Originally published as JCO Early Release 10.1200/JCO.2003.08.054 on September 8 2003

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Syngeneic Hematopoietic Stem-Cell Transplantation for Non-Hodgkin’s Lymphoma: A Comparison With Allogeneic and Autologous Transplantation—The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation

From the University of Nebraska Medical Center, Omaha, NE; University of Colorado Health Sciences Center, Denver, CO; International Bone Marrow Transplant Registry, Milwaukee, WI; University College Hospital, London, United Kingdom; Ireland Cancer Center, Cleveland, OH; Christian Albrechts University, Kiel, Germany; and University of Chicago, Chicago, IL.

Address reprint requests to Philip J. Bierman, MD, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680; e-mail: pjbierma{at}unmc.edu.

	ABSTRACT

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Purpose: To compare results of syngeneic, allogeneic, and autologous hematopoietic stem-cell transplantation for non-Hodgkin’s lymphoma (NHL).

Patients and Methods: The databases of the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation were used to identify 89 NHL patients who received syngeneic transplants. These patients were compared with NHL patients identified from the IBMTR and the Autologous Blood and Marrow Transplant Registry who received allogeneic (T-cell depleted and T-cell replete) and autologous (purged and unpurged) transplants.

Results: No significant differences in relapse rates were observed when results of allogeneic transplantation were compared with syngeneic transplantation for any histology. T-cell depletion of allografts was not associated with a higher relapse risk, but was associated with improved overall survival for patients with low-grade and intermediate-grade histology. Patients who received unpurged autografts for low-grade NHL had a five-fold (P = .008) greater risk of relapse than recipients of syngeneic transplants, and recipients of unpurged autografts had a two-fold (P = .0009) greater relapse risk than patients who received purged autografts. Among low-grade NHL patients, the use of purging was associated with significantly better disease-free survival (P = .003) and overall survival (P = .04) when compared with patients who received unpurged autografts.

Conclusion: These analyses failed to find evidence of a graft-versus-lymphoma effect, but do provide indirect evidence to support the hypothesis that tumor contamination may contribute to lymphoma relapse, and that purging may be beneficial for patients undergoing autologous hematopoietic stem-cell transplantation for low-grade NHL.

	INTRODUCTION

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SEVERAL STUDIES have shown lower relapse rates after allogeneic transplantation for non-Hodgkin’s lymphoma (NHL) when compared with autologous transplantation. These results could be explained by lack of tumor contamination, or by selection bias favoring patients with better prognostic characteristics. However, many investigators have hypothesized that a graft-versus-lymphoma effect is the most likely explanation for this finding.

High-dose therapy followed by autologous hematopoietic stem-cell transplantation has become accepted therapy for certain NHL patients. However, autologous transplantation is associated with the potential risk of reinfusing malignant cells. This has led to trials involving removal of contaminating cells from the autograft. Several of these methods of manipulation (purging) can eliminate significant numbers of tumor cells from the graft. There is indirect evidence for a clinical benefit from purging, although benefits have not been conclusively demonstrated.

Comparisons of syngeneic and allogeneic bone marrow transplantation for leukemia support the existence of a graft-versus-leukemia effect. We reasoned that a comparison of syngeneic and allogeneic NHL transplants could also provide insights into whether a similar graft-versus-lymphoma effect exists. We also reasoned that a syngeneic transplant is representative of an uncontaminated autograft, and consequently, a comparison of syngeneic and autologous transplants could provide indirect evidence regarding the potential contribution of tumor contamination to relapse after autologous transplantation for NHL. This study was undertaken to compare relapse rates after syngeneic, autologous, and allogeneic hematopoietic stem-cell transplantation for NHL.

	PATIENTS AND METHODS

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Data Sources
The International Bone Marrow Transplant Registry (IBMTR) comprises more than 400 transplantation centers that contribute data on allogeneic and syngeneic hematopoietic stem-cell transplantations to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin. The Autologous Blood and Marrow Transplant Registry (ABMTR) comprises more than 250 transplant centers that report data on autotransplantations to the same institution. Approximately 40% of allogeneic transplantations worldwide and more than 50% of autologous transplantations in North and South America are registered with the IBMTR/ABMTR.^1,2 Consecutive transplantations are reported and compliance is monitored with on-site audits.

