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FEATURE ARTICLE

Nursing Considerations for Clofarabine in the Treatment of Acute Lymphoblastic Leukemia in Children
Lisa R. McDonald, RN, MSN, CPNP, CPON, and Colleen H. McCarthy, RN, MSN, CPON
Each year, almost 3,500 children are diagnosed with leukemia, representing approximately 30% of pediatric cancer cases. Acute lymphoblastic leukemia is the most common form of pediatric leukemia, accounting for approximately 80% of cases. A signicant number of children fail to respond to existing chemotherapies or are unable to maintain remission. Their prognosis is poor, with little hope for long-term survival.

lofarabine is a next-generation purine nucleoside analog (NA) approved by the U.S. Food and Drug Administration for use in children with relapsed or refractory acute lymphoblastic leukemia (ALL). In clinical trials, clofarabine induced remission in heavily pretreated patients with limited therapy options. Most treatment-related side effects have been manageable and reversible with appropriate therapeutic interventions. Side effects associated with clofarabine are similar to other chemotherapeutic agents and are manageable with proper treatment. As knowledgeable participants in the management of patients with complex, life-threatening diseases, nurses can facilitate a successful outcome through educating patients and their families and by actively intervening to prevent or reduce side effects.

At a Glance
Clofarabine is a nucleoside analog approved for treatment of relapsed or refractory acute lymphoblastic leukemia in pediatric patients. The recommended dose of clofarabine in children is 52 mg/m2 per day for ve consecutive days. Side effects of clofarabine are similar to those seen with other chemotherapeutic agents and are manageable with timely and appropriate nursing interventions.

Current Treatment of Pediatric Acute Lymphoblastic Leukemias

Initial Disease
The key to securing long-term survival in children diagnosed with ALL is to achieve a complete and durable remission through aggressive induction chemotherapy followed by delayed intensication and maintenance therapy. Most protocols recommend less toxic regimens for low- or standard-risk patients and more aggressive regimens for patients at higher risk. The presence of certain characteristics at initial diagnosis appears to be associated with more favorable prognoses. Factors such as age (110 years) and initial low white blood cell counts (less than 50,000/mcl) (see Figure 1) appear to signify a more positive outcome. Conversely, patients who are older than 10 years, with higher initial white blood cell counts (more than 50,000/mcl) or who also have cer-

tain chromosomal abnormalities, have less favorable prognoses (Bleyer, 1997; Weinstein & Tarbell, 2001). Immunophenotype is another prognostic factor. Patients with preB-cell leukemia are considered to have standard risk, whereas patients with T-cell

Lisa R. McDonald, RN, MSN, CPNP, CPON, is a pediatric nurse practitioner at the University of Texas M.D. Anderson Cancer Center in Houston, and Colleen H. McCarthy, RN, MSN, CPON, is a clinical research nurse for the Leukemia/Lymphoma Program at Childrens Hospital of Los Angeles in California. Both authors are on the nursing advisory committee and McDonald is on the speakers bureau for Genzyme Corporation. A medical writer employed by Genzyme Corporation, S. Lipper, was involved in the writing of this article. The article was accepted prior to the Clinical Journal of Oncology Nursings policy against the use of medical writers. Mention of specic 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 February 2005. Accepted for publication November 21, 2005.)
Digital Object Identier: 10.1188/06.CJON.809-815 809

Clinical Journal of Oncology Nursing Volume 10, Number 6 Nursing Considerations for Clofarabine

White blood cells

Artery Red blood cells Platelets

2004 American Society of Clinical Oncology

Figure 1. Cells in the Blood

Note. Illustration courtesy of the American Society of Clinical Oncology. Used with permission.

leukemia historically have had poorer prognoses, with shorter remission duration and decreased overall survival (Margolin, Steuber, & Poplack, 2002). More aggressive and potentially more toxic regimens have been used for patients considered at higher risk. A standard four-week induction regimen in low-risk patients with ALL includes vincristine, a steroid (prednisone or dexamethasone), and L-asparaginase. In higher-risk patients, anthracycline (daunorubicin or doxorubicin) or cyclophosphamide is added to the regimen (Rubnitz & Pui, 2003; Uderzo et al., 2001; Vora, 2002; Weinstein & Tarbell, 2001). Most patients receive some form of delayed intensication therapy in which the drugs used during induction are repeated, followed by at least two years of maintenance or continuation therapy (e.g., daily 6-mercaptopurine plus intermittent low-dose methotrexate with intermittent monthly pulses of vincristine and steroids) and central nervous system (CNS) disease prophylaxis (Rubnitz & Pui; Weinstein & Tarbell). The rationale behind periodically intensifying treatment has been that drug-resistant strains are less likely to develop with episodic use of high-dose drugs and that toxicity may be reduced by using the drugs for brief, intense periods. In addition, the CNS has been a frequent site of disease relapse because it can serve as a reservoir for leukemia cells and most systemically administered chemotherapy does not effectively cross the blood-brain barrier (Westlake & Bertolone, 2002). Therefore, the standard of care for pediatric ALL involves some form of intrathecally administered CNS prophylaxis. These measures have yielded overall long-term survival rates now approaching 80% (Margolin et al., 2002).

