CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma
Bertrand Coiffier, M.D., Eric Lepage, M.D., Ph.D., Josette Brière, M.D., Raoul Herbrecht, M.D., Hervé Tilly, M.D., Reda Bouabdallah, M.D., Pierre Morel, M.D., Eric Van Den Neste, M.D., Gilles Salles, M.D., Ph.D., Philippe Gaulard, M.D., Felix Reyes, M.D., Pierre Lederlin, Pierre Lederlin, Ph.D., and Christian Gisselbrecht, M.D.
Background The standard treatment for patients with diffuselarge-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine,and prednisone (CHOP). Rituximab, a chimeric monoclonal antibodyagainst the CD20 B-cell antigen, has therapeutic activity indiffuse large-B-cell lymphoma. We conducted a randomized trialto compare CHOP chemotherapy plus rituximab with CHOP alonein elderly patients with diffuse large-B-cell lymphoma.
Methods Previously untreated patients with diffuse large-B-celllymphoma, 60 to 80 years old, were randomly assigned to receiveeither eight cycles of CHOP every three weeks (197 patients)or eight cycles of CHOP plus rituximab given on day 1 of eachcycle (202 patients).
Results The rate of complete response was significantly higherin the group that received CHOP plus rituximab than in the groupthat received CHOP alone (76 percent vs. 63 percent, P=0.005).With a median follow-up of two years, event-free and overallsurvival times were significantly higher in the CHOP-plus-rituximabgroup (P<0.001 and P=0.007, respectively). The addition ofrituximab to standard CHOP chemotherapy significantly reducedthe risk of treatment failure and death (risk ratios, 0.58 [95percent confidence interval, 0.44 to 0.77] and 0.64 [0.45 to0.89], respectively). Clinically relevant toxicity was not significantlygreater with CHOP plus rituximab.
Conclusions The addition of rituximab to the CHOP regimen increasesthe complete-response rate and prolongs event-free and overallsurvival in elderly patients with diffuse large-B-cell lymphoma,without a clinically significant increase in toxicity.
The most frequent type of non-Hodgkin's lymphoma, diffuse large-B-celllymphoma, accounts for approximately 40 percent of new casesof lymphoma.1 More than half of patients with diffuse large-B-celllymphoma are over 60 years of age,2,3,4 and the treatment ofthese elderly patients is a difficult challenge. The CHOP regimen(cyclophosphamide, doxorubicin, vincristine, and prednisone)is the standard of care for younger and elderly patients withdiffuse large-B-cell lymphoma,5 but it induces complete responsesin only 40 to 50 percent of elderly patients, with three-yearevent-free and overall survival rates of 30 percent and 35 to40 percent, respectively.6 Attempts to increase the efficacyof CHOP by adding other cytotoxic drugs have not succeeded,probably because these additional drugs cannot be administeredunless the doses of cyclophosphamide and doxorubicin are reducedbelow those given in the CHOP regimen.5,7 Intensified chemotherapyregimens may improve the outcome in young patients with a poorprognosis,8 but they are not well tolerated by elderly patients.Indeed, CHOP itself may be too toxic for elderly patients.9,10More easily tolerated regimens have been designed for elderlypatients, but although they cause fewer side effects, they areless effective and no more beneficial than CHOP.6,11
Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, iseffective when given as a single agent in the treatment of relapsedor refractory indolent lymphomas and has activity in relapsedor refractory diffuse large-B-cell lymphoma.12,13,14,15 CD20is a cell-surface protein that occurs almost exclusively onmature B cells. The chimeric antibody is a human IgG1 in whichthe CD20-binding region was derived by genetic engineering froma mouse monoclonal antibody. On the basis of phase 2 studiesin which rituximab in combination with CHOP had a good safetyprofile and induced responses in over 90 percent of patientswith indolent or aggressive lymphoma,16,17 the Groupe d'Etudedes Lymphomes de l'Adulte (GELA) undertook a study to compareCHOP plus rituximab with CHOP alone in elderly patients withdiffuse large-B-cell lymphoma.
Methods
Patients
Patients were eligible if they were 60 to 80 years of age andhad untreated diffuse large-B-cell lymphoma that had been diagnosedaccording to the Revised EuropeanAmerican Lymphoma classification18or the World Health Organization classification.19 Patientswere required to have stage II, III, or IV disease and a performancestatus of 0 to 2 (good to fair) according to the criteria ofthe Eastern Clinical Oncology Group. Patients were not eligibleif they had T-cell lymphoma, a history of indolent lymphoma,central nervous system involvement, active cancer, or any seriousactive concomitant disease or if, in the opinion of the investigator,their general status did not permit the administration of eightcourses of CHOP. Patients were also excluded if they had a cardiaccontraindication to doxorubicin therapy (e.g., abnormal contractilityon echocardiography) or a neurologic contraindication to vincristine(e.g., peripheral neuropathy). Finally, patients with a positiveserologic test for the human immunodeficiency virus or unresolvedhepatitis B virus infection were also excluded.
