Originally published as JCO Early Release 10.1200/JCO.2007.13.1391 on March 31 2008

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Phase II Study of Dose-Adjusted EPOCH and Rituximab in Untreated Diffuse Large B-Cell Lymphoma With Analysis of Germinal Center and Post-Germinal Center Biomarkers

Wyndham H. Wilson, Kieron Dunleavy, Stefania Pittaluga, Upendra Hegde, Nicole Grant, Seth M. Steinberg, Mark Raffeld, Martin Gutierrez, Bruce A. Chabner, Louis Staudt, Elaine S. Jaffe, John E. Janik

From the Center for Cancer Research, Bethesda, MD; Massachusetts General Hospital, Boston, MA; and the University of Connecticut, Hartford, CT

Corresponding author: Wyndham H. Wilson, MD, PhD, Metabolism Branch, National Cancer Institute, Building 10, Room 4N/115, 9000 Rockville Pike, Bethesda, MD 20892; e-mail: wilsonw{at}mail.nih.gov

	ABSTRACT

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Purpose To assess the clinical outcome and the influence of biomarkers associated with apoptosis inhibition (Bcl-2), tumor proliferation (MIB-1), and cellular differentiation on the outcome with dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab (R) infusional therapy in diffuse large B-cell lymphoma (DLBCL) with analysis of germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry.

Patients and Methods Phase II study of 72 patients with untreated de novo DLBCL who were at least 18 years of age and stage II or higher. Radiation consolidation was not permitted.

Results Patients had a median age of 50 years (range, 19 to 85) and 40% had a high-intermediate or high International Prognostic Index (IPI). At 5 years, progression-free survival (PFS) and overall survival (OS) were 79% and 80%, respectively, with a median potential follow-up of 54 months. PFS was 91%, 90%, 67%, and 47%, and OS was 100%, 90%, 74%, and 37%, for 0 to 1, 2, 3, and 4 to 5 IPI factors, respectively, at 5 years. The Bcl-2 and MIB-1 biomarkers were not associated with PFS or OS. Based on DA-EPOCH historical controls, rituximab only benefited Bcl-2 positive tumors. Bcl-6 expression was associated with higher PFS whereas GCB exhibited a marginally significant higher PFS compared with post-GCB DLBCL.

Conclusion DA-EPOCH-R outcome was not affected by tumor proliferation and rituximab appeared to overcome the adverse effect of Bcl-2. Bcl-6 may identify a biologic program associated with a superior outcome. Overall, DA-EPOCH-R shows promising outcome in low and intermediate IPI groups. A molecular model of treatment outcome with rituximab and chemotherapy is presented.

	INTRODUCTION

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Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the chemotherapy standard for diffuse large B-cell lymphoma (DLBCL) despite modifications over the past 30 years aimed at overcoming drug resistance.¹ The basis for these strategies drew from classical concepts which held that noncrossresistant drugs and dose intensity would overcome drug resistance.² Evidence today indicates that treatment failure is related to tumor biology, and also to tumor volume, patient condition, and pharmacokinetics.²

To help address these barriers, we hypothesized that continuous drug exposure may modulate the effects of the cell cycle and apoptosis on treatment response. In this regard, studies have suggested that tumor proliferation is an adverse prognostic factor with bolus regimens such as CHOP and possibly rituximab plus CHOP (R-CHOP), while in vitro studies suggest that extended drug exposure may enhance cell kill.^3-5 This concept formed the basis for dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) where doxorubicin, vincristine and etoposide are infused over 96 hours.⁶ Because the efficacy of infusional schedules are constrained by sub-threshold steady-state concentrations (C_ss), below which a drug is ineffective, we incorporated pharmacodynamic dosing based on the neutrophil nadir. A phase II study of DA-EPOCH with filgrastim in 50 patients with untreated de novo DLBCL revealed promising results.⁶