likelihood of survival in patients with late relapse, and (b) site of relapse, with poorer prognosis in bone marrow relapse versus extramedullary disease (Boulad et al., 1999; Buchanan et al., 2000; McCarthy, Pitcher, Hann, & Oakhill, 1999). In general, patients with a longer duration of remission have a better prognosis than patients who relapse early in treatment. Patients who relapse within three years of achieving remission may be considered early, with a poorer chance of survival (Weinstein & Tarbell, 2001). For rst relapse in patients with ALL, reinduction therapies may be similar to prior induction regimens but with increased intensity, especially for patients who experience late relapses. The majority (approximately 80%) of children will achieve second remission; however, remission is less likely to be sustained without a hematopoietic stem cell transplant (HSCT) (Boulad et al., 1999; Buchanan et al., 2000). In patients who achieve remission, allogeneic HSCT is considered, especially in early relapse patients and those with human leukocyte antigenmatched related donors (Boulad et al.). Treatment of a second or third relapse is more difcult because of a greater likelihood of drug resistance and accumulated toxicities from prior regimens.

Robert Morreale/Visual Explanations, LLC

Clofarabine Overview
Clolar (clofarabine, Genzyme Corporation, Cambridge, MA) is a chemotherapy agent approved in December 2004 for pediatric patients with refractory or relapsed ALL aged 121 years who have failed two prior regimens. Clofarabine offers an important new treatment alternative for patients with relapsed or refractory ALL who have few viable therapeutic options. Clofarabine is a next-generation purine NA, which is a broad class of agents that slow or prevent reproduction of malignant cells by interfering with DNA synthesis (Galmarini, 2002). Older NAs, such as udarabine or cladribine, have been associated with potentially severe neurologic effects. Adverse events associated with neurologic toxicity such as agitation, confusion, visual disturbances, and coma have been reported in a small percentage of patients taking udarabine at the recommended dose for chronic lymphocytic leukemia (Berlex Laboratories, Inc., 2003; Ortho Biotech Products, LP, 2002). Clofarabine and udarabine have similar structures and modes of action, but the degree of neurologic toxicity has not been observed with clofarabine. Although the possibility of severe neurologic effects of clofarabine cannot be ruled out, clofarabine appears to have limited ability to penetrate the CNS. Additional monitoring for these types of toxicity is ongoing.

Mechanism of Action
Clofarabine was designed to improve the efcacy of the purine NAs in acute leukemia by combining the most favorable cytotoxic properties of udarabine and cladribine (Gandhi et al., 2003) while attempting to reduce the likelihood of serious adverse events. Clofarabine appears to have a dual mechanism of action (Gandhi et al.). First, it slows or halts the reproduction of leukemic cells by interfering with DNA replication. Like udarabine, the active form of clofarabine inhibits the activity of DNA polymerase, which, in turn, terminates elongation of

Refractory and Relapsed Disease

Despite the dramatic improvements offered by induction regimens, approximately 5% of children with ALL do not respond to the rst induction attempt and as many as 20%25% do not maintain remission (Gaynon et al., 2000; Leukemia and Lymphoma Society, 2003). Upon relapse, key prognostic factors are the (a) duration of initial remission, with a much higher
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the DNA chain or limits a cells ability to repair chain breaks. Like cladribine, it inhibits ribonucleotide reductase, which also interferes with DNA synthesis and cell reproduction. Second, clofarabine directly promotes programmed death of leukemic cells by disrupting the membrane of the mitochondria in the nucleus of the leukemia cell leading to the release of cytochrome C and other factors that cause apoptosis, including caspase 3 (Genini et al., 2000).

Table 1. Clofarabine Efcacy in Acute Pediatric Leukemia in Phase II Clinical Trials

END POINT ALL STUDY (N = 61) AML STUDY (N = 42)

Pharmacokinetics
The pharmacokinetic properties of clofarabine in different patient populations still are under investigation but have been shown to be weight dependent. In a 40 kg pediatric patient, the half-life of clofarabine is relatively short (6.4 hours), with total systemic clearance of 32.8 L per hour (27% between-subject variability) and a volume of distribution at a steady state of 210 L (72% between-subject variability) (Bonate et al., 2004). Clearance is balanced, with approximately 50% of the drug excreted renally. Following this model, clofarabine would have a shorter half-life in smaller patients; therefore, a 10 kg patient would have a clofarabine half-life of approximately four to ve hours (Bonate et al.).

