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Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621

Jonathan E. Kolitz, Stephen L. George, Richard K. Dodge^,, David D. Hurd, Bayard L. Powell, Steven L. Allen, Enrique Velez-Garcia, Joseph O. Moore, Thomas C. Shea, Eva Hoke, Michael A. Caligiuri, James W. Vardiman, Clara D. Bloomfield, Richard A. Larson

From the North Shore University Hospital, New York University School of Medicine, Manhasset, NY; CALGB Statistical Center; Duke University School of Medicine, Durham; Wake Forest University School of Medicine, Winston-Salem; University of North Carolina, Chapel Hill, NC; University of Puerto Rico School of Medicine, San Juan, Puerto Rico; The Ohio State University, Columbus, OH; and University of Chicago, Chicago, IL

Address reprint requests to Jonathan E. Kolitz, MD, Don Monti Division of Oncology and Division of Hematology, Department of Medicine, North Shore University Hospital, New York University School of Medicine, 300 Community Dr, Manhasset, NY 11030; e-mail: kolitz{at}nshs.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.

PATIENTS AND METHODS: A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.

RESULTS: Doses selected for phase III testing were DNR 90 mg/m² and ETOP 100 mg/m² in ADE, and DNR and ETOP each 40 mg/m² in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.

CONCLUSION: A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.

	INTRODUCTION

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Chemotherapy resistance is partly mediated by P-glycoprotein (Pgp), a cell membrane drug efflux pump encoded by the MDR1 gene. Significant expression of Pgp is not commonly observed in patients with de novo acute myeloid leukemia (AML) younger than age 50 years,¹ but has been reported in nearly three fourths of patients older than age 55 years.² Expression is associated with positivity for CD34³ and poor-risk cytogenetic findings.^2,4 Multivariate analyses have shown that only Pgp expression and cytogenetics are independent predictors of complete remission (CR) and overall survival (OS) in de novo AML.^4-6 Even in studies that have not detected an effect of Pgp expression on OS, highly significant and independent effects have been demonstrated on the incidence of CR and primary refractoriness to induction therapy in all age groups.^1,2 Furthermore, the level of Pgp expression in unfractionated leukemic bone marrow samples may not measure minor populations of autonomously proliferating blasts expressing CD34 and Pgp, which may contribute to drug resistance and treatment failure in de novo AML.⁷

Attempts to pharmacologically reverse Pgp activity have centered on the use of cyclosporine (CsA) and its nonimmunosuppressive analog, PSC-833 (Valspodar; Novartis, East Hanover, NJ). Both drugs competitively inhibit Pgp function and diminish drug efflux in vitro.^8-11 In addition to being a more potent inhibitor of Pgp in vitro than CsA,^10,12,13 PSC-833 directly induces apoptosis,¹⁴ impedes the development of doxorubicin resistance,¹⁵ and promotes cytotoxicity via a non-Pgp-dependent mechanism involving ceramide metabolism.¹⁶

Promising results favoring the use of CsA as a Pgp modulator with infusional daunorubicin (DNR) and high-dose cytarabine (HiDAC) in a phase III trial in poor-risk AML conducted by the Southwest Oncology Group¹⁷ have yet to be duplicated using PSC-833. Phase I and II trials combining PSC-833 and natural product-based induction chemotherapy for AML have documented acceptable safety and efficacy in poor-risk patients with relapsed or refractory disease^18-20 and in untreated elderly patients.^21-23 Three phase III studies evaluating PSC-833 have been prematurely terminated, however. Toxicity concerns halted two trials in older patients with de novo AML²⁴ (T.R. Chauncey, personal communication), whereas a phase III trial in patients with relapsed or refractory disease ended because of lack of benefit in the experimental arm.²⁵

