Background Although many patients with intermediate-grade orhigh-grade (aggressive) non-Hodgkin's lymphoma are cured bycombination chemotherapy, the remainder are not cured and ultimatelydie of their disease. The Ann Arbor classification, used todetermine the stage of this disease, does not consistently distinguishbetween patients with different long-term prognoses. This projectwas undertaken to develop a model for predicting outcome inpatients with aggressive non-Hodgkin's lymphoma on the basisof the patients' clinical characteristics before treatment.
Methods Adults with aggressive non-Hodgkin's lymphoma from 16institutions and cooperative groups in the United States, Europe,and Canada who were treated between 1982 and 1987 with combination-chemotherapyregimens containing doxorubicin were evaluated for clinicalfeatures predictive of overall survival and relapse-free survival.Features that remained independently significant in step-downregression analyses of survival were incorporated into modelsthat identified groups of patients of all ages and groups ofpatients no more than 60 years old with different risks of death.
Results In 2031 patients of all ages, our model, based on age,tumor stage, serum lactate dehydrogenase concentration, performancestatus, and number of extranodal disease sites, identified fourrisk groups with predicted five-year survival rates of 73 percent,51 percent, 43 percent, and 26 percent. In 1274 patients 60or younger, an age-adjusted model based on tumor stage, lactatedehydrogenase level, and performance status identified fourrisk groups with predicted five-year survival rates of 83 percent,69 percent, 46 percent, and 32 percent. In both models, theincreased risk of death was due to both a lower rate of completeresponses and a higher rate of relapse from complete response.These two indexes, called the international index and the age-adjustedinternational index, were significantly more accurate than theAnn Arbor classification in predicting long-term survival.
Conclusions The international index and the age-adjusted internationalindex should be used in the design of future therapeutic trialsin patients with aggressive non-Hodgkin's lymphoma and in theselection of appropriate therapeutic approaches for individualpatients.
Combination chemotherapy has transformed aggressive non-Hodgkin'slymphoma from a fatal disease into one that is often curable.However, many patients still die of their disease, underscoringthe need for more accurate methods of prospectively identifyingpatients with different long-term prognoses. The identificationof those at "high" or "low" risk could have important therapeuticimplications. Patients at high risk who are not effectivelytreated with current regimens may benefit from new experimentalapproaches, whereas those at low risk may do well with standardtherapy but sustain severe toxic reactions without additionalbenefit if they are treated with experimental regimens. Theidentification of different risk groups would also aid in thedesign and interpretation of therapeutic trials.
The tumor stage of patients with aggressive non-Hodgkin's lymphomais currently determined with the Ann Arbor classification, whichwas originally developed for Hodgkin's disease1. This classificationemphasizes the distribution of nodal disease sites because Hodgkin'sdisease commonly spreads through contiguous groups of lymphnodes1. Since the patterns of disease spread in Hodgkin's diseaseand non-Hodgkin's lymphoma are different, it is not surprisingthat the Ann Arbor classification system is less accurate inidentifying prognostic subgroups of patients with aggressivenon-Hodgkin's lymphoma2.
In previous analyses of relatively small numbers of patientswith this disease, a variety of clinical characteristics wereconsistently associated with outcome: the age at diagnosis,the presence or absence of systemic (B) symptoms, performancestatus, the serum lactate dehydrogenase (LDH) concentration,the number of nodal and extranodal sites of disease, tumor size,and the distinction between localized disease (Ann Arbor stageI or II) and advanced disease (stage III or IV)3,4,5,6,7,8,9,10,11,12,13.These features were thought to reflect the tumor's growth andinvasive potential (LDH level, tumor stage, tumor size, numberof nodal and extranodal sites of disease, and the presence orabsence of bone marrow involvement), the patient's responseto the tumor (performance status and status for B symptoms),and the patient's ability to tolerate intensive therapy (performancestatus, bone marrow involvement, and age). Many investigatorsidentified a subgroup of clinical features that remained independentlysignificant in multivariate analyses of their patients and usedthis subgroup to develop prognostic models that would predicta given patient's risk of death4,5,6,7,8,9,10,11,13. Althoughthe specific clinical features in these models differed, allmodels included the measurements of disease volume and extentof tumor involvement at presentation. To develop a better prognostic-factormodel for aggressive non-Hodgkin's lymphoma, 16 institutionsand cooperative groups in the United States, Europe, and Canadaparticipated in the project.