CR CRp Partial response Median survival Responders Nonresponders Median duration of remission Responders (CR + CRp)

12% (7 patients) 8% (5 patients) 10% (6 patients) 53.7 weeks 7.6 weeks

2% (1 patient) 24% (10 patients) 35.6 weeks 14.4 weeks

28.6 weeks

12.4 weeks

ALLacute lymphoblastic leukemia; AMLacute myeloid leukemia; CRcomplete response; CRpcomplete response without platelet recovery

Clinical Studies
The rationale for clinical studies of clofarabine was provided by in vitro studies that demonstrated its potent cytotoxic activity in hematologic malignancies and solid tumors (i.e., leukemia; melanoma; and non-small cell lung, colon, ovarian, renal, prostate, and breast cancer lines). Clofarabine has shown therapeutic activity in leukemia, colon, and mammary malignancies in animal and xenograft tumor models. In addition, clofarabine has proven activity against a wide range of human tumor models of hematologic and solid tumor types, both in vivo and in vitro (ILEX Products, Inc., and Genzyme Corporation, 2004c). Phase I clinical studies of clofarabine in children and adults were initiated by the University of Texas M.D. Anderson Cancer Center in 1999. The studies established the maximum tolerated dose of clofarabine and demonstrated promising antileukemic activity in children and adults. The maximum tolerated dose in children was 52 mg/m2 per day for ve days, which was higher than the 40 mg/m2 per day determined for adults. The doselimiting toxicities were reversible skin rash and liver toxicity (Jeha et al., 2004; Kantarjian et al., 2003). In general, children are thought to tolerate higher doses of clofarabine because of less end-organ toxicity and faster clearance of drug compared to adult patients. Following phase I trials, two multicenter phase II trials for pediatric patients with refractory or relapsed ALL and acute myeloid leukemia (AML) were conducted. Enrolled patients were aged 121 years at diagnosis, had a poor prognosis, and were heavily pretreated. All patients had undergone two to six prior regimens (median number of prior regimens was three), and 35 were refractory to one or more prior regimens. Thirty percent of patients with ALL (18 of 61) and 43% of patients with AML (18 of 42) had failed previous HSCT. Key efcacy results are summarized in Table 1. In the ALL study, of the 61 children evaluated, the response rate was 30% with

seven complete responses (CRs), ve CRs without full platelet recovery (CRp), and six partial responses. Response criteria are de ned in Table 2. Fifteen percent (9 of 61) of patients with ALL went on to receive HSCT. Twenty-three percent (14 of 61) of the patients were alive at last follow up, including six of the nine patients who had undergone HSCT. Among responders, median survival was 53.7 weeks (18 of 61), with one CR patient alive at more than 69.7 weeks (ILEX Products, Inc., and Genzyme Corporation, 2004a, 2004e). The median duration of overall remission (CR + CRp) was 28.6 weeks. Many patients with ALL, including some nonresponders, have achieved clinically meaningful benets (e.g., increased mobility, decreased pain, improved appetite) and prolongation of life. Patients often were able to receive treatment in the outpatient setting. The studies are completed, and the surviving patients continue to be followed. Additional studies of clofarabine in the treatment of ALL and AML are ongoing (ILEX Products, Inc., and Genzyme Corporation, 2004b).

Table 2. Response Denitions

RESPONSE CATEGORY RESPONSE CRITERIA

Complete response (CR)

No evidence of circulating blasts or extramedullary disease M1 bone marrow ( 5% blasts) (for acute myeloid leukemia [AML] < 5% blasts) Recovery of peripheral counts (platelets 100 109/L and absolute neutrophil count 1.0 109/L) Meets all of the criteria for a CR except platelet recovery to 100 109/L Complete disappearance of circulating blasts M2 bone marrow (> 5% and 25% blasts) and appearance of normal progenitor cells (for AML 5% blasts) M1 marrow that does not qualify for CR or CRp All other responses

CR without platelet recovery (CRp) Partial response

Treatment failures

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Nursing Considerations for Clofarabine

Dosage
The recommended dose and schedule for clofarabine in children is 52 mg/m2 per day by IV infusion over two hours daily for ve consecutive days (Genzyme Corporation, 2005). Dosage is based on body surface area calculated using the actual height and weight before the start of each cycle. Patients weighing less than 10 kg or those younger than one year will be dosed based on mg/kg (1.7 mg/kg). However, no patients younger than one year were enrolled in either of the phase II studies with clofarabine. Treatment cycles are to be repeated every two to six weeks based on response and toxicity. Once the absolute neutrophil count has recovered or returned to baseline and toxicities have resolved, initiation of subsequent cycles can be considered (Genzyme Corporation). In patients with prolonged neutropenia or other serious toxicities, dose reduction for subsequent cycles or discontinuation of clofarabine should be considered.

practically colorless, and free from foreign matter. Clofarabine should be ltered through a sterile 0.2 mcm syringe lter and then further diluted with 5% dextrose injection USP or European Pharmacopeia (EP) or 0.9% sodium chloride injection (normal saline) USP or EP prior to IV infusion. The resulting mixture may be stored at room temperature but must be used within 24 hours of preparation (Genzyme Corporation, 2005). In children, clofarabine appears to be best tolerated when infused over two hours, although a longer infusion time, over two to four hours, may be recommended in small children (less than 20 kg). Like adults, children were infused initially over a one-hour period. However, some children experienced irritability during infusion. Increasing the infusion time to two hours appeared to reduce this side effect (Faderl et al., 2005). To prevent drug incompatibilities, no other medications should be administered simultaneously through the same IV line. Clofarabine has not been shown to be a vesicant. Clofarabine has been given via a peripheral vein to some children and adolescents without causing venous irritation.

