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Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group

Joseph Gibbons, Merrill J. Egorin, Ramesh K. Ramanathan, Pingfu Fu, Daniel L. Mulkerin, Stephen Shibata, Chris H.M. Takimoto, Sridhar Mani, Patricia A. LoRusso, Jean L. Grem, Anna Pavlick, Heinz-Josef Lenz, Susan M. Flick, Sherrie Reynolds, Theodore F. Lagattuta, Robert A. Parise, Yanfeng Wang, Anthony J. Murgo, S. Percy Ivy, Scot C. Remick

From the Developmental Therapeutics Program, Case Comprehensive Cancer Center, Ireland Cancer Center at University Hospitals of Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH; University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Wisconsin Comprehensive Cancer Center, Madison, WI; City of Hope National Medical Center, Duarte; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; University of Texas Health Science Center, San Antonio, TX; Albert Einstein College of Medicine, Bronx; Kaplan Comprehensive Cancer Center, New York University, New York, NY; Wayne State University, Detroit, MI; National Cancer Institute, Medicine Branch, National Naval Medical Center, Bethesda; Center for Treatment and Evaluation Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Rockville, MD; and Novartis Pharmaceuticals, Florham Park, NJ

Corresponding author: Scot C. Remick, MD, Mary Babb Randolph Cancer Center, West Virginia University, 1801 Health Sciences South, PO Box 9300, Morgantown, WV 26506; e-mail: sremick{at}hsc.wvu.edu

	ABSTRACT

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Purpose This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients.

Patients and Methods Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long.

Results The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose.

Conclusion Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.

	INTRODUCTION

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Imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Florham Park, NJ), is an orally administered, highly selective inhibitor of the tyrosine kinase family containing ABL, the platelet-derived growth factor receptor (PDGFR), c-KIT, and the receptor for stem-cell factor.^1-4 Imatinib has become standard treatment for chronic myeloid leukemia and other hematologic malignancies that express a constitutively active form of the BCR-ABL fusion gene.^5,6 Imatinib has also become standard treatment for gastrointestinal stromal tumors and other less common malignancies that have rearrangement of the PDGFR and PDGFRβ genes.^7-18 The daily imatinib dose ranges from 400 to 800 mg.

Although safety and pharmacokinetic data for imatinib are available for healthy volunteers and patients with cancer who have acceptable renal function, there are currently no data regarding the safety and disposition of imatinib in patients with renal dysfunction. Characterizing the safety and pharmacokinetics of imatinib in patients with impaired renal function is important because renal dysfunction is regularly encountered among patients with cancer, and fluid retention and electrolyte abnormalities occur in patients receiving imatinib. Therefore, this study and one in patients with liver dysfunction¹⁹ were conducted by the National Cancer Institute Organ Dysfunction Working Group.

	PATIENTS AND METHODS

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Patient Eligibility
Eligible patients were required to meet the following criteria: pathologically confirmed malignancy that was no longer curable by standard surgical or medical therapy, age 16 years; Eastern Cooperative Oncology Group performance status 2; life expectancy 3 months; leukocytes 3,000/µL or absolute granulocytes 1,500/µL; platelets 100,000/µL; total bilirubin within institutional normal limits; and AST/ALT 1.5 x the institutional upper limit of normal. Because imatinib is metabolized by CYP3A, patients requiring therapeutic anticoagulation with warfarin were excluded. The institutional review board at each participating institution approved the protocol. Written informed consent was obtained from all patients before study treatment.

Study Design
Ten institutions enrolled patients into four groups on the basis of measured creatinine clearance (CrCL). Group A (normal renal function) had CrCL 60 mL/min; group B (mild dysfunction) had CrCL 40 to 59 mL/min; group C (moderate dysfunction) had CrCL 20 to 39 mL/min; and group D (severe dysfunction) had CrCL less than 20 mL/min. Two separately measured 24-hour urine CrCL determinations, not deviating from each other by more than 25%, were required, with the most recent performed within 1 week of treatment. Stratification was based on the most recent measurement. Laboratories at each institution performed CrCL measurements, and no cross-site standardization was performed. Patients were seen for safety evaluations and examination weekly during cycle 1, biweekly during cycle 2, and every 4 weeks thereafter. CBCs and serum chemistries were performed weekly for the first 12 weeks and biweekly thereafter.