This study complied with all provisions of the Declaration ofHelsinki and its current amendments and was conducted in accordancewith Good Clinical Practice guidelines.20 All patients gavewritten informed consent. The protocol and informed-consentforms were approved by the local and national institutionalreview boards in each participating center and country. Studyoversight was provided by an independent data and safety monitoringcommittee. The study investigators are listed in the Appendix.
Randomization
Eligible patients were randomly assigned by the study coordinatingcenter to treatment with CHOP or CHOP plus rituximab. They werestratified according to center and age-adjusted InternationalPrognostic Index scores (0 or 1 vs. 2 or 3, with a higher scoreindicating a higher risk of death), which are based on diseasestage, performance status, and the lactate dehydrogenase level.2A panel of at least three hematopathologists conducted a centralpathology review, without knowledge of the patients' outcome,to confirm the diagnosis of CD20-positive diffuse large-B-celllymphoma.
Treatment
Patients treated with CHOP received the combination of 750 mgof cyclophosphamide per square meter of body-surface area onday 1; 50 mg of doxorubicin per square meter on day 1; 1.4 mgof vincristine per square meter, up to a maximal dose of 2 mg,on day 1; and 40 mg of prednisone per square meter per day forfive days. They were treated every three weeks for eight cyclesof CHOP. Patients treated with CHOP plus rituximab also receivedrituximab, at a dose of 375 mg per square meter, on day 1 ofeach of the eight cycles of CHOP. The rituximab infusion wasinterrupted in the event of fever, chills, edema, congestionof the head and neck mucosa, hypotension, or any other seriousadverse event and was resumed when such an event was no longeroccurring. No radiation therapy was scheduled or recommendedat the end of treatment.
Patients who had grade 4 (severe) neutropenia or febrile neutropeniaafter any cycle of chemotherapy were given granulocyte colony-stimulatingfactor. If grade 4 neutropenia persisted during the next cycle,the doses of cyclophosphamide and doxorubicin were decreasedby 50 percent. For patients with grade 3 (moderate) or 4 thrombocytopenia,the doses of cyclophosphamide and doxorubicin were decreasedby 50 percent. If the neutrophil count was lower than 1500 percubic millimeter or the platelet count was lower than 100,000per cubic millimeter before a scheduled cycle, the cycle wasdelayed for up to two weeks, and then treatment was stopped.The doses of rituximab were not modified, but rituximab wasdiscontinued when CHOP was stopped. Treatment was stopped iflymphoma progressed or the patient declined to continue or atthe discretion of the investigator in cases of intercurrentillness or adverse events.
Response to Treatment and Adverse Events
Tumor responses were assessed after eight cycles of chemotherapyor at the end of treatment and were classified as complete response,unconfirmed complete response, partial response, stable disease,or progressive disease according to the International Workshopcriteria.21 Complete response was defined as the disappearanceof all lesions and of radiologic or biologic abnormalities observedat diagnosis and the absence of new lesions. An unconfirmedcomplete response was defined as a complete response with thepersistence of some radiologic abnormalities, which had to haveregressed in size by at least 75 percent. Partial response wasdefined as the regression of all measurable lesions by morethan 50 percent, the disappearance of nonmeasurable lesions,and the absence of new lesions. Stable disease was defined asa regression of any measurable lesion by 50 percent or lessor no change for the nonmeasurable lesions, but without growthof existing lesions or the appearance of new lesions. Progressivedisease was defined as the appearance of a new lesion, any growthof the initial lesion by more than 25 percent, or growth ofany measurable lesion that had regressed during treatment bymore than 50 percent from its smallest dimensions.
All adverse events reported by the patient or observed by theinvestigator were collected from the case-report form in predefinedcategories. An adverse event was defined as any adverse changefrom the patient's base-line condition, whether it was consideredrelated to treatment or not. Each event was graded accordingto the National Cancer Institute Common Toxicity Criteria gradingsystem.22 All grade 3 and 4 events plus grade 2 infection wererecorded in detail. Grade 1 and 2 adverse events were not extensivelydescribed.
