcemia Less than 8.5 mg/dl

Cardiac: prolonged QT interval, cardiac arrhythmia, hypotension, and tetany

Gastrointestinal: intestinal cramping and increased bowel activityNeuromuscular: neuromuscular excitability and muscular cramps

a More serious symptoms occur only in severe cases.Note. Based on information from Coiffier et al., 2008; McGraw, 2008.


Hand-Foot SyndromeHand-foot syndrome is not a common toxicity associated with

clofarabine when administered as monotherapy, but it has been reported in some patients (Kantarjian, Gandhi, Cortes, et al., 2003), with onset usually noted during the first two weeks of the treatment cycle. The incidence of hand-foot syndrome ap-pears higher for patients treated with clofarabine and cytarabine (Faderl et al., 2005, 2006). Hand-foot syndrome can be confused

with general cutaneous reactions. However, redness, tender-ness, swelling, and splitting of the skin on hands and feet are more likely characteristics. The skin may blister and peel pain-fully, requiring treatment with appropriate pain medications.

Strategies for management of hand-foot syndrome include application of moisturizing creams and use of medications sug-gested for management of skin rashes and cutaneous reactions (i.e., steroids, diphenhydramine, and hydroxyzine) to achieve acceptable symptom relief. Use of ice packs may control swell-ing and tenderness at the onset of symptoms, which usually oc-curs by the last day of treatment. Patients with severe hand-foot syndrome should be treated similar to patients with burns. Use of hydrocortisone may be necessary to ease the symptoms. In addition, some patients might benefit from an evaluation by a wound care specialist.

FatigueAlthough not one of the most common toxicities of clo-

farabine, fatigue may be particularly troublesome for patients receiving outpatient treatment and who are trying to maintain normal lifestyles. Fatigue often is a side effect of anemia or in-fection caused by the underlying disease process. Fatigue also may be associated with comorbid depression, which may be treated with antidepressants. Proactive education can ensure that patients have realistic expectations about the fatigue they might experience during treatment with clofarabine. Patients should be encouraged to rest as needed.

Mucositis

Mucositis occurs infrequently with clofarabine treatment. The onset of mucositis usually occurs during the first two weeks of a treatment cycle. The incidence of mucositis, particularly grade 3 mucositis, with single-agent clofarabine appears to be lower than the rates observed with the combination of cytara-bine and an anthracycline (7 plus 3 regimen) (Vogler et al., 1992; Waddell & Solimando, 2002; Yates et al., 1982).

To reduce inflammation and irritation, patients should be advised to oral rinse every four hours with sodium bicarbonate mixed with warm water (a half teaspoon in 8 oz. of water). The practice of mouth rinses may be initiated at the start of clofara-bine treatment to minimize the possibility of severe mucositis.

Severe cases of mucositis can be treated with valacyclovir hydrochloride, xyloxylin, or sucralfate, which patients swish in their mouths and spit out or swallow several times a day. Valacy-clovir hydrochloride is used if a viral component is suspected or confirmed, whereas the other agents tend to be used for symptom relief. Exacerbations of mucositis also can be treated by increasing the dose of valacyclovir hydrochloride. Although not curative, xyloxylin and sucralfate coat the mouth to alleviate symptoms and prevent their worsening. Patients should be advised to avoid spicy and sharp foods (i.e., crackers or potato chips) to avoid injuring the oral mucosa.

Pain

Pain is not a common side effect associated with clofara-bine, but some patients require pain medications for head-aches experienced during or within a few hours of clofarabine

Prior to Infusion Checkperipherallineforplacementandsignsofinfection. Monitorchangesinweight,edema,andfluidinputandoutputat

each outpatient appointment to identify patients who are in the early stages of renal impairment.

Administerantiemetics30minutespriortoclofarabineinfusion.

During Administration Monitorvitalsigns(temperature,pulse,bloodpressure,andrespira-

tory rate) immediately before, during, and after each infusion. Beknowledgeableaboutthesignsandsymptomsofinfusionreac-

tions (e.g., difficulty breathing, shortness of breath, palpitation, chest discomfort).

