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Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia

Sima Jeha, Paul S. Gaynon, Bassem I. Razzouk, Janet Franklin, Richard Kadota, Violet Shen, Lori Luchtman-Jones, Michael Rytting, Lisa R. Bomgaars, Susan Rheingold, Kim Ritchey, Edythe Albano, Robert J. Arceci, Stewart Goldman, Timothy Griffin, Arnold Altman, Bruce Gordon, Laurel Steinherz, Steven Weitman, Peter Steinherz

From the St Jude Children's Research Hospital, Memphis, TN; Children's Hospital of Los Angeles, Los Angeles; Children's Hospital of San Diego, San Diego; Children's Hospital of Orange County, Orange, CA; Washington University Medical School, St Louis, MO; M.D. Anderson Cancer Center, Houston; Texas Children's Cancer Center, Houston; Cook's Children's Hospital, Fort Worth; Genzyme Oncology, San Antonio, TX; The Children's Hospital of Philadelphia, Philadelphia; Children's Hospital of Pittsburgh, Pittsburgh, PA; Children's Hospital at Denver, Denver, CO; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD; Children's Memorial Hospital, Chicago, IL; Connecticut Children's Medical Center, Hartford, CT; University of Nebraska Medical Center, Omaha, NE; and Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Sima Jeha, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; e-mail: sima.jeha{at}stjude.org

	ABSTRACT

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PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL).

PATIENTS AND METHODS: In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m² intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens).

RESULTS: The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade 3 were febrile neutropenia, anorexia, hypotension, and nausea.

CONCLUSION: Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

	INTRODUCTION

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Leukemia is the most common pediatric malignancy and remains the leading cause of death from a disease in children despite the high cure rates achieved with contemporary regimens.^1-4 Current front-line protocols intensify therapy for high-risk patients, offering hematopoietic stem-cell transplantation (HSCT) in first remission for some patients. Hence, patients who experience relapse constitute an increasingly challenging population with highly resistant disease and potential underlying organ dysfunction. Novel therapeutic approaches with nonoverlapping toxicities are needed.^5-9

Clofarabine is a second-generation deoxyadenosine analog that was designed to improve the efficacy and minimize the toxicity of its congeners.¹⁰ After intracellular phosphorylation to the triphosphate form, clofarabine inhibits ribonucleotide reductase and DNA polymerase and induces apoptosis through release of mitochondrial cytochrome C and other proapoptotic factors.^11-14 Clofarabine has shown strong in vitro growth inhibition (GI₅₀ < 0.0001 to 0.45 µmol/L) and cytotoxic activity against a variety of leukemia and solid tumor cell lines (National Cancer Institute Developmental Therapeutics Program, in vitro testing results, unpublished data). In addition, clofarabine has shown significant in vivo activity against several human colon, renal, non–small-cell lung, and prostate xenograft tumors.^15,16

Phase I studies in both adult and pediatric patients with multiple relapsed or refractory leukemia showed that clofarabine was active in different leukemia subtypes and lacked the neurotoxicity associated with its congeners.^17-19 In the pediatric phase I study conducted at The University of Texas M.D. Anderson Cancer Center, 25 patients (17 acute lymphoblastic leukemia [ALL] patients and eight acute myelogenous leukemia [AML] patients) received clofarabine at doses ranging from 11.25 to 70 mg/m²/d for 5 days by intravenous infusion over 1 to 2 hours. Hyperbilirubinemia and skin rash were dose limiting at 70 mg/m²/d, and the maximum-tolerated dose was 52 mg/m²/d. Complete remission (CR) was reported in five patients (one AML patient and four ALL patients), and partial remission (PR) was reported in three patients (two AML patients and one ALL patient), for an overall response rate of 32%. CRs were observed at doses of 30 (n = 1), 40 (n = 2), and 52 (n = 2) mg/m²/d. Median remission duration was greater than a year. The results of a multicenter phase II study to establish the efficacy, safety, and pharmacokinetic profile²⁰ of clofarabine in pediatric patients with ALL who were in second or subsequent relapse or were refractory to standard therapies are presented here.