Drug Formulation and Administration
Imatinib was supplied as hard gelatin capsules of 100-mg dosage strength by the Cancer Therapy and Evaluation Program, National Cancer Institute (Rockville, MD), under a Collaborative Research and Development Agreement with Novartis Pharmaceuticals. Imatinib was ingested with 8 ounces of water. Doses 600 mg were given as a single dose. The 800-mg dose was administered as 400 mg bid to avoid local irritant effects on the gastric mucosa, except on day 1, when an 800-mg single dose was given to facilitate pharmacokinetic studies (Table 1). To permit single-dose pharmacokinetic profiling, therapy was started on day 1, held on days 2 and 3, and resumed on day 4. Imatinib was ingested daily without interruption thereafter.

Four patients with normal renal function and three in each renal dysfunction group could accrue to each dose level. If a patient's second CrCL indicated that patient qualified for a different group than indicated by the first CrCL, then the eligible patient was added to the safest known level in the appropriate group.

Assessment of DLT was limited to the first cycle of therapy, which was defined as any drug-related grade 3 or 4 nonhematologic toxicity or worse (excluding alopecia and renal abnormalities); grade 4 neutropenia; occurrence of fever with absolute neutrophil count less than 1,500/µL; grade 4 thrombocytopenia; grade 3 or worse nausea and/or vomiting occurring despite antiemetic therapy and requiring hydration for more than 24 hours; grade 3 or worse diarrhea occurring despite loperamide therapy; or treatment delay lasting more than 4 weeks. Elevation of -glutamyltransferase was not considered a DLT. Assessment of renal toxicity was conducted per previously published guidelines.²¹ Elevations in creatinine or decreases in CrCL that moved a patient to a more advanced renal dysfunction group were considered DLT. If CrCL worsened by 30%, the patient was removed from the study. No dosing changes were made for improvements in renal function. The National Cancer Institute Common Toxicity Criteria, Version 2.0, were used to assess all toxicities.²² The maximum-tolerated dose (MTD) for each group was defined as the highest dose tested in which one patient or fewer experienced DLT when at least six patients had been treated at that dose.

Pharmacokinetic Studies
On day 1, 7-mL heparinized venous blood samples were obtained before and at 0.5, 1, 2, 3, 4, 8, 12, 24, 36, 48, and 72 hours after imatinib ingestion. On day 15, blood samples were obtained just before and at 0.5, 1, 2, 3, 4, 8, 10, 12, 13, 16, and 24 hours after imatinib ingestion. Plasma was prepared by centrifugation and stored at –20°C until analyzed for drug content. Imatinib protein binding on the day 15, 24-hour sample was determined by equilibrium dialysis.²³ Alpha-1 acid glycoprotein (AGP) concentrations in serum obtained before therapy and on day 15 were measured by immunonephelometry (Dade Behring nephelometer; Covance CLS, Indianapolis, IN). On day 1, urine was collected for 24 hours after imatinib ingestion, and an aliquot was stored at –20°C until analyzed for drug content.

Plasma and urinary concentrations of imatinib and its active metabolite N-desmethyl-imatinib (CGP74588) were determined by a validated liquid chromatography/mass spectrometry assay.²⁴ Concentration versus time data for imatinib and CGP74588 were modeled noncompartmentally using the Lagrange function as implemented by the LAGRAN computer program.^25,26

Statistical Methods
Statistical methods are described in detail in the Appendix (online only).²⁷

	RESULTS

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Patient Demographics
Sixty patients were enrolled between September 2001 and February 2005 (Table 2). Fourteen patients were entered in group A, 22 patients were entered in group B; 22 patients were entered in group C, and two patients were entered in group D. One group B patient had incomplete data; only registration and safety data were analyzed. No patients requiring dialysis were enrolled, and it was deemed expeditious not to delay closure of the study for purposes of recruiting only this cohort. Causes of renal insufficiency (groups B through D) were identified retrospectively for 34 (74%) of the 46 patients.

There was a significant difference in cycle 1, day 1 (baseline) albumin among the four patient groups (P = .025; Appendix Table A1, online only). The pair-wise comparison showed no significant difference in baseline albumin between groups A and B, groups B and C, groups B and D, and groups C and D. However, there were significant differences in baseline albumin between groups A and C (P = .0009) and groups A and D (P = .0126). Edema was considerably more frequent among patients with normal renal function (64%) than among those patients with mild (27%) or moderate (27%) dysfunction over the course of study treatment. There was no significant association between renal function group and edema grade or the presence or absence of edema when the analysis was restricted to cycle 1 (data not shown). Similarly, there was no significant association between edema grade and dose level during the first cycle (data not shown). However, when edema was classified as absent or present, logistic regression indicated that dose level was significantly related to edema (P = .033). Specifically, with every 200-mg increase in imatinib dose, the odds of having edema at any time during the study increased 1.87-fold (Appendix Table A2, online only).