Statistical Analysis
The sample size was calculated on the basis of the primary endpoint of event-free survival, and the number of patients requiredwas based on the assumption of an exponential distribution ofevents. On the basis of the results of previous studies withCHOP in elderly patients, a conservative three-year event-freesurvival of 30 percent was assumed for the CHOP regimen.23,24To detect a change from 30 percent to 45 percent with the additionof rituximab, we calculated that 400 patients, recruited overthree years and followed for a minimum of one year, would berequired to provide the study with 80 percent power at an overall5 percent significance level (two-sided, with an alpha levelof 0.05). A single interim analysis of the primary efficacyoutcome was planned; it included the 328 patients who underwentrandomization before January 1, 2000.25
Event-free and overall survival was analyzed by the log-ranktest, and the results were expressed as KaplanMeier plots.A multivariate Cox regression analysis was performed to assessthe effect of pretreatment prognostic factors (specifically,age, sex, number of extranodal sites, presence or absence ofbone marrow involvement, beta2-microglobulin level, serum albuminlevel, presence or absence of bulky disease, B symptoms [weightloss, fever, and night sweats]), and age-adjusted InternationalPrognostic Index scores) on event-free and overall survival.Estimates of the treatment effect, after adjustment for theseprognostic factors, are expressed as risk ratios for event-freeand overall survival (CHOP plus rituximab as compared with CHOP),with 95 percent confidence intervals. Analyses of efficacy andsafety included all randomized patients and followed the intention-to-treatprinciple. All P values are two-tailed. Statistical analyseswere performed with SAS software (SAS Institute, Cary, N.C.)by the investigators at the GELA statistical office, withoutrestrictions or outside control by the sponsor. The investigatorshad complete access to all study data.
Results
This study was conducted at 86 centers in France, Belgium, andSwitzerland. A total of 399 patients were enrolled between July1998 and March 2000, and 398 patients (202 in the CHOP-plus-rituximabgroup and 196 in the CHOP group) received at least one doseof protocol-specified treatment (1 patient was enrolled butdied before treatment was administered).
Base-Line Characteristics
The median age of the patients was 69 years. There was no significantdifference between the two groups in any clinical or pathologicalcharacteristic (Table 1). Prognosis was poor, which is consistentwith the prognosis in elderly patients with aggressive lymphoma.Central pathological review was completed for 97 percent ofpatients; the results confirmed a diagnosis of diffuse large-B-celllymphoma in 90 percent of those who could be assessed in theCHOP-plus-rituximab group and 85 percent in the CHOP group.
The eight scheduled courses of chemotherapy were given to 72percent of patients treated with CHOP and 80 percent of patientstreated with CHOP plus rituximab. This difference was due tothe number of patients who withdrew from the CHOP group becauseof disease progression: 23, as compared with 7 of those treatedwith CHOP plus rituximab. In each treatment cycle, more than90 percent of the patients received at least 90 percent of theplanned doses of doxorubicin and cyclophosphamide, with no significantdifference between treatment groups in dose intensity for eitherdrug in any cycle. In the CHOP-plus-rituximab group, more than95 percent of the patients received the planned dose of rituximab.
Efficacy
With a median follow-up of 24 months, 86 events (progression,relapse, or death) were observed in the CHOP-plus-rituximabgroup and 120 in the CHOP group (in 43 percent and 61 percentof patients, respectively) (Table 2 and Figure 1). Event-freesurvival was significantly longer for patients treated withCHOP plus rituximab than for those treated with CHOP alone (P<0.001).According to the Cox analysis, the regimen of CHOP plus rituximabreduced the risk of events by 42 percent, as compared with therisk with CHOP alone (Table 2). The difference in event-freesurvival between the treatment groups was attributable to thehigher number of patients in the CHOP group who had diseaseprogression during treatment or with relapse. There was a significantbenefit of CHOP plus rituximab over CHOP alone, both among patientswith relatively low risk disease, indicated by a score of 0or 1 on the International Prognostic Index (P<0.001), andthose with high-risk disease, indicated by a score of 2 or 3on the International Prognostic Index (P<0.03). Patientsyounger than 70 years and those 70 years or older, as well asthe patients with diffuse large-B-cell lymphoma, had the samebenefit from the combination of CHOP plus rituximab (data notshown).
Figure 1. Event-free Survival among 399 Patients Assigned to Chemotherapy with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) or with CHOP plus Rituximab.
A complete response or unconfirmed complete response was achievedin 76 percent of the patients treated with CHOP plus rituximab,as compared with 63 percent of those treated with CHOP alone(P=0.005) (Table 3). Disease progression during treatment wasreported for 22 percent of patients in the CHOP group and 9percent in the CHOP-plus-rituximab group. Prolongation of disease-freesurvival (complete remission) and progression-free survivalin the CHOP-plus-rituximab group was of the same magnitude asthe prolongation of event-free survival (data not shown). Survivalwas significantly longer for patients treated with CHOP plusrituximab than for those treated with CHOP alone (P=0.007):at two years, 70 percent of patients treated with CHOP plusrituximab were alive, as compared with 57 percent of those treatedwith CHOP alone (Table 2 and Figure 2).