The addition of rituximab to CHOP significantly improved the outcome of DLBCL and R-CHOP became the new standard.⁷ Several studies, however, suggest the benefit of rituximab varies by tumor pathobiology.^8-10 Two studies found rituximab benefit was primarily in Bcl-2 positive DLBCL, while another study only showed benefit in Bcl-6–negative DLBCL.^8,9 These biomarkers likely relate to the new molecular taxonomy of DLBCL in which three groups, based on cell of origin, have been defined by gene profiling: the germinal center B-cell (GCB) type, derived from germinal center B-cells; the activated B-cell (ABC) and unspecified (previously type III) types, derived from post-GCB cells; and the primary mediastinal B-cell (PMBL) type, derived from thymic B cells.^11-13 These groups also have significant differences in clinical features and outcome.^11-13 Such findings indicate that DLBCL contains several disease entities which likely have therapeutic implications. To more accurately assess the outcome of rituximab with DA-EPOCH and the role of tumor biology in DLBCL, we present clinical and biomarker results from untreated patients with GCB and post-GCB DLBCL.

	PATIENTS AND METHODS

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Study Design, Patients, and Staging
This was a phase II study of DA-EPOCH-R in untreated de novo GCB and post-GCB DLBCL from the National Cancer Institute (Bethesda, MD), Massachusetts General Hospital, (Boston, MA) and Michael & Dianne Bienes Comprehensive Cancer Center, Holy Cross Hospital (Fort Lauderdale, FL). The primary objectives were to assess the complete response (CR), survival end points, and toxicity of DA-EPOCH-R in CD20-positive DLBCL, and to assess if Bcl-2 remained a prognostic factor for progression-free survival (PFS) as was shown with DA-EPOCH alone.⁶ With 33 patients each classified as Bcl-2 positive (estimated target) and Bcl-2 negative, this study would have 79% power to detect a difference between Kaplan-Meier curves according to Bcl-2-positive or -negative expression with 50% and 80% PFS at 2 years using a one-tailed .05 level log-rank test. The actual number of patients enrolled reflects the number of patients with assessable Bcl-2 immunohistochemistry and the actual ratio of Bcl-2–positive and –negative patients. Based on an informal analysis after enrollment of 35 Bcl-2–positive and 24 Bcl-2–negative patients clearly showing no difference in PFS, further enrollment for this biomarker was terminated. The analysis was restricted to patients with GCB and post-GCB DLBCL, and excluded PMBL due to its distinct pathobiology and infrequent expression of Bcl-2.^6,11,13 A secondary study objective included analysis of the impact of MIB-1 on clinical outcome. Overall, 108 patients were enrolled. Eleven patients (11%) were excluded due to transformed lymphoma in five, discordant lymphoma in two, discordant CD20 expression in one, and nonprotocol treatment in three patients. To identify the GCB and post-GCB DLBCL in the 97 eligible/assessable patients, we excluded the 25 patients with PMBL and report our results in the remaining 72 patients.

All pathology was reviewed (by E.S.J. or S.P.). Eligibility included stages II to IV, no indolent lymphoma, HIV negative, negative pregnancy test, and adequate major organ function.⁶ The study complied with the Declaration of Helsinki and all patients gave written informed consent. Initial evaluation included standard blood tests, whole body computed tomography, and bone marrow biopsy. Standard staging and response criteria were employed.^14,15 Sites of disease were restaged after cycle 4 and every two cycles thereafter.

Chemotherapy and Dose Adjustments
DA-EPOCH-R was administered as previously described.⁶ Patients received two cycles beyond CR or stable changes for a minimum of six and a maximum of eight cycles. Pharmacodynamic dose adjustment was based on twice weekly CBCs to achieve limited neutropenia lower than 500/µL.⁶ Patients with or at risk of CNS disease received intrathecal chemotherapy.⁶ Radiation was not permitted on study. Sulfamethoxazole/trimethoprim double strength was administered twice daily for 3 days per week.