Administration Guidelines
Based on clinical trials, clofarabine may be given safely on an outpatient basis; however, inpatient hospitalization for the rst cycle of treatment should be considered. Once stabilized, patients can be discharged and administration of subsequent cycles in the outpatient setting can be considered. As with most cytotoxic agents, premedication with antiemetics, such as 5-HT3 antagonists, promethazine, or lorazepam, prior to each dose is recommended to prevent nausea and vomiting. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on days 13) may be of benet in preventing signs or symptoms of systemic in ammatory response syndrome or capillary leak, which occurred in four pediatric patients treated during the phase II trials. Typically, systemic inammatory response syndrome is manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multiorgan failure. The release of cytokines may contribute to development of systemic inammatory response syndrome or capillary leak syndrome (Ek, Jarfelt, Mellander, & Abrahamsson, 2001). Continuous IV uids are encouraged throughout the rst cycle ( rst ve days of clofarabine infusion) to reduce the effects of tumor lysis and other adverse events, particularly in patients with comorbidities. In stable patients, IV uids could be administered at home via ambulatory pump. Nephrotoxic or hepatotoxic medications should be avoided during the ve days of clofarabine administration. Because the kidneys are the primary route of clofarabine excretion, administration of clofarabine in patients with severe renal impairment (i.e., renal insufciency or failure requiring dialysis) would not be recommended. In the event of increased creatinine, grade 3 or 4 creatinine, and/or decreased urine output, exercise caution and consider discontinuing drug until toxicities resolve. Clofarabine has not been studied in patients with severe renal or hepatic dysfunction, and caution is advised in these populations (Genzyme Corporation, 2005). Clofarabine is supplied in a 20 ml vial containing 20 mg of drug dissolved in 20 ml of 0.9% sodium chloride injection, U.S. Pharmacopeia (USP) (pH range = 4.57.5). The solution is clear,
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Patient Monitoring and Management of Side Effects

Safety data were compiled across six studies for 96 heavily pretreated pediatric patients who received clofarabine at the recommended pediatric dose (52 mg/m2 per day) (ILEX

Table 3. Most Commonly Reported Grade 3 and 4 Adverse Events in Pediatric Trialsa
TOTAL ADVERSE EVENT
b

GRADE 3 n %

GRADE 4 n %

Vomiting Nausea Febrile neutropeniac Diarrhea Pruritus Headache Dermatitis Pyrexia Rigors Abdominal pain Fatigue Tachycardia Anorexia Epistaxis Hypotension Pain in limb Petechiae N = 96

80 72 55 51 45 44 39 39 36 35 35 33 30 30 28 28 28

83 75 57 53 47 46 41 41 38 36 36 34 31 31 29 29 29

08 14 51 10 01 04 07 15 03 07 03 06 05 14 12 05 07

08 15 53 10 01 04 07 16 03 07 03 06 05 15 13 05 07

1 1 3 1 7 7

1 1 3 1 7 7

Note. Events were reported in at least 10% of patients receiving 52 mg/m2 per day for ve days.
a See full prescribing information (Genzyme Corporation, 2005) for a list of all adverse events. b

Patients with more than one occurrence of an adverse event are counted only once (ILEX Products, Inc., and Genzyme Corporation, 2004a, 2004e).

c Colony-stimulating factors were not employed as standard supportive care.

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Table 4. Management of Side Effects Observed in Some Patients Treated With Clofarabine
SIDE EFFECT NURSING INTERVENTION