	PATIENTS AND METHODS

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Study Group
Patients younger than 21 years of age at the time of original diagnosis with second or subsequent relapse and/or refractory ALL were eligible. Patients must have had histologically proven ALL according to the French-American-British classification and 25% bone marrow blasts. Other eligibility criteria included the following: no prior chemotherapy within 2 weeks before entry onto study and resolution of acute toxic effects of prior therapy; adequate liver and renal function with serum bilirubin 1.5x upper limit of normal (ULN) for age, AST and ALT 5x ULN, and serum creatinine less than 2x ULN; Karnofsky performance status (KPS) of 50%, which was later amended to 70%; and absence of active, uncontrolled systemic infection, severe concurrent disease, or symptomatic CNS involvement. The study was amended to also exclude patients with transplantation within the previous 3 months and active graft-versus-host disease. Approval for the study was obtained from the institutional review boards. Informed consent was obtained from parents or guardians, and assent was obtained from patients 7 years of age. The study was conducted in accordance with the basic principles of the Declaration of Helsinki.

Treatment Plan
Clofarabine was administered intravenously at 52 mg/m² over 2 hours daily for 5 consecutive days every 2 to 6 weeks for up to 12 cycles. Dose calculations were based on body-surface area determined from the height and actual weight obtained before each cycle. For patients less than 1 year of age, the dose was based on weight (1.7 mg/kg). Grade 3 nonhematologic, noninfectious events that resolved within 14 days required a 25% dose reduction. Grade 3 nonhematologic, noninfectious events that did not resolve within 14 days and grade 4 nonhematologic, noninfectious events required withdrawal from study. Routine prophylactic use of a colony-stimulating factor was not permitted. Prophylaxis for CNS leukemia was prohibited during the first two cycles of treatment. Prophylaxis with antibiotics, antifungals, and antiviral agents was recommended. The study was amended to require premedication with corticosteroids on days 1 through 3 of clofarabine administration as a result of the development of systemic inflammatory response–like signs and symptoms in some patients (including fever, chills, hypotension, and dyspnea).

Evaluation During Study
Pretreatment evaluations included history and physical examination, KPS assessment, CBC, serum chemistry, echocardiogram or multiple-gated acquisition (MUGA) scan, bone marrow aspiration, and diagnostic lumbar puncture. During treatment, physical examination, CBC, and serum chemistry were performed one to two times weekly and as clinically indicated. History and physical examination, KPS, CBC, serum chemistry, and bone marrow aspirate (for the first six cycles) were performed before each cycle. Echocardiogram or MUGA scans were repeated at least every four cycles and at the end of study in all patients.

Response Criteria
Diagnosis was confirmed centrally by an independent pathologist. In addition, an Independent Response Review Panel (IRRP) determined the response for each patient. The IRRP consisted of three pediatric oncologists who were not participants in the study. A CR required no evidence of circulating blasts or extramedullary disease, an M1 marrow ( 5% bone marrow blasts), and recovery of peripheral counts (platelets 100 x 10⁹/L and absolute neutrophil count 1.0 x 10⁹/L). A CR without platelet recovery (CRp) required all of the criteria for a CR with the exception of platelet recovery. A PR had to meet the following criteria: complete disappearance of circulating blasts and an M2 marrow ( 5% and 25% bone marrow blasts) and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp.

Statistical Methods
The study was an open-label, multicenter, nonrandomized phase II trial. All patients who received any amount of drug were included in the efficacy and safety analyses (intent-to-treat principle). The first patient began treatment on June 13, 2002, and the data cutoff for this study was September 30, 2004. The study's primary objective was to estimate the overall remission (OR) rate, which was defined as patients who achieved a CR or CRp divided by the number of treated patients. Secondary objectives included documenting duration of remission (defined from date of remission to date of first objective documentation of disease relapse or death), PRs, and overall survival (defined from date of first dose of clofarabine to the date of death or the date of last follow-up) for this population and dosing regimen. Kaplan-Meier methods were used to summarize duration of remission and overall survival. Patients who were in remission or alive at last follow-up were censored at that point. In addition, patient performance status on study as well as transplantations that occurred after clofarabine were analyzed.

Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (published April 30, 1999). Two safety reviews were conducted during the study by a panel of three to five clinicians.