Biomarkers
Immunohistochemistry was performed on paraffin-embedded tissue as previously reported.³ Sections were stained with monoclonal antibodies to CD20 (clone L26), CD3 (F7.2.38 clone), Bcl-6 (clone PG-B6p), MUM-1 (clone MUM1p), MIB-1 (clone MIB-1) from Dako (Carpinteria, CA), and CD10 (clone 56C6) from Novocastra (Burlingame, CA). Immunohistochemistry was performed at the National Cancer Institute. For Bcl-2, the staining intensity was compared with the control T cells present in the tumor samples and scored as no tumor cell staining or positive tumor cell staining relative to the T-cells as described. MIB-1 staining was scored as a mean percentile of 200 tumor cells averaged over three high power fields. For Bcl-6 and MUM-1, patients were scored as positive if expressed in at least 20% of neoplastic cells. Classification of tumor biopsies into GCB or non-GCB (ie, post-GCB) subtypes was determined using CD10, Bcl-6, and MUM-1 immunohistochemical markers by the validated method of Hans et al.¹⁶

Statistical Analysis
Survival end points were calculated from on-study date until death, relapse, progression, or last follow-up as appropriate. OS, PFS, and event-free survival (EFS) were calculated using the Kaplan-Meier method and the significance between Kaplan-Meier curves was calculated using the Mantel-Haenszel procedure.^17,18 Potential follow-up was calculated from study entry to study analysis for each patient. The Cox proportional hazards model was used to identify which factors were jointly significant in the association with OS or PFS.¹⁹ Only factors associated with marginal statistical significance or better in a univariate analysis (unadjusted P < .10) were evaluated in a Cox model. All P values are two tailed. The analysis of biomarkers was not adjusted for multiple comparisons. MIB-1 and Bcl-2 were prespecified based on hypotheses from the DA-EPOCH study in which these biomarkers were not adjusted, whereas analysis of GCB/post-GCB and Bcl-6 were for hypothesis generation and thus would not require adjusment.⁶

	RESULTS

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Clinical Characteristics and Outcome
Seventy-two patients with GCB or post-GCB large cell lymphoma were enrolled (Table 1). The patients’ median age was 50 years (range, 19 to 85) and 40% had a high-intermediate or high International Prognostic Index (IPI).²⁰ Pathological diagnosis included DLBCL in 70 patients and follicular grade 3B in two patients.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Survival and progression-free survival (PFS) of all patients. Outcomes are reported at 5 years. (A) PFS was 79% (95% CI, 68 to 87). (B) Overall survival (OS) was 80% (95% CI, 69 to 88). (C) PFS for low, low-intermediate, high-intermediate, and high-risk International Prognostic Index (IPI) was 91% (95% CI, 72 to 98), 90% (95% CI, 71 to 97), 67% (95% CI, 42 to 85), and 47% (95% CI, 21 to 75), respectively (P = .007 for global comparison). (D) OS for low, low-intermediate, high-intermediate, and high-risk IPI 100%, 90% (95% CI, 70 to 97), 74% (95% CI, 50 to 90) and 37% (95% CI, 16 to 64), respectively (P < .0001 for global comparison). inter., intermediate.

Biologic Prognostic Factors
Tumor tissue was analyzed by immunohistochemistry for biomarkers of proliferation (MIB-1), apoptosis inhibition (Bcl-2), and cellular differentiation (CD10, Bcl-6, and Mum-1; Table 2).^2,3,16 As a control group for the effect of rituximab on Bcl-2 PFS, we employed our prior DA-EPOCH study which had identical eligibility and treatment as this study but did include PMBL; their exclusion did not significantly alter the outcome (Fig 2B). Clinical risk factors were similar in patients with biomarkers and the entire population (Table 1).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Progression-free survival (PFS) of patients with biomarkers. Outcomes are reported at 5 years. (A) PFS for MIB-1 < 80% and 80% in dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab (R). (B) PFS for Bcl-2–negative and –positive patients after DA-EPOCH (PFS at 5 years, Bcl-2 negative, 82%, 95% CI, 59 to 94 v positive, 50%, 95% CI, 25 to 75; P = .03). Exclusion of primary mediastinal B-cell (PMBL) patients from this historical cohort did not significantly alter the balance of International Prognostic Index (IPI) factors or PFS at 5 years (Bcl-2 negative, 91%; 95% CI, 62 to 98 v positive, 57%, 95% CI, 25 to 84; P = .039). (C) PFS for Bcl-2 negative and Bcl-2 positive, for DA-EPOCH-R. (D) PFS for germinal center B-cell (GCB) versus post-GCB for DA-EPOCH-R. (E) PFS for Bcl-6 negative and Bcl-6 positive, respectively, for DA-EPOCH-R.