Monitorpatientsforheadacheandfacialflushingduringtheinfu-sion. Manage by administering pain medication (e.g., tramadol) and applying a cool cloth.

Haveareactionkitateachchemotherapystationandacrashcartreadily available in the outpatient clinic.

Discontinueclofarabineatfirstsignofinfusionreaction.

Patient Education Givepatientstheirhealthcareproviderscontactinformationand

encourage patients to call if they have any questions or concerns. Explaintheuseofadailydiarytorecordtemperatureandchangesin

signs, symptoms, and physical well-being to report at the next visit. Describethesignsandsymptomsofaninfusionreaction. Cautionpatientsaboutthepotentialforheadacheandfacialflush-

ing during and for a few hours after the infusion. Noteinfectionpreventionmeasuresandstepstotakeincaseofsig-

nificant fevers (usually 38.1C [100.5F] or higher). Encourageandexplaintheneedtochecktemperaturesofneutrope-

nic patients three times a day to detect early infection. Instructnottousecorticosteroidsandacetaminophentotreatfevers

until evaluated by a healthcare provider. Recommendoptimalhygienepractices(e.g.,frequenthandwashing,

avoiding exposure to crowds and ill individuals) to prevent infections. Encourageplentyoffluidsastoleratedandadequateoutput;monitorfor

signs and symptoms of fluid retention (e.g., weight gain, edema). Explaintheneedforincreasedoralhydration,includingfluidsto

maintain optimal electrolyte balance during diarrhea episodes and the need to record the number and quantity of diarrhea episodes daily in a diary.

Suggestprophylacticskinprotectionmeasuressuchasavoidingsun exposure and using physical sun blocks (i.e., hats, long-sleeved clothing, and umbrellas), mild soaps for skin cleansing, and gloves to protect hands when washing dishes or cleaning.

Cautionpatientstoavoidexposuretocoldandwind. Informpatientsthatleukemiaoftencausesanemia,whichcanlead

to fatigue. Encourage rest as needed.

Figure 1. Key Nursing Considerations for Outpatient Administration of Clofarabine


administration (Genzyme, 2008). The preferred treatment is tramadol hydrochloride rather than acetaminophen or a nonste-roidal anti-inflammatory drug, which can mask a fever. Rest and a cool cloth applied to the head can alleviate headaches as well as facial flushing, which occurs for some patients during or im-mediately after completion of infusions (Genzyme, 2008).

Anorexia

Anorexia is reported to be a significant challenge for patients, affecting eating and drinking (Genzyme, 2008), and can be exacerbated by mucositis and persistent nausea and vomiting. Nurses can encourage family members or caregivers to make special foods that appeal to patients. Some patients require three to four weeks following completion of treatment to re-cover their appetites. During this time, nutrition supplements can be helpful, particularly when prepared as milkshakes and served cold to reduce the odor that is sometimes unappealing to patients. Drinking these supplements through a straw also is a helpful strategy to minimize the unpleasant odor. Nutrition supplements may be particularly beneficial for patients with persistent nausea and vomiting.

Patient Support and Considerations

Nursing staff play a key role in the provision of ongoing pa-tient education and support (see Figure 1). Essential elements of patient education are summarized in Figure 2.

Treatment selection for older patients with AML and other leukemias should take health status and specific disease charac-teristics into consideration (Klepin & Balducci, 2009). General principles of geriatric care that should be applied to the man-agement of older patients include the use of supportive care to minimize toxicities; regular assessment of physical, cognitive, and psychological function; nutrition management; medication management; and maintenance of physical functioning.

Conclusions

Clofarabine offers patients with hematologic cancers a prom-ising treatment option with a favorable safety profile and a low mortality rate. The most frequent toxicities associated with clofarabine are gastrointestinal (i.e., nausea, vomiting, and di-arrhea), myelosuppression, hepatic and renal dysfunction, and anorexia. Careful patient monitoring is essential to ensure early identification and prompt intervention.