Since 1985, the Cancer and Leukemia Group B (CALGB) has focused on developing intensive postremission therapies for de novo AML in patients younger than age 60. These studies have demonstrated the superiority of HiDAC consolidation therapy compared with lower dose cytarabine (Ara-C) treatment schedules,²⁶ particularly in patients with favorable cytogenetics,^27,28 and established that potentially non-cross-resistant intensification therapies offered no advantage over HiDAC alone.²⁹ Renewed attention was then directed toward induction therapy in the current study, in which Pgp modulation and dose-escalation schedules of DNR and etoposide (ETOP) were evaluated. A fixed dose of infusional Ara-C was combined with variable doses of daunorubicin (DNR) and ETOP in the ADE regimen. Lower doses of DNR and ETOP were combined with Ara-C in the presence of PSC-833 in the ADEP (ADE with PSC-833) regimen. The trial design closely followed the structure of CALGB's earlier study of Pgp-modulation in untreated older patients.²¹ Clinical rather than pharmacologic end points were used to determine doses because of concern that purely pharmacokinetic measurements in sera would not accurately reflect intracellular biologic effects mediated by Pgp inhibition.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Eligibility Criteria
Adults younger than 60 years old with French-American-British classifications of AML, excluding acute promyelocytic leukemia, were eligible for study entry. Diagnostic samples were centrally reviewed at the University of Chicago (J.W.V.). Patients with previously treated and therapy-related AML were excluded, as were patients with AML arising from a prior myelodysplastic or myeloproliferative disorder.

Study Design
The major aim of this study was to determine doses of DNR and ETOP that could be combined with a fixed dose of Ara-C, with or without a fixed dose of PSC-833, that would produce grade 3 or 4 treatment-related nonhematologic toxicity judged to be dose-limiting in no more than one third of patients. Dose-limiting stomatitis was defined as mucosal toxicity attributable to the induction regimen and requiring total parenteral nutrition. Consequently, all instances of dose-limiting toxicity (DLT) associated with stomatitis were grade 4. Conversely, grade 3 or 4 hepatotoxicity was defined as DLT only if irreversible or if it caused death or removal from protocol therapy. Prolonged myelosuppression, defined as failure of granulocyte recovery to at least 500/µL or platelets to at least 20,000/µL within 42 days after the start of induction treatment, was included as a DLT. We applied a model-based approach to determine the maximum-tolerated doses (MTDs), as previously described.²¹

Induction Therapy
The two regimens evaluated were ADE and ADEP. Ara-C was given by continuous intravenous (IV) infusion at a dose of 100 mg/m² daily for 7 days to all patients (days 1 to 7). All patients received DNR by IV bolus followed by ETOP given as a 2-hour IV infusion, each given daily for the first 3 days of induction therapy. The initial group of patients treated with ADE received daily doses of DNR 60 mg/m² and of ETOP 100 mg/m². The corresponding initial doses for the patients assigned to receive ADEP were 40 mg/m² of DNR and 60 mg/m² of ETOP. These were the doses of DNR and ETOP that had emerged from the prior CALGB trial for older adults²¹ for use in the phase III study comparing ADE and ADEP in patients 60 years.²⁴ Before initiation of chemotherapy, patients receiving ADEP were given a loading dose of PSC-833 of 2.8 mg/kg IV during 2 hours, followed by 10 mg/kg/d by continuous IV infusion for 72 hours on days 1 to 3. DNR and ETOP were given immediately after completion of the PSC-833 loading dose, concurrently with the start of the PSC-833 and Ara-C infusions.

The need for a second induction course was based on findings from a bone marrow examination on day 14. Presence of 5% blasts in a marrow with at least 20% cellularity indicated that the initial induction course had failed. Repeat induction treatment consisted of the same doses of chemotherapy, with DNR and ETOP each given on days 1 and 2, and Ara-C given on days 1 to 5. Patients receiving ADEP were given the same loading dose of PSC-833, with the continuous-infusion portion limited to 48 hours. PSC-833 frequently induces reversible hyperbilirubinemia. Treating physicians were cautioned that hyperbilirubinemia was a relative contraindication to re-treating patients who required a second induction with ADEP.

Dose Escalation or De-Escalation and Determination of Phase III Doses
Consecutive treatment groups of nine or more patients were assigned to receive induction therapy with ADE or ADEP, as previously described.²¹ ADE or ADEP treatment groups were opened in alternate months, as long as nine or more patients had been treated and evaluated for toxicity. DLT was defined as nonhematologic grade 3 or 4 treatment-related toxicity occurring in at least one third of patients within a treatment group. The initial trial design called for DNR dose escalations only. The protocol was amended in January 1999 to permit ETOP dose escalations also. The progress of the study was monitored via regularly scheduled telephone conference calls involving the study chair, statisticians, and data coordinator. Attributions of DLT to treatment were made during biweekly data review using definitions noted in Study Design, whereas all grade 3 and 4 toxicities were assigned by the treating institutions. This accounts for the differences between the DLT findings outlined in Table 1 and the grade 3 and 4 toxicity determinations in Tables 2 and 3.