We examined the outcome of GCB and post-GCB DLBCL with DA-EPOCH-R. Post-GCB tended to be associated with a worse PFS compared with GCB DLBCL (Table 2; Fig 2D).¹⁶ We also examined Bcl-6, a germinal center associated transcription factor. Bcl-6 expression was significantly associated with a higher PFS and OS compared with negative cases (Table 2; Fig 2E). There were insufficient cases with Bcl-6 staining in our prior DA-EPOCH study to provide a historical control.

The prognostic significance of the biomarkers and clinical factors were evaluated in a Cox model. For PFS, the final model included IPI (P = .006; HR, 8.98; 95% CI, 1.90 to 42) and Bcl-6 nonexpression (P = .066; HR, 3.46; 95% CI, 0.91 to 13.1), and for OS, the final model included performance status (P = .0007; HR, 11.89; 95% CI, 2.83 to 49.4) and Bcl-6 nonexpression (P = .0005; HR, 12.94; 95% CI, 3.09 to 54.1).

Treatment Dose and Toxicity
Most patients required dose escalations to achieve absolute neutrophil count (ANC) nadirs below 500 with 47% of cycles 144% (level 3) above the entry level (Table 3). Treatment was delayed on 2% of cycles. Toxicity was assessed in 72 patients over 414 cycles. ANC nadirs between 100 and 499/µL occurred on 38% of cycles and ANC lower than 100/µL on 24% of cycles. Thrombocytopenia below 25,000/µL occurred on 9% of cycles. Hospitalization for fever with neutropenia was observed on 19% of cycles. Grade 3 gastrointestinal and neurological toxicities occurred on 5% of cycles each. No cardiac complications occurred. Three deaths occurred on treatment. One patient died from Aspergillus fumigatus infection; one patient died from a subdural hematoma after anticoagulation for a pulmonary embolus; and one patient died at home with presumed sepsis.

	DISCUSSION

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To evaluate the effect of rituximab, we explored differences in outcome between our DA-EPOCH and DA-EPOCH-R studies.⁶ All benefit occurred in the patients with low IPI where the PFS of DA-EPOCH and DA-EPOCH-R was 79% and 91%, respectively, at 5 years.⁶ In contrast, patients with high IPI had a similar PFS of 58% and 60%, respectively. Our findings of greatest benefit in patients with low IPI, similar to other studies, are consistent with the fractional cell kill hypothesis, which postulates that chemotherapy kills a fraction of tumor cells based on their relative sensitivity.^2,22-24 Thus, the likelihood of eradicating all tumor cells would be stochastically determined by the fractional cell kill and tumor volume given a fixed number of cycles. Because the relative impact of increased tumor sensitivity on cure, as might be conferred by rituximab, would be greatest in smaller volume tumors, low-risk patients who generally have less disease should benefit most.