Figure 2. Overall Survival among 399 Patients Assigned to Chemotherapy with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) or with CHOP plus Rituximab.
Base-line prognostic factors were analyzed by multivariate Coxregression analysis. A high concentration (more than 3 mg perliter) of beta2-microglobulin was identified as a negative prognosticfactor in terms of both event-free and overall survival (riskratio, 1.58 [95 percent confidence interval, 1.14 to 2.21] fordeath, disease progression, or another event and 1.82 [1.22to 2.72] for death from any cause, respectively). The presenceof more than one extranodal site of disease was another significantnegative prognostic factor in terms of overall survival (riskratio for death from any cause, 1.46). After adjustment forthese prognostic factors, the risk ratio associated with treatmentwith CHOP plus rituximab, as compared with CHOP alone, was 0.55(95 percent confidence interval, 0.41 to 0.75) for death, diseaseprogression, or another event and 0.53 (0.37 to 0.77) for deathfrom any cause, as compared with the unadjusted values of 0.58(0.44 to 0.77) and 0.64 (0.45 to 0.89), respectively.
Adverse Effects
Table 4 presents all reported adverse events in each group.The grade 3 and 4 adverse events were consistent with the expectedtoxic effects of CHOP chemotherapy and occurred with similarfrequency in both groups. Infection was one of the most frequentgrade 3 or 4 adverse events in both groups. The difference inthe incidence of cardiac events during treatment (47 percentfor CHOP plus rituximab, as compared with 35 percent for CHOP)(Table 4) was due to a higher incidence of grade 1 events inthe CHOP-plus-rituximab group than in the CHOP group (24 percentvs. 13 percent). This difference was consistent with the mild-to-moderateinfusion-related events described in phase 2 studies of rituximab.12,13,14,26The incidence of grade 3 or 4 cardiac toxicity was the samein both groups (8 percent), with more reports of supraventriculararrhythmias and tachycardias in the CHOP-plus-rituximab group.Grade 3 or 4 cardiac failure or left ventricular dysfunctionoccurred in 18 patients in the CHOP-plus-rituximab group and19 patients in the CHOP group.
Table 4. Nonhematologic Adverse Events Observed in Patients Treated with CHOP plus Rituximab or CHOP Alone.
Grade 3 or 4 adverse events related to the infusion of rituximabwere observed in 19 patients in the CHOP-plus-rituximab group(9 percent); the most frequent of these were respiratory symptoms(with or without bronchospasm), chills, fever, and hypotension.In all cases, the symptoms disappeared after the infusion wasslowed or stopped, and no patient died as a result of such anadverse event. All patients were able to receive further cyclesof CHOP plus rituximab without recurrence of grade 3 or 4 infusion-relatedreactions.
Thirty-four patients (13 in the CHOP group and 21 in the CHOP-plus-rituximabgroup) died from causes not attributable to lymphoma; 23 diedduring the treatment period from infection (16 patients), cachexia(4 patients), or cardiovascular events (3 patients), withoutany significant difference between the groups. The remaining11 patients (2 in the CHOP group and 9 in the CHOP-plus-rituximabgroup) died from infection (4 patients), cachexia (2 patients),cardiac disease (2 patients), suicide (1), another type of cancer(1), or gastrointestinal hemorrhage (1) while in a completeremission after completing therapy.
The median nadir of the neutrophil count after each cycle ofchemotherapy was similar in both groups. After the first cycle,neutrophil counts fell to 400 per cubic millimeter in both groups.Thereafter, the median was slightly higher in the CHOP groupthan in the CHOP-plus-rituximab group. Neutropenia was not associatedwith an increase in episodes of infection during treatment,as shown in Table 4. The percentages of patients who requiredtreatment with granulocyte colony-stimulating factor increasedto a similar degree in each treatment group, to 37 percent forthe fourth cycle and 43 percent for the eighth cycle. Therewere a few more cases of herpes zoster after treatment in patientsreceiving CHOP plus rituximab than in those receiving CHOP (ninevs. two, P=0.40). During treatment, 19 percent of patients receivingCHOP and 14 percent of those receiving CHOP plus rituximab hadgrade 3 or 4 anemia. The median nadir platelet counts remainedabove 130,000 per cubic millimeter in both treatment groupsfor all eight cycles.