	RESULTS

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Patients and Treatment
Sixty-two patients were entered onto the study; 61 received any amount of drug. Patient characteristics are listed in Table 1. The median age was 12 years (range, 1 to 20 years); 61% were males. Twenty-six patients (43%) were white, and 23 (38%) were Hispanic. The median number of prior induction therapies was three, and approximately one third of patients had received at least one prior transplantation. Thirty-five patients (57%) were refractory to the last therapeutic regimen.

Efficacy
The OR rate was 20% (seven CRs and five CRps). Median duration of remission for the 12 patients who achieved OR was 29 weeks (Table 2). An additional 10% of patients achieved a PR. Median duration of remission for the 30% of patients who achieved at least a PR (CR + CRp + PR) was 9.7 weeks. Of the 35 patients who were refractory to their most recent prior regimen, 17% achieved OR (four CRs and two CRps), and 26% had at least a PR. Responses were observed in patients with both B- and T-cell lineage. Characteristics of the patients who responded to clofarabine are listed in Table 3.

View larger version (11K): [in this window] [in a new window]   Fig 1. Overall survival of patients receiving clofarabine in all patients (), in patients achieving a complete remission (CR) or CR without platelet recovery (CRp) (), and in patients with at least a partial remission (PR) ().

Safety
Adverse events of grade 3 that occurred in more than 10% of the patients, regardless of causality, are listed in Table 4. In addition, the most commonly reported grade 3 or 4 laboratory abnormalities included hypokalemia (46%), increases in ALT (43%) and AST (38%), hyperbilirubinemia (16%), and hypophosphatemia (15%). Liver transaminases usually peaked at day 7 of the cycle and recovered (< grade 2) by day 16.

View this table: [in this window] [in a new window]   Table 4. Grade 3, 4, and 5 Adverse Events Regardless of Causality That Occurred in 10% of Patients (N = 61)

Evidence of a potential cytokine release–like event was observed in several patients; however, many of these patients had concomitant sepsis or tumor lysis. Signs and symptoms included hypotension, respiratory distress, and multiorgan failure.

Echocardiograms or MUGA scans were available for 40 patients before and after clofarabine. Of these patients, 25 (61%) had no significant cardiac abnormalities develop during the study, and 12 (29%) had pericardial effusions, which were typically small and of no hemodynamic significance. However, of these 12 patients, two had moderate pericardial effusions; one patient showed increased intrapericardial pressure that improved without intervention, and the other patient had a clinical history of edema and pleural effusion. Increases in right ventricular pressure were reported in four patients, and evidence of decrease in left ventricle systolic function was noted in seven patients. In addition, seven patients (17%) had some evidence of decrease in left ventricle systolic function that developed while on study. One patient developed congestive heart failure, which correlated with a low fractional shortening; however, this patient was septic at the time of the study, and the fractional shortening in this patient improved over the next month.

Fifteen patients (25%) died either within 30 days of study drug administration or as a result of an adverse event that was determined to be drug related. Of these 15 deaths, eight were attributed to disease progression or to a disease-related adverse event, and two were attributed to adverse events not related to study drug. Two deaths were reported as possibly drug related by the investigators. The first was a 17-year-old patient who was enrolled 4 months after total-body irradiation and HSCT. At study entry, he was febrile and receiving amphotericin B because of a past history of Candida parapsilosis fungemia. On day 4 of study drug, the patient developed orbital cellulitis, an increase in pleural effusion, capillary leak, and elevation in liver function tests. He died on day 16 of study. A limited autopsy showed an aplastic marrow and liver necrosis. Postmortem cultures of the liver and pleural effusion were positive for Staphylococcus epidermidis. The second patient was 9 years old and tolerated the first three doses of clofarabine. On day 4 of study drug, he underwent sinus debridment secondary to mucor sinusitis and developed fever and positive blood cultures for S epidermidis, fluid overload, respiratory distress, and multiorgan failure. He died on day 14 of study. Three patient deaths were reported as multifactorial, including events that were assessed as both disease and study drug related. The first patient was 20 years old and was hospitalized 2 days after completing the second clofarabine cycle with narcotic overdose–induced respiratory failure; the patient subsequently developed linezolid-resistant, vancomycin-resistant enterococci sepsis complicated by renal failure. The second patient was 12 years old and was hospitalized before clofarabine treatment for fever and pancytopenia. His course was complicated with fever, shortness of breath, hypotension, catheter infection, progressive pulmonary fungal disease, progressive pleural effusion, pericardial effusion, disseminated intravascular coagulation, and acute vascular leak syndrome, resulting in cardiac arrest. The third patient was 15 years old and became hypotensive with possible sepsis 24 hours after the first dose of his second cycle of clofarabine. He developed capillary leak syndrome, increased pulmonary edema, disseminated intravascular coagulation, and renal failure. Bone marrow revealed persistent ALL. The patient died from multiorgan failure.