Methods
Characteristics of the Patients
Participating centers submitted data on each eligible patientincluded in electronic files.
Adult patients were eligible for this study if they had diffusemixed, diffuse large-cell, or large-cell immunoblastic lymphoma(International Working Formulation14 categories F, G, and H);diffuse centroblastic-centrocytic, centroblastic, immunoblastic,or unclassified high-grade lymphoma (Kiel classification15);or diffuse mixed lymphocytic-histiocytic or diffuse histiocyticlymphoma (Rappaport classification16). All the patients weretreated with a combination-chemotherapy regimen containing doxorubicinas part of a phase 2 or 3 study between 1982 and 1987. The inclusionof only patients who had completed therapy by 1987 ensured aminimum of 3 years of follow-up for all patients and a medianof 4 1/2 years of follow-up for surviving patients. The stagesof the tumors were determined and their pathologic characteristicswere reviewed according to guidelines at the participating institutions.
The clinical features evaluated for potential prognostic importancewere sex, age, tumor stage, performance status, B symptoms,sites of lymphomatous involvement, number of extranodal diseasesites, size of the largest tumor, and serum concentrations ofLDH, albumin, and beta2-microglobulin. The Ann Arbor stage ofthe tumor was designated as I, II non-bulky (largest tumor dimension,<10 cm), II bulky (largest dimension, 10 cm), III, or IV.Performance status was assessed according to the Eastern CooperativeOncology Group scale, in which 0 indicated that the patienthad no symptoms; 1, the patient had symptoms but was ambulatory;2, the patient was bedridden less than half the day; 3, thepatient was bedridden half the day or longer; and 4, the patientwas chronically bedridden and required assistance with the activitiesof daily living. Performance status was classified as 0 or 1(the patient was ambulatory) or 2, 3, or 4 (the patient wasnot ambulatory) (equivalent Karnofsky scores, 80 and 70).B symptoms were defined as recurrent fever (temperature, >38.3°C [101 °F]), night sweats, or the loss of more than10 percent of body weight. The recorded sites of extranodallymphomatous involvement included the bone marrow, gastrointestinaltract, liver, lung, central nervous system, and other sites;the numbers of extranodal disease sites were recorded as 0,1, or more than 1. Splenic involvement was also recorded. Thelargest dimension of the largest site of bulky disease was measuredand reported as being less than 10 cm or as 10 cm or more. Theserum LDH level was expressed as the ratio of the measured valueto the upper limit of the normal range reported in the laboratoryof each participating institution.
Assessment of Response
A complete response to treatment was defined by the participatinginstitutions as the disappearance of all clinical evidence ofdisease and the normalization of all laboratory values and radiographicresults that had been abnormal before treatment. The relapse-freesurvival of patients with complete responses was measured asthe interval between the end of treatment and relapse or deathor the date of the last follow-up evaluation in patients whohad no relapse. Survival was measured as the interval betweenthe beginning of treatment and death or the date of the lastfollow-up evaluation.
Statistical Analysis
The univariate associations between response and individualclinical features were analyzed with Fisher's exact test fortwo-by-k tables17. Relapse-free survival among patients withcomplete responses and overall survival among all patients wereestimated with the method of Kaplan and Meier18. The univariateassociations between individual clinical features and overallsurvival and relapse-free survival were determined with thelog-rank test19.
Since all centers had not originally gathered all the requestedinformation on their patients, data on several prognostic factorswere missing from the patients' files. No data on outcome weremissing. Missing data were dealt with by carrying out "completecase" analyses, in which patients were excluded from particularanalyses if their files did not contain data on the requiredvariables. This method did not bias analysis, since the availabilityof data at each center was determined by the data collectionat the time of treatment rather than by the eventual outcome.
Features independently associated with overall survival andrelapse-free survival were identified in multivariate analysesby proportional-hazards regression20. Step-down regression methodswere used to build parsimonious statistical models for the associationof prognostic factors with overall survival and relapse-freesurvival among patients with complete responses. Time-dependentdeath rates (hazard functions) were estimated according to thenonparametric kernel smoothing methods of Gray21.