Discussion
This randomized trial compared the efficacy and safety of rituximabin combination with CHOP chemotherapy with that of CHOP chemotherapyalone in elderly patients with diffuse large-B-cell lymphoma.We found higher response rates and improved event-free and overallsurvival among patients treated with the combination of rituximaband CHOP. The longer survival in the CHOP-plus-rituximab groupwas due to a lower rate of disease progression during therapyand fewer relapses among patients who had a complete response.Treatment with CHOP plus rituximab was well tolerated, and theincidence of severe or serious adverse events was no differentfrom that in the CHOP group.
The event-free survival among elderly patients with diffuselarge-B-cell lymphoma was only 12 to 18 months in previous randomizedstudies of chemotherapy.6,9,24 We chose CHOP for use in thisstudy because it is as effective as, and less toxic than, other,more recently developed chemotherapeutic regimens5,27,28; itis also considered to be standard therapy for elderly patientswith diffuse large-B-cell lymphoma.6,11,29 The results withCHOP alone in our trial were similar to those previously reportedin elderly patients.6,9,10,11,23,29 For this reason, we believethat the better results with CHOP plus rituximab are not attributableto an unusually poor outcome among patients in the CHOP group.
In a study comparing a regimen of doxorubicin, cyclophosphamide,vindesine, bleomycin, and prednisone (ACVB) with CHOP in elderlypatients, we found that ACVB was associated with longer event-freesurvival because patients who received ACVB had a lower incidenceof relapses.23 However, the rate of death due to toxic effectsof the therapy was higher with ACVB than with CHOP, particularlyin patients over 65 years of age, and for this reason, treatmentwith ACVB was not associated with prolonged survival.
In conclusion, the addition of rituximab to CHOP chemotherapy,given for eight cycles to elderly patients with newly diagnoseddiffuse large-B-cell lymphoma, significantly increases the rateof complete response, decreases the rates of treatment failureand relapse, and improves event-free and overall survival ascompared with standard CHOP alone. These gains were achievedwithout a significant increase in clinically significant toxiceffects.
Supported by grants from HoffmannLaRoche.
Drs. Coiffier, Salles, Reyes, and Gisselbrecht have served asconsultants to Roche, Genentech, or IDEC, the manufacturersof rituximab; have been members of speakers' bureaus sponsoredby Roche, Genentech, or IDEC; or have done both for Roche, Genentech,or IDEC, as well as for other companies involved in the manufactureof antilymphoma drugs or other monoclonal antibodies.
Source Information
From the Hospices Civils de Lyon and the Université Claude Bernard, Lyons (B.C., G.S.); Hôpital Henri-Mondor, Paris (E.L., P.G., F.R.); Assistance PubliqueHôpitaux de Paris, Hôpital Saint-Louis, Paris (J.B., C.G.); Hôpital de Hautepierre, Strasbourg (R.H.); the Centre Becquerel, Rouen (H.T.); the Institut Paoli-Calmette, Marseilles (R.B.); and the Centre Hospitalier de Lens (P.M.) all in France; and the Université Catholique de Louvain, Brussels, Belgium (E.N.). Pierre Lederlin, Ph.D., Centre Hospitalier Universitaire de Brabois, Nancy, France, was also an author.
Address reprint requests to Dr. Coiffier at the Service d'Hématologie, Centre Hospitalier Lyon-Sud, 69495 Pierre Bénite CEDEX, France, or at bertrand.coiffier{at}chu-lyon.fr.