Serious adverse events (SAEs) were more common in patients with renal impairment than in patients with normal renal function. SAEs were reported in two (14%) of 14 patients with normal renal function, 13 (59%) of 22 patients with mild dysfunction, nine (43%) of 21 patients with moderate dysfunction, and two (100%) of two patients with severe dysfunction (P = .0096). There was no correlation between imatinib dose and SAEs in any group. All 13 patient deaths that occurred on this study were related to disease progression; none were considered to be treatment-related.

Time on Study and Efficacy Evaluation
The median duration of treatment was 52 days (range, 8 to 588 days; 95% CI, 43 to 59 days). No objective responses were observed. Fourteen patients had stable disease, several of which were longstanding: a group A patient with gastrointestinal stromal tumor (c-kit+) treated with 600 mg/d (511 days), a group C patient with liposarcoma treated with 200 mg/d (224 days), a group C patient with invasive thymoma (c-kit+) treated with 600 mg/d (203+ days), and a group D patient with non–small-cell lung cancer treated with 100 mg/d (143 days). The median duration of treatment of patients with c-kit+ tumors (n = 7) was 105 days, whereas that of patients with c-kit status unknown tumors was 50.5 days (P = .108). Group A patients remained on the study longer than did those in groups B and C (P = .025; Appendix Fig A1, online only).

Pharmacokinetics
Pharmacokinetic data after the first dose of imatinib (day 1) and at steady-state (day 15) were available for 51 and 47 patients, respectively (Table 5). The rate of imatinib absorption, as reflected by time to maximum serum concentration, was similar in all groups, although there was considerable interpatient variability. After the first imatinib dose, the imatinib elimination half-lives were similar among the four groups, with mean values of approximately 19 hours on day 1 and 28 hours on day 15. On days 1 and 15, the dose-normalized maximum serum concentration (C_max) was approximately 1.6- and 2.2-fold greater in the mild and moderate renal dysfunction groups, respectively, than in the normal group; however, there was large variability within each group. As with C_max, imatinib exposure, as expressed by dose-normalized AUC_0- (area under the curve from 0 to infinity) on day 1 and AUC_0-24 (AUC from 0 to 24 hours) on day 15, was significantly greater in patients with mild or moderate dysfunction than in those with normal renal function. In that apparent clearance is defined as dose/area under the curve (AUC), there was a corresponding significant decrease in imatinib clearance as renal function worsened (Table 5 and Fig 1). The apparent volume of distribution on days 1 and 15 was significantly lower for patients with mild and moderate dysfunction than for patients with normal renal function. The percentage of unbound imatinib ranged between 2.1% and 14.5% (Table 5).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Relationship between creatinine clearance and imatinib apparent clearance. Points represent individual patients. (A) Alpha-1 acid glycoprotein (AGP) concentration and dose-normalized imatinib area under the curve (AUC); (B) AGP concentration and imatinib clearance (CL/F); (C) AGP concentration and creatinine clearance.

0-

There was a positive correlation between AGP concentration and dose-normalized imatinib AUC_0- on day 1 and AUC_0-24 on day 15, inverse correlation between AGP concentration and imatinib apparent clearance, and an inverse relationship between AGP concentrations and CrCL (Fig 1, Table 5). Urinary excretion of imatinib and CGP74588 accounted for less than 10% of the imatinib dose and was not significantly different among the various groups (Table 5).

	DISCUSSION

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This study is the first systematic, prospective investigation of the safety and pharmacokinetics of imatinib in patients with renal dysfunction. Initial pharmacokinetic studies of imatinib were done primarily in patients with chronic myeloid leukemia and demonstrated rapid absorption; approximately 100% bioavailability; a plasma half-life of 10 to 23 hours; a two- to three-fold accumulation at steady-state; no effect of food on pharmacokinetic parameters; mainly hepatic metabolism, primarily by CYP3A; binding to AGP; and 10% renal excretion.^28-32 Earlier-phase studies of imatinib also identified electrolyte abnormalities, fluid retention and edema as toxicities, and the potential for significant drug-drug interactions, all of which provided the rationale to explore dosing in patients with renal dysfunction.^5-10

The overall safety, side effect profile, and tolerability of imatinib in patients with renal dysfunction are similar to those in patients with acceptable renal function. An MTD was not reached in either the minimal or moderate renal dysfunction groups. Only two patients with severe renal dysfunction and no patients on renal dialysis were treated, which precludes any firm conclusion on dosing of such patients.