The European Group for Blood and Marrow Transplantation (EBMT) comprises 436 transplantation centers in Europe and associated members from non-European countries. Data are checked by the Statistical Office of the EBMT at the University College of London Hospitals and at random site visits. The registry accrues data on transplantations from participating centers, and requests basic patient and clinical information and annual follow-up on all patients. Additional data are requested if patients are included in a study. Institutions were contacted on three occasions to obtain data for this study before the variable was coded as missing or unknown.

Patients
This study included NHL patients who received high-dose therapy followed by syngeneic, autologous, or HLA-matched sibling allogeneic transplants between 1985 and 1998, and were reported to the IBMTR, ABMTR, or EBMT. Syngeneic transplants reported to the IBMTR and EBMT were checked for overlap. These patients were then compared with autologous and allogeneic transplant recipients from the IBMTR/ABMTR. Nonmyeloablative allogeneic transplants were excluded.

Lymphoma classification evolved during the study period and specific histologic criteria were applied to ensure comparability of diagnoses. Only patients with a descriptive histologic classification conforming to the Working Formulation were included.³ Entities such as mantle-cell lymphoma and marginal zone lymphoma that are only recognized in the Revised European-American Lymphoma or WHO classification systems were excluded.^4,5 Follicular large-cell lymphoma and large-cell immunoblastic lymphoma were classified as intermediate grade.

End Points
The primary end point was relapse, defined as persistent or recurrent NHL in patients surviving at least 28 days after transplantation. Patients were also analyzed for disease-free survival and overall survival. Disease-free survival was defined as survival without evidence of NHL. Patients with persistent disease were classified as experiencing relapse at day 28, even if they did not subsequently progress. Overall survival was defined as the interval between transplantation and death from any cause. Surviving patients were censored at the date of last contact.

Statistical Analysis
Patient-, disease-, and transplantation-related variables for cohorts were compared using the ² statistic for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate probabilities of disease-free and overall survival were calculated using the Kaplan-Meier estimator.⁶ The log-rank test was used for univariate comparisons of survival curves.⁷ Probabilities of relapse and transplantation-related mortality were calculated using cumulative incidence curves to accommodate competing risks.⁸ Transplantation-related mortality, defined as death during continuous remission or death in the first 28 days after transplantation, was used as a competing risk factor for estimation of relapse. Ninety-five percent CIs for all probabilities and P values of pairwise comparisons were derived from pointwise estimates and calculated using standard techniques.⁹

Cox proportional hazards models were constructed for each histologic subtype. The primary covariate analyzed was graft type (syngeneic, allogeneic T-cell depleted, allogeneic T-cell replete, autologous purged, and autologous unpurged). The following factors were also analyzed in the multivariate analyses for their association with relapse and their potential confounding effect on the associations between relapse and type of transplantation. The first set of categories were patient-related factors at the time of transplantation: age (< 40 v 40 years) and sex. The second set of categories were disease-related factors at diagnosis: histology (low grade v intermediate grade v high grade). The third set of categories were disease-related factors at the time of transplantation: disease sensitivity (chemotherapy sensitive v resistant v unknown or untested), presence of bone marrow involvement at diagnosis or transplantation, and disease status (first remission v never in remission v second remission v first relapse v second relapse v unknown). The fourth set of categories were transplantation-related factors: year of transplantation (1985 to 1989 v 1990 to 1995 v 1996 to 1998), conditioning regimen (containing total-body irradiation [TBI] v not containing TBI), graft source (blood v marrow), and use of hematopoietic growth factors within 7 days of transplantation. A separate category for missing data was created for each covariate included in the multivariate analysis whenever applicable.

Allogeneic transplants were analyzed for the effects of acute graft-versus-host disease (GVHD) and chronic GVHD entered as time-dependent covariates. We tested the proportional hazards assumption for each factor in the Cox model using time-dependent covariates.¹⁰ When this indicated differential effects over time (nonproportional hazards), models were constructed that broke the posttransplantation course into two periods using the maximized partial likelihood method to find the most appropriate breakpoint. After time-varying effects were modeled, the final multivariate model was built using a forward stepwise model selection approach. Each model contained the main effect (syngeneic [as the reference group], allogeneic T-cell depleted, allogeneic T-cell replete, autologous purged, or autologous unpurged transplant). The inclusion of the main effect allowed us to examine differences in the outcome risk by type of transplant while controlling for other significant covariates. Factors significantly associated with the outcome variable at the 5% level were kept in the final model. First-order interactions were examined between the type of transplant and all significant prognostic factors. Examination for center effects used a random effects or frailty model.¹¹ We found no evidence of correlation between transplantation center and any outcomes. All P values are two-sided.