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Appendix
The following persons and institutions participated in thisGELA study: External advisory committee E. Montserrat(chairman, Spain), M. Björkholm (Sweden), M. Buyse (Belgium),F. Cavalli (Switzerland), and M. Pfreundschuh (Germany); Pathologicalreview committee J. Brière, P. Gaulard, J. Bosq,J.F. Emile, B. Fabiani, and T. Petrella; Statistics E. Lepage and N. Nio; Pharmacist I. Madelaine; GELAclincial research R. Chvetzoff; study centers (all inFrance, unless otherwise specified) Centre HospitalierLyon-Sud, Pierre-Bénite B. Coiffier and G. Salles;Hôpital de Hautepierre, Strasbourg R. Herbrecht;Centre Becquerel, Rouen H. Tilly; Centre Jean Bernard,Le Mans P. Solal-Celigny; Institut Paoli Calmette, Marseilles R. Bouabdallah; Centre Hospitalier Universitaire deBrabois, Nancy P. Lederlin; Centre Léon Bérard,Lyons C. Sebban; Institut Gustave Roussy, Villejuif J.N. Munck and C. Fermé; Centre Hospitalier deLens, Lens P. Morel; Hôpital Henri Mondor, Creteil F. Reyes and C. Haioun; Centre Hospitalier de Chambéry,Chambéry M. Blanc; Hôpital Bon Secours,Metz B. Christian; Centre Hospitalier Universitairede Lille, Lille B. Quesnel; Academisch Ziekenhuis Sint-Jan,Bruges, Belgium A. van Hoof; Hôpital Saint-Louis,Paris C. Gisselbrecht; Hôpital Purpan, Toulouse M. Attal; Centre Hospitalier Universitaire Dupuytren,Limoges D. Bordessoule; Hôpital Jean Bernard,Poitiers V. Delwail; Université Catholique deLouvain, Ivoir, Belgium A. Bosly; Centre HospitalierUniversitaire Clemenceau, Caen M. Macro; Centre FrançoisMagendie, Pessac G. Marit; Hôpital PitiéSalpétrière, Paris J. Gabarre; HôpitalAndré Mignot, Le Chesnay S. Castaigne; CentreHospitalier Universitaire de Nîmes, Nîmes E. Jourdan; Centre Hospitalier de la Durance, Avignon E. Lepeu; Hôpital Pasteur, Colmar B. Audhuy; CentreAntoine Lacassagne, Nice A. Thyss; Clinique Pasteur,Evreux N. Albin; Centre Médical Foch, Suresnes E. Baumelou; Hôtel Dieu, Paris A. Delmer;Centre Hospitalier de Brive, Brive S. Lefort; CentreHospitalier de Bourg en Bresse, Bourg en Bresse H. Orfeuvre;Hôpital V. Prouvo, Roubaix I. Plantier; HôpitalBicêtre, Le Kremlin-Bicêtre G. Tertian;Hôpital Necker, Paris B. Varet; HôpitalBeclere, Clamart F. Boué; Centre HospitalierUniversitaire de Dijon, Dijon O. Casasnovas and D. Caillot;Université Catholique de Louvain, Brussels, Belgium E. Van Den Neste; Institut Curie, Paris D. Decaudin;Centre Hospitalier Universitaire Saint-LouisLariboisière,Paris P. Brice, H. Dombret, J.P. Fermand, and J.M. Zini;Centre Hospitalier Universitaire de Liège, Liège,Belgium G. Fillet; Fondation Drevon, Dijon M.Flesch; Centre Hospitalier R. Dubos, Pontoise Y. Kerneis;Centre Hospitalier d'Annecy, Annecy C. Martin; Hôpitalde Valence, Valence P.Y. Péaud; Centre Hospitalierde Blois, Blois P. Rodon; Centre Hospitalier Saint-Vincent,Lille C. Rose; Hôtel Dieu, Clermont-Ferrand P. Travade; Clinique Saint-Jean, Lyons B. Velay; Hôpitalde Bayonne, Bayonne F. Bauduer; Centre Hospitalier deLibourne, Libourne K. Bouabdallah; Hôpital EmileMuller, Mulhouse J.C. Eisenmann; Hôpital MarcJacquet, Melun C. Kulekci; Centre Hospitalier Bois del'Abbaye, Seraing, Belgium S. Lampertz; HôpitalInter Armées Percy, Clamart G. Nedellec; CentreFrançois Baclesse, Caen A.M. Peny; Centre HospitalierVictor Dupouy, Argenteuil V. Pulik; Hôpital deChalon, Chalon B. Salles; Centre Hospitalier de Perpignan,Perpignan X. Vallantin; Centre Hospitalier Robert Ballanger,Aulnay sous Bois P. Agranat; Centre Hospitalier Universitairede Nice, Nice J.P. Cassuto; Centre Hospitalier Hutois,Huy, Belgium J. Collignon; Centre Hospitalier de laCitadelle, Liège, Belgium B. de Prijck; HôpitalJolimont, Haine Saint Paul, Belgium A. Delannoy; CentreHospitalier Gilles de Corbeil, Corbeil Essonnes A. Devidas;Hôpital La Fontonne, Antibes J.F. Dor; HôpitalCochin, Paris F. Dreyfus; Clinique Saint Jean, Brussels,Belgium C. Dubois; Clinique de Chaumont, Chaumont G. Dupont; Centre Val d'Aurelle, Montpellier M. Fabbro;Hôpital J. Monod, Le Havre C. Fruchart; Cliniqueles Fougères, Dieppe J.P. Gaillard; Centre HospitalierUniversitaire de Rennes, Rennes B. Grosbois; CentreRené Huguenin, Saint-Cloud M. Janvier; CentreHospitalier Universitaire Vaudois, Lausanne, Switzerland N. Ketterer; Centre Hospitalier du Val de Sambre, Sambreville,Belgium C. Leroy; Clinique Saint Pierre, Ottignies,Belgium M. Maerevoet; Hôpital des Canaux, Macon F. Marechal; Hôpital Saint Joseph, Gilly, Belgium P. Mineur; Hôpital Saint Joseph, Arlon, Belgium P. Pierre; Centre Hospitalier Universitaire Nord, Marseilles G. Sebahoun; Centre Hospitalier de Meaux, Meaux C. Soussain; and Hôpital Nord, Amiens C. Traulle.