Days 15: With each infusion of clofarabine Check vital signs before and after each infusion. Record daily weights. Strictly record intake and output. Perform daily nursing assessment. Premedicate with antiemetics (5-HT3 antagonists, promethazine, lorazepam). Continue antiemetics until 24 hours after last infusion. Encourage an increase in oral uid intake. Encourage patients to eat a soft, bland diet on days of clofarabine administration; it may help to decrease nausea. Administer lorazepam (0.52 mg) or low-dose diphenhydramine (1 mg/kg; maximum dose is 50 mg). Consider premedication with 0.5 mg lorazepam prior to subsequent cycle(s). Use distraction techniques. Provide emotional support to patients or caregivers. Treat with acetaminophen or acetaminophen with codeine. Treat with acetaminophen. Obtain blood culture(s); consider prophylactic antibiotics. Begin aggressive hydration (23 L/m2 per day). Treat with hyperuricemic agents (allopurinol, rasburicase). Monitor electrolytes and uric acid frequently (one to four times per day) days 15 or until risk for lysis resolved. Monitor uid balance. Treat with an antidiarrheal, and increase uids. Avoid concomitant renal or hepatic toxic drugs until the levels return to baseline. Hold clofarabine administration until return to normal or baseline. Hold clofarabine administration until toxicity resolves. Prepare to administer IV uid support or resuscitation. Provide appropriate supportive care according to physician orders. Treat with an antidiarrheal, and increase uids. Treat with acetaminophen or acetaminophen with codeine. Apply massage or heat therapy. Apply ice packs during infusion. Use Bag Balm (Dairy Association Co., Inc., Lyndonville, VT) or unfragranced moisturizer to alleviate dryness. Consider dexamethasone 10 mg/m2 via IV every day for 24 hours following the last dose of clofarabine. Syndrome generally resolves within a week to 10 days. Inform patients or caregivers of the potential for desquamation and steps to decrease the superimposed skin infection. For symptom relief, give diphenhydramine (1 mg/kg every four to six hours; maximum of 50 mg per dose) or hydroxyzine (0.51 mg/kg every four to six hours; maximum of 600 mg per 24 hours). To prevent progression, consider cetirizine (2.5 mg by mouth once daily for children aged two to ve years; 5 10 mg by mouth once daily for children aged six years to adult) and hydrocortisone IV (1 mg/kg; maximum of 200 mg) once per day. Consider premedicating subsequent doses of clofarabine with cetirizine and hydrocortisone. Rash usually begins to resolve by week 2. Instruct patients or caregivers to contact a medical provider if the rash worsens. Anticipate a rapid drop in blood counts and the potential for blood product support. Follow standard myelosuppression recommendations (e.g., careful hand washing, avoiding crowds). Consider prophylactic antibiotic, antifungal, or antiviral coverage while neutropenic. Consider granulocytecolony-stimulating factor for prolonged neutropenia (lasting more than six weeks). Initiate antibiotic therapy immediately. Anticipate hospital admission. Provide emotional support to patients or caregivers. Obtain blood cultures (central and peripheral per institution guidelines). Give acetaminophen 1015 mg/kg for comfort when the temperature is higher than 101F. The condition is generally asymptomatic and reversible. Dose delay or suspension generally is not necessary or recommended. Avoid concomitant hepatotoxic drugs until return to baseline.

Day 1 Nausea or vomiting

Anxiety (usually during infusion) Headache Fever Tumor lysis syndrome (days 15) (Doane, 2002)

Diarrhea Days 128 Bilirubin or creatinine elevation Hypotension or capillary leak syndrome Days 25 Diarrhea Lower-extremity pain (generalized aching and cramps in legs) Hand-foot syndrome

Random rash (at red; not puffy or edematous) or buttery rash

Days 628 Myelosuppression

Febrile neutropenia

Transaminase elevation

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813

Products, Inc., and Genzyme Corporation, 2004e). The overall tolerability pro le of clofarabine is acceptable. The commonly reported side effects in this population are similar to those seen with most chemotherapeutic agents: myelosuppression, nausea, vomiting, diarrhea, fever, infection, chills, and headache (see Table 3). In addition, some less-frequent side effects have been observed in patients receiving clofarabine such as anxiety, early-onset fever or infection, and rash, including hand-foot syndrome. The development of signicant hypotension (i.e., hypotension requiring pharmacologic support) has been observed in some patients. The cause of the hypotension is not clear and is being studied further. Nurses are advised to monitor patients closely for changes in blood pressure, prepare to provide additional uids, and alert a physician if pharmacologic support is required to maintain blood pressure. Most of the side effects observed to date with clofarabine in heavily pretreated patients have been reversible, manageable, and noncumulative. Increases in liver function parameters, particularly elevations in transaminases (aspartate amino transferase [AST] and alanine amino transferase [ALT]), are expected and should be monitored closely. Although elevations in AST and ALT were transient and returned to baseline or less than or equal to grade 2 in several days, extended elevations and/or concurrent increases in bilirubin may require physicians to reduce or hold additional clofarabine doses (Genzyme Corporation, 2005). The increases in total bilirubin, which typically are reversible, may be slow to recover. Timely and appropriate nursing intervention is crucial to effective management of side effects and improving the outcome of treatment. Clofarabine causes a rapid drop in white blood cell counts that should be anticipated in most patients. All patients should have a complete physical examination at baseline, and vital signs should be monitored before and after each infusion. In particular, nurses should monitor carefully for fever, hypotension, weight gain, and edema, which could be signs of possible tumor lysis syndrome, capillary leak syndrome, or sepsis (Tan, 2002). Required laboratory tests will depend on a patients clinical status during the cycle of therapy. For patients with elevated white blood cell counts at baseline, complete blood count, electrolytes, liver and renal function, and uric acid tests should be conducted at least once daily during the rst cycle of treatment to monitor for the possibility of a rapid drop in counts necessitating blood product transfusions or other supportive care measures. During subsequent cycles, complete blood cell counts should be monitored closely, with the frequency dependent on patients clinical condition. Generally, peripheral counts recover in 2128 days and may require longer recovery times with additional cycles of treatment. In patients with ALL, median time to recovery was 24 days following bone marrow suppression resulting from treatment with clofarabine (ILEX Products, Inc., and Genzyme Corporation, 2004a). Clofarabine treatmentrelated side effects can be grouped into three categories: those most likely to be seen during the infusion or on the rst day of treatment, those presenting during the next four days of treatment, and delayed effects that are observed between cycles. Table 4 summarizes the nursing interventions recommended for the side effects. The interventions have improved patients quality of life, increased their ability
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to stay on treatment, and may have contributed to the overall effectiveness of the treatment.