While these results suggest DA-EPOCH-R may represent a therapeutic advance, it is difficult to find equivalent R-CHOP studies for reference. A study of R-CHOP by Vose et al²⁵ included follicular or marginal zone lymphomas and at least 46% harbored t(14;18). A study of dose-dense R-CHOP had limited 20-month median follow-up, and two relatively large reports of R-CHOP were retrospective.^26-28 Of three prospective, randomized, phase III studies of CHOP versus R-CHOP, the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and US intergroup randomized studies were restricted to elderly patients.^23,29 The phase III MabThera International Trial appears to be the best reference, but was limited to favorable patients 60 years, low (0 to 1) age-adjusted IPI, allowed stage I disease more than 5 cm, and 49% of patients received radiotherapy.³⁰ At 4 years, the estimated EFS was 75% for the MInT study compared with 91% and 90% at 5 years for DA-EPOCH-R in patients with low and low-intermediate IPI, respectively. The lower survival of our patients with high IPI was in part due to four deaths without progression, and a recent study showed good outcomes with DA-EPOCH-R in high-risk patients.³¹

Biomarkers were analyzed to help understand the biologic basis of treatment outcome. Tumor proliferation was not associated with outcome, affirming our hypothesis that infusional schedules may avert the adverse effect of high proliferation, a finding we also observed with DA-EPOCH.^5,6 We also did not find Bcl-2 expression to be prognostic with DA-EPOCH-R, unlike our results with DA-EPOCH. Interestingly, when we compare our two studies, only patients with Bcl-2–positive DLBCL benefited from rituximab, similar to an analysis of Bcl-2 in the GELA study, and suggests biologic specificity for rituximab benefit.^8,9,32 While Bcl-2 is overexpressed in some GCB DLBCL due to t(14;18), expression is highest in ABC DLBCL (a post-GCB subset) due to nuclear factor B (NFB) or amplification and carries a poor prognosis.^6,13,33 These observations suggest Bcl-2 may be a biomarker for a post-GCB DLBCL subset and if so, rituximab might overcome its poor prognosis.^6,32,33 In support of this hypothesis is a retrospective study by Nyman et al²⁸ where they showed that the addition of rituximab to CHOP overcame the unfavorable outcome of non-GCB (ie, post-GCB) DLBCL but did not benefit GCB DLBCL. Thus, with R-CHOP, GCB and post-GCB DLBCL showed similar outcomes with an EFS of 68% and 63%, respectively, at 27 months.

Our biomarker analysis suggests GCB may be more favorable than post-GCB DLBCL with DA-EPOCH-R. To help further address this, we assessed Bcl-6 which is overexpressed in most GCB but only a minority of post-GCB DLBCL.³⁴ We undertook this analysis based on the US intergroup study R-CHOP versus CHOP which showed that rituximab significantly improved the EFS (64% v 9%, respectively) of Bcl-6–negative but not Bcl-6–positive DLBCL at 3 years (40% and 54%, respectively).¹⁰ Recently, this group also analyzed p21, which is negatively regulated by Bcl-6, and showed that only p21–positive DLBCL benefited from the addition of rituximab.^35,36 Taken together, these and other studies provide additional evidence that R-CHOP compared with CHOP mostly benefits post-GCB and obviates the prognostic difference among these biomarkers.³⁷ In our study, however, Bcl-6–positive DLBCL fared significantly better than Bcl-6–negative tumors. The excellent outcome of DA-EPOCH-R in Bcl-6–positive or GCB DLBCL, where rituximab appears to have a less important role, suggests it may be superior to R-CHOP in this biologic group.^10,28 When interpreting the meaning of biomarkers, however, it is important to recognize the limitations of immunohistochemistry. Indeed, a recent study concluded that while semiquantitative immunohistochemistry of biomarkers in DLBCL is feasible, their interpretation may be significantly affected by methodology and inter-reader reproducibility.³⁸