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Ponzoni, M., Ferreri, A. J.M., Campo, E., Facchetti, F., Mazzucchelli, L., Yoshino, T., Murase, T., Pileri, S. A., Doglioni, C., Zucca, E., Cavalli, F., Nakamura, S.
(2007). Definition, Diagnosis, and Management of Intravascular Large B-Cell Lymphoma: Proposals and Perspectives From an International Consensus Meeting. JCO
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Armitage, J. O.
(2007). How I treat patients with diffuse large B-cell lymphoma. Blood
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Morschhauser, F., Illidge, T., Huglo, D., Martinelli, G., Paganelli, G., Zinzani, P. L., Rule, S., Liberati, A. M., Milpied, N., Hess, G., Stein, H., Kalmus, J., Marcus, R.
(2007). Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood
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Herrmann, K., Wieder, H. A., Buck, A. K., Schoffel, M., Krause, B.-J., Fend, F., Schuster, T., Meyer zum Buschenfelde, C., Wester, H.-J., Duyster, J., Peschel, C., Schwaiger, M., Dechow, T.
(2007). Early Response Assessment Using 3'-Deoxy-3'-[18F]Fluorothymidine-Positron Emission Tomography in High-Grade Non-Hodgkin's Lymphoma. Clin. Cancer Res.
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Bjorkholm, M, Hagberg, H, Holte, H, Kvaloy, S, Teerenhovi, L, Anderson, H, Cavallin-Stahl, E, Myhre, J, Pertovaara, H, Ost, A, Nilsson, B, Osby, E
(2007). Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up. Ann Oncol
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Nyman, H., Adde, M., Karjalainen-Lindsberg, M.-L., Taskinen, M., Berglund, M., Amini, R.-M., Blomqvist, C., Enblad, G., Leppa, S.
(2007). Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood
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Zhang, M., Yao, Z., Patel, H., Garmestani, K., Zhang, Z., Talanov, V. S., Plascjak, P. S., Goldman, C. K., Janik, J. E., Brechbiel, M. W., Waldmann, T. A.
(2007). Effective therapy of murine models of human leukemia and lymphoma with radiolabeled anti-CD30 antibody, HeFi-1. Proc. Natl. Acad. Sci. USA
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Cittera, E., Leidi, M., Buracchi, C., Pasqualini, F., Sozzani, S., Vecchi, A., Waterfield, J. D., Introna, M., Golay, J.
(2007). The CCL3 Family of Chemokines and Innate Immunity Cooperate In Vivo in the Eradication of an Established Lymphoma Xenograft by Rituximab. J. Immunol.
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Sehn, L. H., Donaldson, J., Filewich, A., Fitzgerald, C., Gill, K. K., Runzer, N., Searle, B., Souliere, S., Spinelli, J. J., Sutherland, J., Connors, J. M.
(2007). Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood
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Thieblemont, C., Coiffier, B.
(2007). Lymphoma in Older Patients. JCO
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(2007). Management and Preparedness for Infusion and Hypersensitivity Reactions. The Oncologist
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Hess, P. R., Barnes, C., Woolard, M. D., Johnson, M. D. L., Cullen, J. M., Collins, E. J., Frelinger, J. A.
(2007). Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin. Blood
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Gopal, A. K., Rajendran, J. G., Gooley, T. A., Pagel, J. M., Fisher, D. R., Petersdorf, S. H., Maloney, D. G., Eary, J. F., Appelbaum, F. R., Press, O. W.
(2007). High-Dose [131I]Tositumomab (anti-CD20) Radioimmunotherapy and Autologous Hematopoietic Stem-Cell Transplantation for Adults >= 60 Years Old With Relapsed or Refractory B-Cell Lymphoma. JCO
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Rubenstein, J. L., Fridlyand, J., Abrey, L., Shen, A., Karch, J., Wang, E., Issa, S., Damon, L., Prados, M., McDermott, M., O'Brien, J., Haqq, C., Shuman, M.