Conclusion
A signicant challenge in the treatment of pediatric leukemia is the development of effective treatments in children refractory to existing therapies. Clofarabine represents a new addition to the therapeutic options available for treatment of pediatric acute leukemia. As a single agent, it has induced remission in a number of cases, extended survival, and improved quality of life for many heavily pretreated relapsed and refractory patients. The safety pro le of clofarabine appears to be comparable to other NAs and may be preferable because of the absence of serious CNS and renal toxicities. Tolerability is similar to other chemotherapeutic agents, with the most commonly reported side effects being myelosuppression, nausea, vomiting, diarrhea, fever, infection, chills, headache, and pruritus. Most of the side effects observed with clofarabine were reversible and noncumulative and can be managed with skilled nursing interventions. Nurses will play a critical role in ensuring that the therapeutic potential of clofarabine is realized in appropriate patients. Nurses will inform patients or family members regarding the possible side effects and can manage their expectations of efcacy and tolerability during clofarabine therapy. Nurses can encourage and assist patients and family members to become full partners in identifying treatment-related side effects. Given the potency of clofarabine and the possibility that complications may be associated with the expected rapid drop in white blood cells, administration of relevant prophylaxis and careful monitoring of patient condition may be critical to keeping patients on therapy, especially during the rst cycle. Additional interventions have proven effective in relieving the symptoms of less serious side effects, such as anxiety, headache, and rash. Nurses experienced with clofarabine will play an important role in educating colleagues in the healthcare community about the scientic and medical aspects of this new chemotherapeutic agent. Author Contact: Lisa R. McDonald, RN, MSN, CPNP, CPON , can be reached at lrmcdona@mdanderson.org, with copy to editor at CJONEditor@ons.org.

References
Berlex Laboratories, Inc. (2003). Fludara (udarabine phosphate) for injection [Prescribing information]. Montville, NJ: Author. Bleyer, W.A. (1997). The U.S. pediatric cancer clinical trials programmes: International implications and the way forward. European Journal of Cancer, 33, 14391447. Bonate, P.L., Craig, A., Gaynon, P., Gandhi, V., Jeha, S., Kadota, R., et al. (2004). Population pharmacokinetics of clofarabine, a secondgeneration nucleoside analog, in pediatric patients with acute leukemia. Journal of Clinical Pharmacology, 44, 13091322. Boulad, F., Steinherz, P., Reyes, B., Heller, G., Gillio, A.P., Small, T.N., et al. (1999). Allogeneic bone marrow transplantation versus chemotherapy for the treatment of childhood acute lymphoblastic leukemia in second remission: A single-institution study. Journal of Clinical Oncology, 17, 197207. Buchanan, G.R., Rivera, G.K., Pollock, B.H., Boyett, J.M., Chauvenet,

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A.R., Wagner, H., et al. (2000). Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: A Pediatric Oncology Group study. Cancer, 88, 11661174. Doane, L. (2002). Overview of tumor lysis syndrome. Seminars in Oncology Nursing, 18(3, Suppl. 3), 25. Ek, T., Jarfelt, M., Mellander, L., & Abrahamsson, J. (2001). Proinflammatory cytokines mediate the systemic inflammatory response associated with high-dose cytarabine treatment in children. Medical and Pediatric Oncology, 37, 459464. Faderl, S., Gandhi, V., Keating, M.J., Jeha, S., Plunkett, W., & Kantarjian, H.M. (2005). The role of clofarabine in hematologic and solid malignancies Development of a next-generation nucleoside analog. Cancer, 103, 19851995. Galmarini, C.M. (2002). Nucleoside analogues in cancer treatment. Electronic Journal of Oncology, 1, 2232. Gandhi, V., Kantarjian, H., Faderl, S., Bonate, P., Du, M., Ayres, M., et al. (2003). Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias. Clinical Cancer Research, 9, 63356342. Gaynon, P.S., Trigg, M.E., Heerema, N.A., Sensel, M.G., Sather, H.N., Hammond, G.D., et al. (2000). Childrens Cancer Group trials in childhood acute lymphoblastic leukemia: 19831995. Leukemia, 14, 22232233. Genini, D., Adachi, S., Chao, Q., Rose, D.W., Carrera, C.J., Cottam, H.B., et al. (2000). Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood, 96, 35373543. Genzyme Corporation. (2005). Clolar (clofarabine) for injection [Prescribing information]. Cambridge, MA: Author. ILEX Products, Inc., and Genzyme Corporation. (2004a, March 4). [Clinical reportProtocol CLO-212: A phase II, open-label study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.] Unpublished raw data. ILEX Products, Inc., and Genzyme Corporation. (2004b, March 8). [Clinical reportProtocol CLO-222: A phase II, open-label study of clofarabine in pediatric patients with refractory or relapsed acute myelogenous leukemia.] Unpublished raw data. ILEX Products, Inc., and Genzyme Corporation. (2004c, March 11). [Integrated summary of effectiveness. New drug application for clofarabine. IND number 63,641.] Unpublished raw data. ILEX Products, Inc., and Genzyme Corporation. (2004d, March 14).