Despite comparable toxicity across normal, mild, and moderate renal dysfunction groups, an unexpected observation was that imatinib pharmacokinetics were altered significantly in patients with renal dysfunction. Although Pappas et al³³ reported that imatinib pharmacokinetics parameters in a patient on hemodialysis were not different than those in patients with normal renal function, the imatinib clearance in that patient was 4.2 L/h, which is approximately the same as the mean imatinib clearance in our moderate and severe renal dysfunction groups and significantly less than the mean imatinib clearance in our patients with normal renal function. Altered imatinib pharmacokinetics were not expected in patients with decreased renal function because the major route of imatinib clearance is through CYP3A-mediated metabolism to CGP74588, and 13% of an imatinib dose is excreted in the urine.^30-32,34 In retrospect, however, decreased imatinib clearance might have been expected in patients with renal dysfunction because of the recognized decreased in vivo activity of hepatic CYPs in chronic renal failure.^35-38 Another likely explanation for the decreased apparent clearance is the increased AGP concentrations in patients with renal dysfunction, which would result in increased total plasma imatinib but decreased free fraction or unchanged free drug level. This implies the need to monitor free as well as total imatinib concentrations. Regardless of the mechanism for the observed increase in imatinib AUC in patients with renal dysfunction, the metabolite CGP74588 to imatinib AUC ratio seemed to be unchanged, except for the two patients in the severe renal dysfunction group. These results suggest that the metabolism of imatinib is probably not affected in patients with moderate renal dysfunction.

The finding that edema was more common over the course of study in patients with normal renal function was also unexpected. Edema and fluid retention are commonly encountered side effects of imatinib, and the cautionary emergence of congestive heart failure as a late toxicity of imatinib treatment raises concern about this clinical sign and toxicity.^39-43 It is difficult to ascertain the significance of edema over the course of a phase I trial treating patients with refractory solid tumors as well as renal dysfunction. However, patients with normal renal function remained on study longer than did patients with mild or moderate dysfunction, which may be related to why normal patients were more prone to develop edema over the course of therapy. Nonetheless, there was no apparent increased risk of edema during the critical evaluative first cycle for safety across the renal function cohorts, and there may have been a dose-response effect when we analyzed dose level and grouped patients by absence or presence of edema. In a large phase II sarcoma study, edema, particularly periorbital edema, was seen in 84% of patients studied, which tended to occur within the first 8 weeks of therapy.⁴⁴ Esmaeli et al⁴⁵ reported that edema from imatinib may result from inhibition of c-kit in dermal dendrocytes, and our results suggest that this may be dose-dependent.

In summary, although there was an unanticipated increase in drug exposure in patients with mild or moderate renal dysfunction, this was not associated with any increased clinically meaningful toxicity or drug-related adverse events. Too few patients with CrCL less than 20 mL/min were evaluated to draw any conclusions about the behavior of imatinib in such patients. Given our results, there is no requirement for modification of initial imatinib doses given to patients with mild or moderate renal dysfunction who can tolerate daily imatinib doses up to 800 mg and 600 mg, respectively. It may be prudent to reduce the initial dose of imatinib given to patients with severe renal dysfunction until more experience is gained in this subset of patients.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.

Employment or Leadership Position: Yanfeng Wang, Novartis Pharmaceuticals (C) Consultant or Advisory Role: Merrill J. Egorin, Novartis (C); Patricia A. LoRusso, Takeda (C), AstraZeneca (C), Pfizer (C), Genentech (C); Heinz-Josef Lenz, Advisory Board for Novartis (C) Stock Ownership: Yanfeng Wang, Novartis Honoraria: Merrill J. Egorin, Novartis; Patricia A. LoRusso, Roche, AstraZeneca, Aventis; Heinz-Josef Lenz, Novartis Advisory Board Research Funding: Merrill J. Egorin, Novartis; Chris H.M. Takimoto, Novartis; Patricia A. LoRusso, Amgen, Ariad, AstraZeneca, Boeringer-Ingelheim, Bristol-Myers Squibb Co, Endocyte, Glaxo-SmithKline, ImClone, Merck, Novartis, Pfizer; Heinz-Josef Lenz, Novartis Clinical Trials; Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Merrill J. Egorin, Ramesh K. Ramanathan, Anthony J. Murgo, S. Percy Ivy, Scot C. Remick