	RESULTS

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Patient characteristics are presented in Table 1. Allogeneic transplant recipients were younger. All groups had a higher percentage of males. Allogeneic recipients were more likely to have high-grade histology and autologous transplant recipients were more likely to have intermediate-grade and low-grade histology. Allogeneic transplant recipients were also more likely to have a history of marrow involvement. The groups were similar with respect to systemic symptoms at diagnosis, stage at diagnosis, and disease status at transplantation. Allogeneic recipients were more likely to have untested or unknown sensitivity and were more likely to have received TBI conditioning. Bone marrow was used for most of the allogeneic transplants and purged autografts, whereas most unpurged autografts were performed with peripheral blood.

The median follow-up for syngeneic transplants, unpurged autologous transplants, purged autologous transplants, T-cell–replete allogeneic transplants, and T-cell–depleted allogeneic transplants was 44 months (range, 4 to 186 months), 36 months (range, < 1 to 125 months), 46 months (range, 3 to 128 months), 48 months (range, 2 to 174 months), and 60 months (range, 3 to 159 months), respectively. The interval between diagnosis and transplantation was not significantly different when syngeneic transplants were compared with other transplant types.

Relapse
The cumulative incidence of relapse for each type of transplant is displayed in Figure 1. Results of the multivariate analysis of factors independently associated with relapse risk are listed in Table 2.

View larger version (21K): [in this window] [in a new window]   Fig 1. Cumulative incidence of relapse after transplantation for all patients according to type of transplant. (A) Low-grade histology, (B) intermediate-grade histology, (C) high-grade histology.

No significant differences in relapse risk were identified when allogeneic transplants for intermediate-grade NHL were compared with syngeneic transplants. An increased risk of relapse was not associated with T-cell depletion. Patients who received unpurged autografts had a higher risk of relapse than did syngeneic transplant recipients, although this difference was not statistically significant (P = .08). Among patients with intermediate-grade NHL, there were no significant differences in relapse risk when results of unpurged and purged autologous transplants were compared (RR, 1.23; P = .12).

Among patients with high-grade histology, there were no significant differences in relapse risk when allogeneic, autologous, and syngeneic transplants were compared. There were no significant differences when T-cell–depleted and T-cell–replete allogeneic transplants were compared, and no significant differences between unpurged and purged autografts.

For allogeneic transplant recipients who survived at least 90 days, the relapse rate at 1 year was estimated to be 20% (95% CI, 14% to 26%) for patients who developed chronic GVHD, as compared with 17% (95% CI, 13% to 22%) for patients without chronic GVHD (P = .41). When time-dependent Cox regression was used, the RR of relapse for patients with chronic GVHD was 0.82 (95% CI, 0.52 to 1.28; P = .39) when compared with patients without chronic GVHD. There was no evidence of graft-versus-lymphoma effects associated with acute GVHD or chronic GVHD, and this was true for all grades of lymphoma.

Disease-Free Survival
The actuarial disease-free survival for each type of transplant is shown in Figure 2. Results of the multivariate analysis of factors independently associated with disease-free survival are listed in Table 3.

View larger version (22K): [in this window] [in a new window]   Fig 2. Actuarial probability of disease-free survival after transplantation for all patients according to type of transplant. (A) Low-grade histology, (B) intermediate-grade histology, (C) high-grade histology.

Patients with intermediate-grade NHL who received allogeneic transplants that were not T-cell depleted had significantly poorer disease-free survival than recipients of syngeneic transplants (RR, 1.85; P = .03). No significant differences in disease-free survival were observed when recipients of T-cell–replete and T-cell–depleted allogeneic transplants were compared (RR, 1.16; P = .61). No significant differences in disease-free survival were seen when results of autologous and syngeneic transplants were compared, or when purged and unpurged autologous transplants were compared (RR, 1.09; P = .46).

Among patients with high-grade histology, no significant differences in disease-free survival were noted when autologous or allogeneic transplants were compared with syngeneic transplants. No advantages were associated with T-cell depletion or purging.