Although most patients receive the first course of clofarabine while hospitalized, many can be subsequently treated as outpa-tients with proper monitoring, support, and education. Younger patients and those of any age with no comorbid health issues, good ECOG performance status (2 or lower), and an adequate support network are most likely to tolerate outpatient clofara-bine administration. Nurses should discuss the importance of treatment compliance with patients and assess patients home support networks.

Nurses can minimize the severity and occurrence of com-mon toxicities associated with clofarabine through patient

At Any Time Contactthisofficeifyouhaveanyquestionsorconcerns.

During the Infusion Tellthenurseifyouhavetroublebreathing,feelshortofbreath,or

have palpitations or chest discomfort.

Once at Home Keepadailydiarytorecordyourtemperatureandhowyoufeel. Are you tired? Do you have any pain? If so, where? Do you feel bloated? How is your appetite? Have you gained or lost weight? Have the frequency and amount of your bowel movements

changed? Bringthediarytoyournextvisit.

Monitor Your Temperature Checkyourtemperaturethreetimesaday(inthemorning,after-

noon, and evening), particularly when your neutrophil count is low. Callthenurseorphysicianorgototheemergencydepartment

within one hour if your fever is higher than 38.1C (100.5F). Uncheckedfevercanleadtoseriouscomplications.

Keep Hydrated Drinkplentyoffluidsthroughouttheday. Tellthenurseifyourweighthasincreasedordecreased,ifyoufeel

bloated, or if you have trouble urinating.

If You Feel Tired Restandtakeshortnapsasneeded. Rememberthatlongnapscaninterferewithnightsleeping.

Take Precautions: Treatment Can Weaken Your Immune System Avoidcrowdsandstayathometopreventorreduceexposureto

infections from others when your neutrophil count is low. Followexcellenthygienetechniques:washyourhandsoften,have

someone else take care of your pets; if possible, spend most of your time in a clean room in your dwelling to reduce exposure to germs.

You Might Be Susceptible to Easy Bleeding and Bruising Thoroughlyandregularlycleancutsorabrasions. Useantibioticointments. Covertheinjuryuntilthehealingprocessisunderway.

You Might Feel Nauseous or Develop Diarrhea Takethemedicationsprescribedtoyoutopreventandmanage

current symptoms of diarrhea and nausea and vomiting after your clofarabine infusion.

Ifyouhavediarrhea,drinkplentyofliquids(waterorjuices)andwrite down the number of diarrhea episodes daily in a diary.

Drinkcaffeinatedteaorcoffeeinmoderationandavoidalcoholasmuch as possible.

Contacttheofficeifyouhavefourormorediarrheaboutsinoneday.

Chemotherapy Makes Your Skin SensitiveProtect It Avoidexposuretosun,cold,wind,sunscreen,agentsthatdrythe

skin (e.g., acne products, household cleaning agents), and other chemical products.

Wearhatsandlong-sleevedclothing;useumbrellas. Usemildsoapsforskincleansingandgloveswhenwashingdishes

or cleaning.

Figure 2. Sample Patient Education Information for Outpatient Administration of Clofarabine


education, support, and monitoring. Early identification and proactive pharmacologic and nonpharmacologic interventions may reduce the severity of these toxicities and prevent their progression. Patient education about strategies for prevention and management of symptoms also is essential. Management of treatment-related toxicities has the potential to maintain a patients quality of life and promote treatment adherence, which will yield optimal patient outcomes.

Nursing staff are essential participants in patient support networks through the continuum of care and ongoing patient education, particularly with regard to infection control and man-agement of other treatment-related toxicities. Nurses establish ongoing relationships with patients during the course of their treatment regimens. Nurses can learn more about patients personal situations through these relationships. This can help ensure that education and support are tailored to individual lifestyles and needs.

The authors gratefully acknowledge Carole Alison Chrvala, PhD, and Monica Nicosia, PhD, for medical writing and editorial support sponsored by Genzyme Corporation.

Author Contact: Amanda Dressel, RN, BSN, CCRC, can be reached at [email protected], and Monica Kwari, RN, BSN, CCRP, can be reached at [email protected], with copy to editor at [email protected].

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