	DISCUSSION

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This multicenter phase II study shows promising activity of clofarabine in pediatric patients with highly resistant ALL. Approximately one third of the patients achieved at least a PR. Responses were observed in patients who had become refractory to standard salvage treatments. Six (50%) of the 12 patients achieving CR or CRp had not responded to the last regimen received before clofarabine, including etoposide, ifosfamide, and carboplatin; cytarabine and idarubicin; fludarabine and cytarabine; and mitoxantrone and cytarabine. The response rates are consistent with those previously reported in the phase I study conducted at the M.D. Anderson Cancer Center in which 50% of patients (two of four patients) with ALL who achieved CR had primary refractory disease and had never achieved a CR before clofarabine therapy.¹⁷

Clofarabine activity compares favorably with other single agents or salvage regimens that were studied in less heavily pretreated ALL patients.^21-25 Unlike the nucleoside analogs cladribine and nelarabine, where activity is specific to AML and T-cell ALL, respectively, clofarabine has demonstrated efficacy in both ALL lineages and in AML.^17,26,27 In addition, clofarabine does not seem to be associated with the neurotoxicity reported with other agents in this class.

The responses achieved with clofarabine were of sufficient duration to allow many patients with suitable donors to proceed to HSCT. Because transplantation outcome was not a study end point, no formal analysis was conducted on patients proceeding to HSCT. However, there was no apparent increase in transplantation-related organ damage or toxicity in these patients, including five patients with history of prior transplantation at study enrollment. Six of the patients (67%) who received transplantation were alive at data cutoff. Five patients who did not proceed to transplantation after achieving a CR had a median remission duration of 6 weeks, with two patients maintaining CR for 37+ and 48 weeks on 10+ and 11 cycles of single-agent clofarabine, respectively. No cumulative hepatotoxicity was observed with repeated cycles; however, myelosuppression necessitated dose reduction with prolonged therapy.

Infections were a common event observed in this study, as expected in this heavily pretreated population with long-standing immune and myelosuppression. Several patients experienced systemic inflammatory response–like or cytokine release–like events including respiratory distress, fever, and hypotension. These events have been reported in association with other agents such as cytarabine, gemcitabine, and rituximab.^28-34 These symptoms may result from drug reaction, infections, or tumor lysis. Most events observed in this trial occurred in the setting of documented or clinically presumed infection resulting in sepsis and organ failure. However, clofarabine administration was associated with significant rapid decrease in peripheral blasts even in nonresponders; thus, close monitoring for tumor lysis is indicated, along with cardiovascular status and fluid balance. Finally, approximately 10% of patients had drug-related fever, skin rash, or hand-foot syndrome that generally responded to antihistamines and occasionally required low-dose corticosteroids once infection was excluded.

Cytokine release–like events may have contributed to the decline in cardiac function that was observed in several patients, although a direct effect of clofarabine cannot be ruled out. However, many of the echocardiograms that showed a decline in cardiac function were obtained at a time that coincided with other serious events such as documented sepsis. In addition, other treatments received within months from enrollment, including substantial amounts of anthracyclines and total-body irradiation, could have also contributed.