Overall Survival
The actuarial survival for each type of transplant is shown in Figure 3. Results of the multivariate analysis of factors independently associated with survival are listed in Table 4.

View larger version (22K): [in this window] [in a new window]   Fig 3. Actuarial probability of overall survival after transplantation for all patients according to type of transplant. (A) Low-grade histology, (B) intermediate-grade histology, (C) high-grade histology.

Patients with intermediate-grade NHL who received allogeneic transplants that were not T-cell depleted had significantly poorer survival than syngeneic transplant recipients (RR, 2.19; P = .008). In addition, a comparison of T-cell–replete and T-cell–depleted allogeneic transplants showed poorer survival when T-cell depletion was not used (RR, 1.18; P = .03). No significant survival differences were observed when autologous and syngeneic transplants were compared, and no survival advantage was associated with purging.

There were no significant survival differences when autologous or allogeneic transplants were compared with syngeneic transplants. No survival advantages were associated with T-cell depletion or purging.

	DISCUSSION

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The first part of this study was designed to look for evidence of a graft-versus-lymphoma effect. Relapse rates after allogeneic hematopoietic stem-cell transplantation for NHL are lower than relapse rates after autologous transplantation.^12–17 However, survival advantages are not seen with allogeneic transplantation because of higher transplantation-related mortality. Lower relapse rates following allogeneic transplantation suggest that a graft-versus-lymphoma effect exists. However, these differences might also be explained by other factors such as lack of tumor contamination in the allograft.

We reasoned that comparing syngeneic transplantation with allogeneic transplantation would eliminate the confounding variable of tumor contamination and provide more definitive evidence for the existence of a graft-versus-lymphoma effect, in the same way that graft-versus-leukemia effects were demonstrated.¹⁸ Studies of syngeneic transplantations for NHL are limited. Investigators from Seattle compared autologous, allogeneic, and syngeneic bone marrow transplantations in 100 lymphoma patients.¹⁹ No significant differences in relapse rate or disease-free survival were identified, but only 13 syngeneic transplantations were studied and two of these patients had Hodgkin’s disease.

The multivariate analyses in our study failed to show a lower risk of relapse when allogeneic and syngeneic transplants were compared. Furthermore, there were no significant differences in relapse between T-cell–depleted and non–T-cell–depleted allografts, although T-cell depletion was associated with survival advantages in patients with low-grade and intermediate-grade histology. The analyses also failed to show a lower relapse rate in patients who developed GVHD.

Our failure to find evidence of a graft-versus-lymphoma effect must be examined in light of clinical evidence supporting this effect derived from comparisons of autologous and allogeneic transplants and the fact that graft-versus-lymphoma effects have been demonstrated in some animal models.²⁰ The existence of a graft-versus-lymphoma effect is also supported by reports of lymphoma regression when immunosuppression is withdrawn following relapse after allogeneic transplantation,^21–23 and by reports of response to donor leukocyte infusion.^24,25 Finally, lower rates of relapse or progression have been reported in patients who develop chronic GVHD after allogeneic transplantation for NHL.²⁶

Although this study does not provide evidence for a graft-versus-lymphoma effect, it is possible that this analysis lacked statistical power to show a difference in rates of relapse between allogeneic and syngeneic transplants. However, no trends in favor of this association were noted. A graft-versus-lymphoma effect might be obscured by an increased frequency of adverse prognostic factors, such as chemotherapy resistance, in recipients of allogeneic transplants, although adjustment for prognostic factors in the multivariate analyses did not alter the results. Our analysis is also hampered by missing data, which made it impossible to include certain variables in the multivariate analyses. However, statistical adjustments for missing data did not indicate that this accounted for the results. For known prognostic factors, such as performance status, we included a category for missing data in the models. This allowed us to make adjustments to the fullest extent of the data available to us and to ensure that no patient cases were discarded, as would be necessary in a matched-pair analysis. Moreover, even with a more complete database, the use of case-matching does not improve statistical power when compared with regression analysis using all available patients.^27,28 Although important variables such as history of marrow involvement, disease status, and chemotherapy sensitivity were included in the analyses, it is possible that allogeneic transplant recipients were more likely to have unidentified adverse prognostic features because this is not a randomized study.