(2007). Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma. JCO
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Wohrer, S, Troch, M, Zwerina, J, Schett, G, Skrabs, C, Gaiger, A, Jaeger, U, Zielinski, C., Raderer, M
(2007). Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serologic parameters and clinical course in lymphoma patients with autoimmune diseases. Ann Oncol
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Strobel, K, Schaefer, N., Renner, C, Veit-Haibach, P, Husarik, D, Koma, A., Hany, T.
(2007). Cost-effective therapy remission assessment in lymphoma patients using 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography: is an end of treatment exam necessary in all patients?. Ann Oncol
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Mohammad, R. M., Goustin, A. S., Aboukameel, A., Chen, B., Banerjee, S., Wang, G., Nikolovska-Coleska, Z., Wang, S., Al-Katib, A.
(2007). Preclinical Studies of TW-37, a New Nonpeptidic Small-Molecule Inhibitor of Bcl-2, in Diffuse Large Cell Lymphoma Xenograft Model Reveal Drug Action on Both Bcl-2 and Mcl-1. Clin. Cancer Res.
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Verdonck, L. F., Notenboom, A., de Jong, D. D., MacKenzie, M. A., Verhoef, G. E. G., Kramer, M. H. H., Ossenkoppele, G. J., Doorduijn, J. K., Sonneveld, P., van Imhoff, G. W.
(2007). Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood
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Cairo, M. S., Gerrard, M., Sposto, R., Auperin, A., Pinkerton, C. R., Michon, J., Weston, C., Perkins, S. L., Raphael, M., McCarthy, K., Patte, C., on behalf of the FAB LMB96 International Study Com,
(2007). Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood
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Bonnet, C., Fillet, G., Mounier, N., Ganem, G., Molina, T. J., Thieblemont, C., Ferme, C., Quesnel, B., Martin, C., Gisselbrecht, C., Tilly, H., Reyes, F.
(2007). CHOP Alone Compared With CHOP Plus Radiotherapy for Localized Aggressive Lymphoma in Elderly Patients: A Study by the Groupe d'Etude des Lymphomes de l'Adulte. JCO
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Ng, A. K., Mauch, P. M.
(2007). Role of Radiation Therapy in Localized Aggressive Lymphoma. JCO
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Chiu, G. N.C., Edwards, L. A., Kapanen, A. I., Malinen, M. M., Dragowska, W. H., Warburton, C., Chikh, G. G., Fang, K. Y.Y., Tan, S., Sy, J., Tucker, C., Waterhouse, D. N., Klasa, R., Bally, M. B.
(2007). Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs. Molecular Cancer Therapeutics
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Sehn, L. H., Berry, B., Chhanabhai, M., Fitzgerald, C., Gill, K., Hoskins, P., Klasa, R., Savage, K. J., Shenkier, T., Sutherland, J., Gascoyne, R. D., Connors, J. M.
(2007). The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood
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Stel, A. J., ten Cate, B., Jacobs, S., Kok, J. W., Spierings, D. C. J., Dondorff, M., Helfrich, W., Kluin-Nelemans, H. C., de Leij, L. F. M. H., Withoff, S., Kroesen, B. J.
(2007). Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis. J. Immunol.
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Egyed, M., Kollar, B., Prievara, F.T., Viski, A., Bajzik, G., Pajor, L., Torday, L.
(2007). Successful treatment of a primary uterine B-cell lymphoma with rituximab-CHOP immunochemotherapy. haematol
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Nitta, E, Izutsu, K, Sato, T, Ota, Y, Takeuchi, K, Kamijo, A, Takahashi, K, Oshima, K, Kanda, Y, Chiba, S, Motokura, T, Kurokawa, M
(2007). A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study. Ann Oncol
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Arnold, D. M., Dentali, F., Crowther, M. A., Meyer, R. M., Cook, R. J., Sigouin, C., Fraser, G. A., Lim, W., Kelton, J. G.
(2007). Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura. ANN INTERN MED
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Sperr, W. R., Lechner, K., Pabinger, I.
(2007). Rituximab for the treatment of acquired antibodies to factor VIII. haematol
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Kolstad, A., Holte, H., Fossa, A., Lauritzsen, G. F., Gaustad, P., Torfoss, D.
(2007). Pneumocystis jirovecii pneumonia in B-cell lymphoma patients treated with the rituximab-CHOEP-14 regimen. haematol
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Ramadan, K., Shenkier, T, Sehn, L., Gascoyne, R., Connors, J.
(2007). A clinicopathological retrospective study of 131 patients with primary bone lymphoma: a population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann Oncol
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Bello, C., Sotomayor, E. M.
(2007). Monoclonal Antibodies for B-Cell Lymphomas: Rituximab and Beyond. ASH Education Book
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