[Integrated summary of safety. New drug application for clofarabine. IND number 63,641.] Unpublished raw data. ILEX Products, Inc., and Genzyme Corporation. (2004e, December 1). [Oncologic Drug Advisory Committee brie ng document]. San Antonio, TX: Author. Jeha, S., Gandhi, V., Chan, K.W., MacDonald, L., Ramirez, I., Madden, R., et al. (2004). Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood, 103, 784789. Kantarjian, H.M., Gandhi, V., Kozuch, P., Faderl, S., Giles, F., Cortes, J., et al. (2003). Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. Journal of Clinical Oncology, 21, 11671173. Leukemia and Lymphoma Society. (2003). Facts 2003: Leukemia, lymphoma, myeloma. White Plains, NY: Author. Margolin, J.F., Steuber, C.P., & Poplack, D.G. (2002). Acute lymphoblastic leukemia. In P.A. Pizzo & D.G. Poplack (Eds.), Principles and practice of pediatric oncology (4th ed., pp. 489544). Philadelphia: Lippincott Williams and Wilkins. McCarthy, A.J., Pitcher, L.A., Hann, I.M., & Oakhill, A. (1999). FLAG (udarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children. Medical and Pediatric Oncology, 32, 411415. Ortho Biotech Products, LP. (2002). Leustatin (cladribine) injection [Prescribing information]. Raritan, NJ: Author. Rubnitz, J.E., & Pui, C.H. (2003). Recent advances in the treatment and understanding of childhood acute lymphoblastic leukaemia. Cancer Treatment Reviews, 29, 3144. Tan, S.J. (2002). Recognition and treatment of oncologic emergencies. Journal of Infusion Nursing, 25, 182188. Uderzo, C., Conter, V., Dini, G., Locatelli, F., Miniero, R., & Tamaro, P. (2001). Treatment of childhood acute lymphoblastic leukemia after the rst relapse: Curative strategies. Haematologica, 86, 17. Vora, A. (2002). Acute lymphoblastic leukemia: Optimizing treatment strategies in children. Paediatric Drugs, 4, 405416. Weinstein, H.J., & Tarbell, N.J. (2001). Leukemias and lymphomas of childhood. In V.T. DeVita, S. Hellman, & S.A. Rosenberg (Eds.), Cancer: Principles and practice of oncology (6th ed., pp. 2235 2256). Philadelphia: Lippincott Williams and Wilkins. Westlake, S., & Bertolone, K. (2002). Acute lymphoblastic leukemia. In C. Baggott, K. Kelly, D. Fochtman, & G. Foley (Eds.), Nursing care of children and adolescents with cancer (3rd ed., pp. 466490). Philadelphia: W.B. Saunders.

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CONTINUING EDUCATION TEST 2

Goal
The goal of this continuing education program is to further enhance the nurses knowledge of the topic areas discussed in the articles. Credit Hours: 2.5 Passing Score: 80% Test ID# 06-10/6-12 Test Processing Fee: $15 The Oncology Nursing Society is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Centers Commission on Accreditation California Board of Nursing, Provider #2850.

Objectives
At the end of this program, the participant should be able to 1. Explain the role of immune reconstitution in the continuum of care for post-transplant patients. 2. Describe the implications and use of extracorporeal photopheresis in treating chronic graft-versus-host disease. 3. Reect on patient self-determination and informational seeking in the end stage of cancer. 4. Discuss the nursing care and management of pediatric patients undergoing treatment with clofarabine for lymphoblastic leukemia.