Our results raise the hypothesis that lower relapse rates after allogeneic transplantation for NHL may be largely explained by other factors such as lack of tumor contamination of the autograft, and that graft-versus-lymphoma effects may not be as powerful as previously suspected. If true, an obvious implication is that the utility of nonmyeloablative allogeneic transplantations may need to be reconsidered.²⁹ However, it must also be noted that the 5-year cumulative incidence of relapse after syngeneic transplantation was only 9% for patients with low-grade histology. This result is similar to the relapse rate after allogeneic transplantation in this series, as well as other reports of allogeneic transplantation for low-grade NHL.^15,16,30 The similarly low rate of relapse after syngeneic and allogeneic transplantation suggests that long-term disease-free survival may be a result of the high-dose preparative regimen. This observation also suggests that graft-versus-lymphoma effects might be difficult to detect after high-dose therapy, and that effects could become more evident with less intensive conditioning regimens.

The second part of this study was a comparison of syngeneic and autologous hematopoietic stem-cell transplantation for NHL. Gene marking studies have shown that tumor contamination may contribute to relapse after autologous transplantation for acute myelogenous leukemia, chronic myelogenous leukemia, and neuroblastoma.^31–33 Although this has not been demonstrated for NHL, indirect evidence suggests that tumor contamination might also contribute to relapse.

The first evidence comes from reports of rapid disseminated relapse after autologous bone marrow transplantation for aggressive NHL.^34,35 Other evidence comes from studies showing lower relapse-free survival after autologous marrow transplantation in NHL patients whose marrow contains clonogenic tumor cells.³⁶ Additional evidence supporting the importance of tumor contamination comes from studies showing better survival in patients who received autografts that did not contain detectable tumor cells after purging.³⁷ Another analysis showed a lower incidence of relapse after autologous hematopoietic stem-cell transplantation for NHL when more aggressive purging was used.³⁸ Finally, a case-matching study comparing purged and unpurged autologous transplants showed that low-grade NHL patients who received purged autografts had significantly better survival.³⁹

We reasoned that a syngeneic transplant is similar to an uncontaminated autograft and a comparison would provide another way to indirectly study whether tumor contamination contributes to relapse. A previous comparison of syngeneic and autologous bone marrow transplantations found no significant differences in relapse or disease-free survival in lymphoma patients.¹⁹

The multivariate analyses in our study showed a five-fold greater risk of relapse when results of unpurged autologous transplantations were compared with syngeneic transplantations for low-grade NHL. In addition, recipients of unpurged autologous transplants had a significantly greater risk of relapse than those who received purged autografts. In low-grade NHL, purging was also associated with improved disease-free and overall survival. Among patients with intermediate-grade histology, those receiving unpurged autografts had a two-fold higher risk of relapse than did recipients of syngeneic transplants, although this difference was of borderline statistical significance, and was not associated with improved survival.

Only one trial has prospectively studied the value of purging autologous transplants for NHL.⁴⁰ A preliminary analysis showed no significant differences in disease progression or survival between purged and unpurged transplants. Other analyses also failed to show a benefit from purging.^39,41,42 Most relapses after autologous transplantation for NHL occur at sites of prior disease, suggesting that treatment failure most likely is due to inadequacy of high-dose therapy, rather than tumor contamination.

Nevertheless, our analyses provide additional indirect evidence that tumor contamination of the autograft may contribute to relapse after autologous hematopoietic stem-cell transplantation for low-grade, and possibly intermediate-grade, NHL. It is possible that a syngeneic graft-versus-lymphoma effect could explain these results.⁴³ However, it seems unlikely that this effect is important given the lack of evidence for an allogeneic graft-versus-lymphoma effect in our study, although a potent syngeneic graft-versus-lymphoma effect might make it impossible to identify an allogeneic graft-versus-lymphoma effect in this analysis. A syngeneic graft-versus-lymphoma effect could also explain the observed differences in relapse rate between syngeneic and autologous transplants.