View this table: [in this window] [in a new window]   Table 2. Nonhematologic Toxicity Grade 3 in 204 Patients Receiving ADE

View this table: [in this window] [in a new window]   Table 3. Nonhematologic Toxicity Grade 3 in 192 Patients Receiving ADEP

Quality Control, Quality Assurance, and Auditing
This trial was reviewed and approved by the institutional review board of each participating institution. Each patient provided written, informed consent before registration. Patients were registered at the CALGB Statistical Center (Durham, NC) and statistical analyses were performed by CALGB statisticians. Eligibility for study entry as well as institutional assessments of toxicity and response were regularly reviewed by the study chair according to standard CALGB policy on case evaluations. The medical records of 141 of the 410 patients (34%) participating in this study were randomly selected and audited by members of the CALGB Data Audit Committee; records included some patients from each involved institution.³³

Toxicity and Response Measurements
The National Cancer Institute Common Toxicity Criteria were used to grade toxicity. National Cancer Institute Workshop criteria were used to define CR.³⁴ Relapse was defined as recurrent and persistent circulating blasts or more than 5% bone marrow blasts, or the development of extramedullary leukemia.

Statistical Methods
The primary purpose of the induction phase of this study was to identify the appropriate doses of agents in the two regimens, ADE and ADEP, to use in a subsequent phase III trial directly assessing the relative clinical benefit of these regimens. Logistic regression techniques³⁵ were used to estimate the MTDs in each regimen and to assess the shape of the dose-toxicity curves over the range of doses studied. To carry out such an analysis, a much larger number of patients were required than in a conventional phase I study. It was deemed important to have a large number of participants because of the intent to move directly to a phase III study based on these results. In addition to the primary analyses, secondary exploratory analyses were based on clinical outcomes, including response rate, disease-free survival (DFS), and OS, and their relationship to pretreatment characteristics such as age and cytogenetics.

Survival times were calculated from date of study entry to date of death as a result of any cause. DFS was calculated from date of CR to relapse, or to death as a result of any cause if relapse had not occurred. Patients alive at the date of last follow-up were right-censored for survival analysis, and patients alive without relapse were similarly censored for DFS analysis. The distribution of survival and DFS times was estimated using the Kaplan-Meier method³⁶ The analysis of proportions was carried out using either Fisher's exact test³⁷ or ² tests, as noted in the results.

	RESULTS

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Patient Population
Between April 1997 and April 2000, 410 patients were registered onto this study. All analyses are based on the study database frozen on April 15, 2003. The median follow-up for surviving patients was 3.4 years. Demographic and clinical data are presented in Table 4. Eleven patients (3%) were ineligible for study entry because they did not have AML. Although these patients are not included in the response analysis, eight received their assigned induction therapy and are included in the toxicity analysis. Five patients never received protocol therapy, and one was dosed incorrectly; these patients are not included in response or toxicity assessments. One patient treated with ADEP inadvertently received PSC-833 in markedly reduced doses and achieved CR; that patient is assessable for response but not for toxicity. Thus, of the 410 patients entered, 397 (97%) were assessable for toxicity and survival analyses, and 394 (96%) were assessable for the analysis of response.

Toxicity
The incidence of DLT during induction as well as deaths as a result of all causes within 30 days of starting induction therapy are listed in Table 1. The frequencies of DLT listed in Table 1 do not appear to vary much in patients treated with ADE as a function of either DNR or ETOP dose. However, patients who received ADEP experienced greater toxicity than patients treated with ADE (proportion of DLTs in ADE v ADEP; P < .0001), with toxicity apparently increasing according to DNR dose. The ADEP regimen using the lowest doses of both Pgp substrates used in this trial was associated with the least toxicity among ADEP regimens tested. These observations are supported by the logistic model results presented below.