Financial support: S. Percy Ivy, Scot C. Remick

Administrative support: Sherrie Reynolds, S. Percy Ivy, Scot C. Remick

Provision of study materials or patients: Joseph Gibbons, Merrill J. Egorin, Ramesh K. Ramanathan, Daniel L. Mulkerin, Stephen Shibata, Chris H.M. Takimoto, Sridhar Mani, Patricia A. LoRusso, Jean L. Grem, Anna Pavlick, Heinz-Josef Lenz, Susan M. Flick, Scot C. Remick

Collection and assembly of data: Merrill J. Egorin, Chris H.M. Takimoto, Patricia A. LoRusso, Heinz-Josef Lenz, Susan M. Flick, Sherrie Reynolds, Theodore F. Lagattuta, Robert A. Parise, Yanfeng Wang, S. Percy Ivy, Scot C. Remick

Data analysis and interpretation: Joseph Gibbons, Merrill J. Egorin, Pingfu Fu, Heinz-Josef Lenz, Susan M. Flick, Robert A. Parise, Yanfeng Wang, Anthony J. Murgo, S. Percy Ivy, Scot C. Remick

Manuscript writing: Joseph Gibbons, Merrill J. Egorin, S. Percy Ivy, Scot C. Remick

Final approval of manuscript: Joseph Gibbons, Merrill J. Egorin, Ramesh K. Ramanathan, Daniel L. Mulkerin, Stephen Shibata, Chris H.M. Takimoto, Robert A. Parise, S. Percy Ivy, Scot C. Remick

	Appendix

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Statistical methods. The Cochran-Armitage test was used to detect trends between the renal function group and the number of patients with drug-related grade 3 to 4 toxicities as well as trends between imatinib dose and the number of patients with drug-related grade 3 to 4 toxicities. The effect of renal dysfunction on imatinib pharmacokinetics was assessed by 90% CIs for the geometric mean ratio:

where ‘g’ stands for either dose-normalized area under the curve or dose-normalized maximum concentration. All pharmacokinetic parameters were log-transformed before analysis. The normal group was the reference group, and the mild, moderate, and severe dysfunction groups were the test groups. Point estimates of the difference between the test and reference group as well as the corresponding 90% CIs were antilogged to obtain the point estimate and the corresponding 90% CIs for the geometric mean ratio. An absence of the effect of renal dysfunction was assumed if the CI fell completely in the so-called no-effect interval (0.75 to 1.33). Included in the analysis of variance model was renal function as a fixed factor. All statistical analyses were performed using SAS (version 8.2; SAS Institute Inc, Cary, NC).

The difference in cycle 1 albumin across all four groups (groups A through D) was examined by analysis of variance, followed by pair-wise comparison of any two cohorts (P value not adjusted for multiple comparisons). The association between dose level and cycle 1 albumin was estimated by Pearson correlation coefficient. The association between cycle 1 edema grade and dose level and the distribution of cycle 1 edema grade across the four patient groups were first examined by Fisher's exact test. Edema grade was also grouped into two categories: none (edema grade = 0) and present (edema grade = 1 or 2), and logistic regression was used to evaluate potential dose-related toxicity. The percentage of patients still on study was estimated by the Kaplan-Meier method, and the difference in that percentage between and among groups was examined by log-rank test.²⁷ All tests were two-sided, and P values less than .05 were considered statistically significant.

Safety profile. The three most frequently reported adverse events that were considered to be possibly, probably, or definitely related to imatinib therapy were gastrointestinal disorders (nausea, 64%; vomiting, 46%; diarrhea, 27%; anorexia, 25%; and dyspepsia/heartburn, 12%), fatigue (36%), and edema (31%).

Time on study and efficacy evaluation is shown in Appendix Fig A1.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Kaplan-Meier estimation of percentage of on-study patients by renal function cohort.

	ACKNOWLEDGMENTS

 
We thank Kim Wood of Technical Resources International for preparation of the study report and the University of Pittsburgh Hematology/Oncology Writing Group for helpful suggestions regarding the manuscript.

	NOTES

 
Supported by National Institutes of Health Grants No. U01 CA62502, M01 RR-000080, P30 CA43703, U01 CA099168, 5M01 RR-00056, P30 CA47904, 5 U01 CA62505, U01 CA062491, and 5U01CA069853 and Translational Research Initiative Contract No. 22XS041A.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003 Chicago, IL.

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

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Submitted July 23, 2007; accepted September 27, 2007.

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