In conclusion, clofarabine is active in relapsed and refractory pediatric ALL. Responses are durable, allowing patients to proceed to transplantation. As observed in this study, clofarabine is not associated with the neurotoxicity that has been observed with other similar nucleoside analogs.¹⁰ The safety profile is acceptable in this heavily pretreated population, and the lack of severe extramedullary effects further supports the feasibility of combining clofarabine with other effective agents based on pharmacologic properties and mechanism of action. A subset of the data contained within this article formed, in part, the basis of a New Drug Application to the US Food and Drug Administration for clofarabine. On December 28, 2004, the US Food and Drug Administration granted accelerated approval for clofarabine for the treatment of pediatric patients aged 1 to 21 years old with relapsed or refractory ALL who have experienced treatment failure with two prior regimens. Pediatric leukemia studies that rationally combine clofarabine with current salvage regimens are ongoing with the aim to test the superior regimen in a randomized phase III trial.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Sima Jeha ILEX Oncology, Inc (A); Genzyme Oncology, Inc (A); Bioenvision (A) ILEX Oncology, Inc (A); Genzyme Oncology, Inc (A); Bioenvision (A) ILEX Oncology, Inc (C) ILEX Oncology, Inc; Genzyme Oncology, Inc; Bioenvision (N/R) Paul S. Gaynon Genzyme Oncology, Inc (A) Enzon (B) Genzyme Oncology, Inc (B) Bassem I. Razzouk ILEX Oncology, Inc (A); Genzyme Oncology, Inc (A) ILEX Oncology, Inc (A); Genzyme Oncology, Inc (A) ILEX Oncology, Inc (C) Janet Franklin Genzyme Oncology, Inc (A) Richard Kadota Genzyme Oncology, Inc (A) Bioenvision (B) Genzyme Oncology, Inc (A) Genzyme Oncology, Inc (B) Violet Shen ILEX Oncology, Inc (B) Michael Rytting ILEX Oncology, Inc (A) ILEX Oncology, Inc (B) Susan Rheingold ILEX Oncology, Inc (A) Kim Ritchey ILEX Oncology, Inc (B) Robert J. Arceci ILEX Oncology, Inc (A) ILEX Oncology, Inc (N/R) Laurel Steinherz Genzyme Oncology, Inc (B) Steven Weitman Genzyme Oncology, Inc (C) Genzyme Oncology, Inc (B) Peter Steinherz Genzyme Oncology, Inc (B) Genzyme Oncology, Inc (A) ILEX Oncology, Inc (N/R)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Sima Jeha, Steven Weitman Provision of study materials or patients: Sima Jeha, Paul S. Gaynon, Bassem I. Razzouk, Janet Franklin, Richard Kadota, Violet Shen, Lori Luchtman-Jones, Lisa R. Bomgaars, Susan Rheingold, Kim Ritchey, Edythe Albano, Robert J. Arceci, Stewart Goldman, Timothy Griffin, Arnold Altman, Bruce Gordon, Peter Steinherz Collection and assembly of data: Sima Jeha, Paul S. Gaynon, Bassem I. Razzouk, Janet Franklin, Richard Kadota, Violet Shen, Lori Luchtman-Jones, Michael Rytting, Lisa R. Bomgaars, Susan Rheingold, Kim Ritchey, Edythe Albano, Robert J. Arceci, Stewart Goldman, Timothy Griffin, Arnold Altman, Bruce Gordon, Laurel Steinherz, Steven Weitman, Peter Steinherz Data analysis and interpretation: Sima Jeha, Bassem I. Razzouk, Janet Franklin, Richard Kadota, Violet Shen, Lisa R. Bomgaars, Susan Rheingold, Kim Ritchey, Edythe Albano, Robert J. Arceci, Arnold Altman, Laurel Steinherz, Steven Weitman, Peter Steinherz Manuscript writing: Sima Jeha, Steven Weitman Final approval of manuscript: Sima Jeha, Steven Weitman Other: Paul S. Gaynon, Bassem I. Razzouk, Janet Franklin, Richard Kadota, Violet Shen, Lori Luchtman-Jones, Michael Rytting, Lisa R. Bomgaars, Susan Rheingold, Kim Ritchey, Edythe Albano, Robert J. Arceci, Stewart Goldman, Timothy Griffin, Arnold Altman, Bruce Gordon, Laurel Steinherz, Peter Steinherz

 

	ACKNOWLEDGMENTS

 
We acknowledge the contributions and efforts of the following individuals: Manuel Fernandez, Jane Weiss, Susan Smith, Michael Bernstein, Kim Norris, Sherri Lipper, Bret Wacker, and Laurajae Rodriguez.

	NOTES

 
Supported in part by a grant from Genzyme Oncology (successor to ILEX Oncology), San Antonio, TX; also supported in part by Cancer Center Support Grant No. CA21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 21, 2005; accepted February 9, 2006.

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