Grade 3 or greater stomatitis, dysphagia, and esophagitis were the most prevalent DLTs in patients receiving ADE (Table 2). Significant mucosal toxicity was observed more often in patients receiving ADEP (Table 3). Reversible grade 3 hepatotoxicity, most often consisting of hyperbilirubinemia without elevations in ALT, AST, or alkaline phosphatase, occurred far more often in patients receiving PSC-833. Grade 4 hyperbilirubinemia was less frequent, but was associated with serious adverse events. Outcomes were analyzed in patients who developed grade 4 hyperbilirubinemia according to baseline liver function. DLT or induction death (ID) occurred in six of 13 patients with normal liver function before treatment and in two of three patients with abnormal liver function (baseline > grade 2 abnormalities in total bilirubin, AST, or ALT) treated with ADE. Among patients receiving ADEP, DLT or ID occurred in 22 of 40 patients with normal antecedent liver function and six of nine with abnormal liver function. Furthermore, ID occurred in all four patients given second inductions in whom abnormal LFTs either preceded or developed during or after the second course; two received ADE and two received ADEP. This compares with four of 32 IDs among all other second inductions.

Hepatotoxicity was clearly exacerbated by the presence of confounding clinical variables likely to affect liver function, such as sepsis and associated hemodynamic changes. Reversible cerebellar toxicity was observed in only two patients and was successfully managed with interruptions and dose reductions of PSC-833, as prescribed in the protocol.

Table 2 illustrates the weak correspondence between daunorubicin and etoposide doses and serious toxicity in the ADE regimen. For simplification, patients have been combined into three groups of comparable size, with similar daunorubicin and etoposide doses within each subgroup, as shown. The data are presented for all four ADEP regimens in Table 3. A clearer relationship between dose and toxicity was observed in the presence of Pgp inhibition. This relationship was apparent over a substantially narrower dosing range of the cytotoxic agents than was seen in patients treated with ADE.

Cardiotoxicity attributed to a single course of induction therapy was observed in one 55-year-old patient treated with ADEP. Two patients who each received two inductions with ADE using 80 and 85 mg/m² of DNR developed marked decreases in left ventricular ejection fraction, but this was observed only after additional treatment with non-anthracycline-containing protocol chemotherapy. Both subsequently underwent autologous PSCT uneventfully. Six patients, four of whom were older than age 50, developed significant decreases in left ventricular ejection fraction after treatment with ADE using 90 mg/m² of DNR. Four of the six patients received two courses of induction therapy, and two had abnormal liver function at the time of the second induction course. One patient died with persistent leukemia and one died in CR as a result of complications of heart failure. Two patients were unable to receive their planned postremission therapy, at least in part due to cardiac complications. In total, six of 112 (5%) patients treated with ADE using DNR at a dose of 90 mg/m² developed cardiotoxicity that was attributed to their treatment, but no such toxicity was observed in 34 other patients receiving ADE regimens with DNR doses approaching (80 and 85 mg/m²; n = 22) or exceeding (95 mg/m²; n = 12) the DNR dose in question. Neither cardiotoxicity nor other induction-related toxicity significantly impeded the progression of patients through postremission therapy.

Figure 1 shows the fitted logistic regression curves as a function of DNR dose for ADE and ADEP along with the observed proportion of DLTs and 95% CIs for each dose of DNR studied. This Figure increases the precision of the earlier observations based on a simple examination of the toxicity tables. Over the range of DNR doses studied, the probability of a DLT increases slowly as a function of dose for the ADE treatment, and the addition of PSC-833 produces a dramatically higher probability of DLT. Furthermore, if we define the MTD as the 33rd percentile of the dose-toxicity curve, it is not possible to estimate a reasonable MTD for ADE from these data. Thus, the selected dose of DNR for ADE in the subsequent phase III trial was chosen as 90 mg/m², a dose with a reasonable safety profile based on a considerable number of patients treated at this dose on the current trial. For ADEP, the MTD for DNR is estimated from the fitted logistic model as 48 mg/m² (95% CI, 41 to 57 mg/m²). However, for the subsequent phase III trial, the selected dose was chosen to be 40 mg/m², both to allow a safety margin and because, as with the chosen dose for ADE, we have considerable experience with this dose on the current trial. These doses were associated with comparable incidences of significant nonhematologic toxicities and of clinical efficacy as reflected in CR rates (results presented below), and with acceptable cardiac toxicity.

View larger version (17K): [in this window] [in a new window]   Fig 1. Estimation of maximum-tolerated dose of DNR by logistic regression model in acute myeloid leukemia patients younger than 60 years old. The 95% CI for the DNR doses for the phase III trial (40 mg/m2 in DNR, etoposide, and cytarabine with PSC-833 [ADEP] and 90 mg/m2 for DNR, etoposide, and cytarabine [ADE]) do not exceed the 33% incidence line for dose-limiting toxicity.