In summary, this analysis failed to show evidence of a graft-versus-lymphoma effect. In contrast, this analysis provides additional evidence to suggest that tumor contamination can contribute to relapse after autologous hematopoietic stem-cell transplantation for low-grade, and possibly intermediate-grade, NHL. Although registry-based analyses are hindered by treatment heterogeneity and missing data, our results suggest the possibility that absence of tumor contamination accounts for some of the differences in relapse that have been attributed to a graft-versus-lymphoma effect when autologous and allogeneic transplants for NHL have been compared. Our results suggest that in vitro purging, positive selection,⁴⁴ or in vivo purging⁴⁵ may be beneficial, although randomized trials are the only way to prove the value of these approaches. In rare instances when a syngeneic donor is available, this may be the preferred type of transplant.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	APPENDIX

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Other authors of the Lymphoma Study Writing Committee from the International Bone Marrow Transplant Registry, Autologous Blood and Marrow Transplant Registry, and the European Group for Blood and Marrow Transplantation include the following: Karen K. Ballen (University of Massachusetts Medical Center, Worcester, MA); Asad Bashey (University of California San Diego Cancer Center, La Jolla, CA); Jacob D. Bitran (Lutheran General Cancer Care Center, Park Ridge, IL); Brian J. Bolwell (Cleveland Clinic, Cleveland, OH); Linda J. Burns (University of Minnesota Medical Center, Minneapolis, MN); Mitchell S. Cairo (Columbia University, New York, NY); Richard E. Champlin (M.D. Anderson Cancer Center, Houston, TX); Cesar O. Freytes (University of Texas Health Science Center, San Antonio, TX); Robert P. Gale (Center for Advanced Studies in Leukemia, Los Angeles, CA); Roger H. Herzig (Brown Cancer Center, Louisville, KY); John Lister (Western Pennsylvania Cancer Institute, Pittsburgh, PA); Rodrigo Martino (Hospital de Sant Pau, Barcelona, Spain); Alan M. Miller (Tulane University, New Orleans, LA); Gustavo Milone (Angelica Ocampo Hospital and Research Center, Buenos Aires, Argentina); Anne N. Parker (Glasgow Royal Infirmary, Glasgow, Scotland); David P. Schenkein (New England Medical Center, Boston, MA); Shimon Slavin (Hadassah University Hospital, Jerusalem, Israel); Mei-Jie Zhang (International Bone Marrow Transplant Registry, Milwaukee, WI).

	ACKNOWLEDGMENTS

 
Supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute, and Contract No. CP-21161 from the National Cancer Institute of the U.S. Department of Health and Human Services; Grant No. DAMD17-95-I-5002 from the Department of the U.S. Army Medical Research and Development Command; and grants from Abgenix Inc, AmCell Corp, American Cancer Society, American Society of Clinical Oncology, Amgen Inc, Anonymous, Aventis Pharmaceuticals, Berlex Laboratories, Blue Cross and Blue Shield Association, Lynde and Harry Bradley Foundation, Bristol-Myers Squibb Oncology, Center for Advanced Studies in Leukemia, Cerus Corp, Chimeric Therapies, Chiron Therapeutics, Eleanor Naylor Dana Charitable Trust, Deborah J. Dearholt Memorial Fund, Empire Blue Cross Blue Shield, Fujisawa Healthcare Inc, Gambro BCT Inc, Genentech Inc, GlaxoSmithKline Inc, Human Genome Sciences, ICN Pharmaceuticals Inc, IDEC Pharmaceuticals Corp, Immunex Corp, IntraBiotics Pharmaceuticals, Kettering Family Foundation, Kirin Brewery Co, Robert J. Kleberg Jr and Helen C. Kleberg Foundation, LifeTrac/Allianz, Liposome Co, Nada and Herbert P. Mahler Charities, Market Certitude LLC, Mayer Ventures, MedImmune Inc, Merck & Co Inc, Milliman & Robertson Inc, Milstein Family Foundation, Greater Milwaukee Foundation/Elsa Schoeneich Research Fund, NeoRx, Nexell Therapeutics, Novartis Pharmaceuticals, Orphan Medical, Ortho Biotech Inc, John Oster Family Foundation, Pfizer U.S. Pharmaceuticals, Pharmacia Corp, Principal Life Insurance Co, Response Oncology Inc, RGK Foundation, Roche Laboratories Inc, SangStat, Schering AG, Schering Oncology/Biotech, Stackner Family Foundation, The Starr Foundation, SuperGen Inc, TheraTechnologies Inc, Unicare Life & Health Insurance, and Wyeth/Genetics Institute.

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Submitted August 5, 2002; accepted April 30, 2003.

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