Immune Reconstitution After Transplantation, p. 787

11. Immune reconstitution is de ned as a. The resolution of normal hematopoietic cell counts. b. The recovery of antigen-specic T-cell function. c. The production of functioning white blood cells. d. The absence of immunodeciency. 12. Allogeneic transplant recipients most likely will die from which of the following post-treatment complications? a. Graft-versus-host disease b. Bone marrow failure c. Disease recurrence d. Opportunistic infection 13. Which of the following most often is responsible for increasing the risk of infection many years after hematopoietic transplantation? a. CD4+ levels remain below normal. b. CD8+ suppressor T cells are elevated. c. Anatomical barriers remain chronically compromised. d. Serum immunoglobin levels remain below normal. 14. When considering transplantation with peripheral blood stem cells versus bone marrow cells, the nurse recognizes that a. Engraftment is faster with bone marrow transplantation.
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b. B-cell reconstitution is faster with bone marrow transplantation. c. Recipients of peripheral blood stem cells are at higher risk for viral infections. d. Platelet recovery is slower with peripheral blood stem cell transplantation. 15. A patient who received an allogeneic peripheral blood stem cell transplantation 80 days ago reports to the clinic with complaints of increasing fatigue and is noted to have a mild fever (99.6F) as well as slightly swollen submandibular lymph glands. The nurse anticipates that which of the following actions should be taken rst? a. Lymph node biopsy to rule out secondary lymphoma b. Complete blood cell count to identify disease recurrence c. Stool sample to rule out gastrointestinal Streptococci d. Chart review to determine patient and donor cytomegalovirus status

c. Tapering or discontinued immunosuppressive medications. d. Increased responsiveness of naive T cells. 17. Which of the following symptoms is the most common manifestation of limited chronic graft-versus-host disease? a. Local skin irritations b. Pulmonary inammation c. Excessive tearing d. Diarrhea 18. Typical treatment for graft-versushost disease results in which of the following complications? a. Secondary malignancies b. Infection c. Bleeding d. Infertility 19. A nurse counseling a patient undergoing extracorporeal photopheresis would accurately explain the procedure in which of the following ways? a. Harvested bone marrow will be used to grow healthy cells in the laboratory that later will be reinfused. b. By injecting you with photosensitive chemicals, the natural exposure of your skin to the sun will destroy cells that have absorbed the chemicals. c. Exposure to special ultraviolet lamps will stimulate the production of mononuclear cells in your body.

Extracorporeal Photopheresis to Treat Chronic Graft-Versus-Host Disease, p. 795

16. The primary benet of extracorporeal photopheresis is a. Complete remission of acute leukemia. b. Reduced incidence of graft-versushost disease.

December 2006 Volume 10, Number 6 Clinical Journal of Oncology Nursing

d. A chemotherapy agent will be mixed with some of your blood cells that then will be exposed to ultraviolet light and returned to your body. 10. Which of the following factors is an important consideration when determining whether a patient is appropriate for extracorporeal photopheresis? a. Extent of disease b. Patient age c. Agents included in the treatment history d. Presence of a vascular access device

b. Her anxiety was reduced. c. Con ict with other decision makers was nonexistent. d. Her need for nursing care was reduced. 14. Which of the following may be critical to sustaining hope? a. Accuracy b. Acceptance c. Compassion d. Choice 15. Based on the theoretical discussion presented, which of the following statements reects a nurses adoption of the principles reviewed? a. I encourage you to seek information to help you feel prepared. b. Having cancer is hard; you should rest whenever you can. c. We all have to accept the inevitable reality of death. d. I think you might feel better if you could eat more.

a white blood cell count of 42,000/ mcl 17. Which of the following would be considered an appropriate induction regimen for a patient with low-risk acute lymphoblastic leukemia? a. Doxorubicin, vincristine, prednisone, and L-asparaginase b. Vincristine, dexamethasone, and L-asparaginase c. Daunorubicin, vincristine, dexamethasone, and L-asparaginase d. Vincristine, prednisone, L-asparaginase, and cyclophosphamide 18. Which of the following is considered an advantage of the next-generation nucleoside analog clofarabine over older drugs in this class? a. Increased ability to cross the blood-brain barrier b. Decreased occurrence of neurologic side effects c. Achievement of prolonged remissions d. Improved renal clearance with a shortened half-life 19. Systemic clearance of clofarabine is most dependent on which of the following factors? a. Hepatic function b. Patient age c. Diluent volume d. Patient weight 20. Nurses caring for patients receiving clofarabine recognize that which of the following side effects may be prevented with prophylactic steroids? a. Tachycardia and hypotension b. Hand and foot syndrome c. Nausea and vomiting d. Tumor lysis syndrome

Self-Determination and Information Seeking in End-Stage Cancer, p. 803

11. According to Germino (2006), which of the following must be present before self-care activities can be optimized? a. Effective pain management b. Self-actualization c. Extrinsic motivation d. Supportive social network 12. According to the authors, one major motive that guided Carolines behavior was a. Role con ict. b. Denial. c. Desire for survival. d. Projection. 13. Which of the following resulted from clear information provided to Caroline during active participation in her treatment decisions? a. Her mobility improved.

Clofarabine in the Treatment of Acute Lymphoblastic Leukemia in Children, p. 809

16. Which of the following patients diagnosed with pediatric lymphoblastic leukemia would have the best prognosis? a. A 12-year-old girl presenting with a white blood cell count of 65,000/ mcl b. A six-year-old boy presenting with a white blood cell count of 81,000/ mcl c. A 15-year-old boy presenting with a white blood cell count of 48,000/ mcl d. A two-year-old girl presenting with

The continuing education form for the preceding test questions appears on the next page.

Clinical Journal of Oncology Nursing Volume 10, Number 6 Continuing Education Test 2

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