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival by treatment regimen. ADE, daunorubicin, etoposide, and cytarabine; ADEP, ADE with PSC-833.

View larger version (16K): [in this window] [in a new window]   Fig 3. Disease-free survival by treatment regimen. ADE, daunorubicin, etoposide, and cytarabine; ADEP, ADE with PSC-833.

View larger version (14K): [in this window] [in a new window]   Fig 4. Overall survival by treatment regimen among patients 45 years. ADE, daunorubicin, etoposide, and cytarabine; ADEP, ADE with PSC-833.

View larger version (15K): [in this window] [in a new window]   Fig 5. Disease-free survival by treatment regimen among patients 45 years. ADE, daunorubicin, etoposide, and cytarabine; ADEP, ADE with PSC-833.

For patients with CBF leukemia, the estimated 3-year DFS was 38% (95% CI, 21% to 56%) after ADE induction therapy and 59% (95% CI, 40% to 79%) after ADEP. For patients with non-CBF leukemia, the estimated 3-year DFS was 37% (95% CI, 28% to 45%) after ADE and 42% (95% CI, 33% to 50%) after ADEP.

	DISCUSSION

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The principal findings of this clinical trial are that adults younger than 60 years old with de novo AML tolerate substantially higher doses of DNR in induction therapies than have been used in clinical practice; such therapy leads to high CR rates with an acceptable risk of cardiac toxicity; in the presence of PSC-833, the doses of agents that are substrates for Pgp must be substantially reduced; and ADEP was associated with comparable CR rates, although with a higher probability of inducing reversible mucosal and hepatotoxicity.

We estimate that the DNR and ETOP doses must be reduced by 55% to 60% in the experimental arm (ADEP) to achieve comparable toxicity to the control arm (ADE). With respect to possible interactions when Pgp-susceptible agents are combined, data from phase I trials using mitoxantrone plus ETOP^19,20 and doxorubicin plus paclitaxel³⁹ with PSC-833 have demonstrated pharmacokinetic and/or toxicity data that indicate the need for dose reductions ranging between 60% and 66%. Our phase I trial in older patients with AML (CALGB 9420) suggested that DNR and ETOP dose reductions of 60% and 40%, respectively, would be appropriate for testing as compared with a comparable regimen not using PSC-833.²¹ The subsequent phase III trial in older patients was closed prematurely because the induction death rate was higher in the experimental arm,²⁴ although additional follow-up has not revealed any difference in overall survival between the two arms. The 1-year survival rates are similar.

The high proportion of patients achieving CR after one course of either induction therapy highlights the clinical efficacy of the ADE and ADEP regimens. The relatively low probability of entering CR after a second course of ADEP (32%) may be explained by selection of resistant leukemia after exposure to Pgp inhibition or, alternatively, the impaired ability of these patients to undergo additional intensive therapy.

Although subset analyses are potentially risky, we reviewed the data by age in this trial because AML blasts may differ between younger and older patients. The results suggest that induction therapy incorporating Pgp inhibition with PSC-833 might yield longer OS and DFS in patients younger than 45 years old, although this observation requires confirmation. Although expression of multidrug resistance protein (MRP) and lung resistance protein in AML is not associated with age,⁴⁰ coexpression of Pgp and MRP increases with age as well as with the adverse cytogenetic findings, which are more prevalent in older patients.⁴¹ Furthermore, AML arising from antecedent myelodysplasia, which is more prevalent in older patients, has been observed to overexpress MRP.⁴² Primary drug resistance in AML blasts due to BCL-2 overexpression also increases with age.^43,44 Consequently, strategies aimed at reversing Pgp might be more successful in patients whose leukemic cells are less resistant to death signals. The ability of PSC-833 to induce apoptosis via Pgp-dependent and -independent mechanisms^14,16 provides additional justification for its clinical evaluation in the treatment of younger patients with de novo AML, particularly in light of recent data suggesting that Pgp itself may be implicated in resistance to apoptosis.⁴⁵ It is therefore reasonable to hypothesize that AML stem cells in younger adults display lesser degrees of drug resistance than those in older patients, which are characterized by multiple mechanisms of resistance.