These findings raise an hypothesis on the biology of rituximab and chemotherapy treatment outcome (Fig 3). On a molecular level, gene expression signatures of ABC (post-GCB) DLBCL and tumor proliferation are associated with unfavorable survival after CHOP.¹³ Biologically, this may be related to the constitutive activation of NF-B and its antiapoptotic target genes, including Bcl-2 and A1.^13,39 While GCB DLBCL has a better prognosis, many patients are not cured which may relate to the effect of Bcl-6 on cell growth and survival.^35,40 Mechanistically, the negative regulation by Bcl-6 of cell-cycle arrest genes, p21 and p27Kip1, and DNA damage response genes, p53 and ATR, restrain the apoptotic stress response and promote proliferation, both of which are associated with treatment failure.^3,41,42 Thus, we propose that outcome of post-GCB DLBCL is primarily constrained by high antiapoptotic protein levels, whereas GCB DLBCL is constrained by the DNA damage response and high tumor proliferation. Indeed, in some lymphoma cell lines, in vitro treatment with rituximab decreases activated NFB and its target genes, PRDM1β (positive regulatory domain I) and Bcl-2.^8,32,43,44 In GCB DLBCL, however, the DNA damage response may be dependent on the chemotherapy regimen.^45,46 In vitro, the sustained exposure of tumor cells to topoisomerase II inhibition by etoposide and low-dose doxorubicin promote the p53-p21 pathway and activates the checkpoint kinase (Chk2) independently of ATR, and the cell cycle dependency of topoisomerase II may be advantaged by high proliferation.^45,46 Such studies indicate that prolonged exposure to topoisomerase II inhibition, as achieved in DA-EPOCH-R, may be particularly effective in Bcl-6–positive or GCB DLBCL. Indeed, it is interesting that DA-EPOCH-R is highly active in Burkitt's lymphoma, another germinal center lymphoma with myc activation and high proliferation.^47,48 Definitive evidence for superiority of DA-EPOCH-R over R-CHOP, however, requires a randomized study which is currently ongoing in the Cancer and Leukemia Group B cooperative group in conjunction with microarray analysis.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Model of drug resistance in germinal center B-cell (GCB) and post-GCB diffuse large B-cell lymphoma (DLBCL). In germinal center B-cells, Bcl-6 encodes a transcriptional repressor which negatively regulates the cell cycle inhibitors p21 and p27Kip1 and promotes proliferation. Bcl-6 also suppresses the p53 tumor suppressor gene and ATM, and modulates DNA damage-induced apoptosis. Constitutive activation of nuclear factor B (NF-B), a transcriptional regulator, in postgerminal center B-cells increases Bcl-2 and A1 and increases the apoptotic threshold. Clinical evidence that rituximab primarily benefits post-GCB DLBCL and inhibits NF-B in vitro suggests rituximab modulates post-GCB DLBCL drug resistance. In GCB DLBCL, topoisomerase inhibitors can differentially activate DNA damage checkpoints and may be selectively important. Theoretical relative cytotoxic responses (high to low: light to dark shading) of rituximab, and cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted (DA) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with and without rituximab (R) along the continuum from germinal center to postgerminal center DLBCL are shown. Rituximab benefit is primarily in post-GCB DLBCL where it modulates drug resistance and equalizes differences among chemotherapy regimens. In GCB DLBCL, DA-EPOCH-R may show an advantage in part due to extended delivery of topoisomerase II agents.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Wyndham H. Wilson, Stefania Pittaluga, Seth M. Steinberg, Bruce A. Chabner

Administrative support: Wyndham H. Wilson

Provision of study materials or patients: Wyndham H. Wilson, Kieron Dunleavy, Upendra Hegde, Mark Raffeld, Martin Gutierrez, Elaine S. Jaffe, John E. Janik

Collection and assembly of data: Wyndham H. Wilson, Kieron Dunleavy, Nicole Grant, Louis Staudt

Data analysis and interpretation: Wyndham H. Wilson, Stefania Pittaluga, Nicole Grant, Seth M. Steinberg, Mark Raffeld, Louis Staudt, Elaine S. Jaffe, John E. Janik

Manuscript writing: Wyndham H. Wilson

Final approval of manuscript: Wyndham H. Wilson, Kieron Dunleavy, Stefania Pittaluga, Upendra Hegde, Nicole Grant, Seth M. Steinberg, Mark Raffeld, Martin Gutierrez, Bruce A. Chabner, Louis Staudt, Elaine S. Jaffe, John E. Janik

	NOTES

 
published online ahead of print at www.jco.org on March 31, 2008.

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

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Submitted June 21, 2007; accepted February 13, 2008.

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