The feasibility of administering doses of DNR substantially higher than typically used for induction therapy of AML has been shown in this study. Additional follow-up of treated patients as well as a planned analysis of observed clinical responses as a function of DNR dose, treatment with PSC-833, and phenotypic and functional expression of Pgp in blasts collected pretreatment and at relapse will aid in clarifying the impact of higher doses of DNR in this patient population. Also of importance will be long-term follow-up of cardiac status in treated patients.

The CALGB initiated a randomized phase III comparative study of ADE and ADEP (CALGB 19808) using the doses of DNR and ETOP developed in this trial. In August 2003, after 303 patients had been randomly assigned, PSC-833 for IV use became unavailable. The results of that randomized study are now being analyzed. In the meantime, as newer inhibitors of Pgp function enter clinical trials,^46,47 the data from the randomized induction portion of the 19808 trial will provide useful additional information regarding the importance of Pgp reversal in the therapy of de novo AML in younger patients.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The following institutions participated in this study: CALGB Statistical Center, Durham, NC-Stephen George, PhD, supported by CA33601; Dana-Farber Cancer Institute, Boston, MA-George P Canellos, MD, supported by CA32291; Dartmouth Medical School - Norris Cotton Cancer Center, Lebanon, NH-Marc S. Ernstoff, MD, supported by CA04326; Duke University Medical Center, Durham, NC-Jeffrey Crawford, MD, supported by CA47577; Georgetown University Medical Center, Washington, DC-Edward Gelmann, MD, supported by CA77597; Long Island Jewish Medical Center, Lake Success, NY-Marc Citron, MD, supported by CA11028; Medical University of South Carolina, Charleston, SC-Mark Green, MD, supported by CA03927; Mount Sinai School of Medicine, New York, NY-Lewis R. Silverman, MD, supported by CA04457; North Shore University Hospital, Manhasset, NY-Daniel R Budman, MD, supported by CA35279; Rhode Island Hospital, Providence, RI-William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY-Ellis Levine, MD, supported by CA02599; SUNY Upstate Medical University, Syracuse, NY-Stephen L. Graziano, MD, supported by CA21060; The Ohio State University Medical Center, Columbus, OH-Clara D. Bloomfield, MD, supported by CA77658; University of Alabama Birmingham, Birmingham, AL-Robert Diasio, MD, supported by CA47545; University of California at San Diego, San Diego, CA-Stephen L Seagren, MD, supported by CA11789; University of California at San Francisco, San Francisco, CA-Alan P. Venook, MD, supported by CA60138; University of Chicago Medical Center, Chicago, IL -Gini Fleming, MD, supported by CA41287; University of Illinois MBCCOP, Chicago, IL-Thomas Lad, MD, supported by CA74811; University of Iowa, Iowa City, IA-Gerald Clamon, MD, supported by CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD-Martin Edelman, MD, supported by CA31983; University of Massachusetts Medical Center, Worcester, MA-Mary Ellen Taplin, MD, supported by CA37135; University of Minnesota, Minneapolis, MN-Bruce A. Peterson, MD, supported by CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO-Michael C Perry, MD, supported by CA12046; University of Nebraska Medical Center, Omaha, NE-Anne Kessinger, MD, supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC-Thomas C. Shea, MD, supported by CA47559; University of Tennessee Memphis, Memphis, TN-Harvey B. Niell, MD, supported by CA47555; Vermont Cancer Center, Burlington, VT-Hyman B. Muss, MD, supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC-David D Hurd, MD, supported by CA0392; Walter Reed Army Medical Center, Washington, DC-Joseph J. Drabeck, MD, supported by CA26806; Washington University School of Medicine, St. Louis, MO, Nancy Bartlett, MD, supported by CA77440; Weill Medical College of Cornell University, New York, NY-Scott Wadler, MD, supported by CA07968.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We acknowledge the editorial assistance of Michael Kelly and statistical analyses contributed by Robert Barrier.

	NOTES

 
Supported in part by grants from the National Cancer Institute to the Cancer and Leukemia Group B (CA31946, CA101140) and The Leukemia Clinical Research Foundation. J.E.K. and S.L.A. were supported by CA35279; S.L.G. and R.K.D. were supported by CA33601; B.L.P. was supported by CA03927; E.V.-G. was supported by CA32291; J.O.M. was supported by CA47577; T.C.S. was supported by CA47559; M.A.C. was supported by CA77658; and R.A.L. was supported by CA41287.

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

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

Deceased.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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Submitted November 18, 2003; accepted August 11, 2004.

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