Results
Univariate Analysis of Predictive Features
The presenting characteristics of the 3273 patients with tumorsin Ann Arbor stages I through IV who were included in the analysisare shown in Table 1. Of these patients, 66 percent had completeresponses. The five-year relapse-free survival rate among thepatients with complete responses was 59 percent, and the five-yearoverall survival among all patients was 52 percent (Table 2).The associations between the patients' characteristics and theresponse rate, relapse-free survival among those with completeresponses, and overall survival are shown in Table 2. Giventhe size of the study population, it is not surprising thatthe majority of the listed clinical characteristics were significantlyassociated with outcome.
Table 2. Outcome According to the Patients' Characteristics.
Independent Prognostic Factors and the Prognostic-Factor Model
Information on seven prognostic factors (age at diagnosis, performancestatus, serum LDH level, Ann Arbor stage, tumor size, numberof extranodal disease sites, and presence or absence of B symptoms)that had been associated with outcome in many previous studies3,4,5,6,7,8,9,10,11,12,13was complete for 1872 patients, of whom 1385 (74 percent) wererandomly selected as a training sample in which to identifyindependent prognostic factors to form a model. A training sampleof nearly 75 percent was chosen because it would be large enoughto detect a 20 percent increase in the relative risk of deathassociated with even a relatively rare characteristic.
The step-down regression analysis of overall survival in thetraining sample evaluated 12 variables: the 7 prognostic factorsmentioned above, 4 individual sites of extranodal disease (bonemarrow, liver, lung, and central nervous system), and the spleen.These 12 variables included all those in our data set exceptsex (which was not associated with survival), gastrointestinalinvolvement (which had a statistically significant but clinicallyunimportant association with survival [Table 2]), and serumbeta2-microglobulin and albumin levels (on which we had insufficientdata). In the regression analysis, age was coded as 60 yearsor less or more than 60 years because this dichotomy was mostcommonly used in previous analyses and because patients 60 oryounger were the most likely candidates for intensive experimentaltherapy. The Ann Arbor stage and the number of extranodal diseasesites were coded so that the individual categories and all naturaldichotomous groupings for each variable were included (e.g.,Ann Arbor stage I vs. II vs. III vs. IV; stage I vs. stagesII through IV; stage I or II non-bulky disease vs. stage IIbulky disease, stage III, or stage IV; and stage I or II vs.stage III or IV.) The most discriminating cutoff point for serumLDH was determined by applying classification and regressiontrees (which separate patients into homogeneous subgroups)22to martingale residuals (the differences between the numberof events observed and the number predicted by the model)23.The most predictive cutoff point for LDH was a level 1.2 timesnormal ( 1.2 times normal vs. >1.2 times normal) in bothunivariate and multivariate analyses; however, a level 1 timesnormal ( 1 vs. >1) was chosen as the cutoff point becauseit was almost as predictive as 1.2 times normal and easier touse.
The five pretreatment characteristics that remained independentlysignificant in the analysis of the training sample were age( 60 vs. >60 years), tumor stage (stage I or II [localizeddisease] vs. stage III or IV [advanced disease]), the numberof extranodal sites of disease ( 1 vs. >1), performance status(0 or 1 vs. 2), and serum LDH level ( 1 times normal vs. >1times normal) (Table 3). These five features were used to designa model to predict an individual patient's risk of death --the international index. Since the relative risks associatedwith each of the independently significant risk factors werecomparable (Table 3), the relative risk of death could be characterizedby summing the number of risk factors present at diagnosis.Risk groups were defined by comparing the relative risk of deathin patients with each possible number of presenting risk factors(0, 1, 2, 3, 4, or 5) and combining categories with similarrelative risks (e.g., 0 with 1 or 4 with 5). Patients were thenassigned to one of four risk groups on the basis of their numberof presenting risk factors: 0 or 1, low risk; 2, low intermediaterisk; 3, high intermediate risk; or 4 or 5, high risk. The survivalcurves and death rates over time for the four risk groups inthe training sample are shown in Figure 1. To provide a basisfor comparison, the survival curve and death rate for all 3273patients in the study are also included (Figure 1).
Figure 1. Survival According to Risk Group Defined by the International Index.
The left panels show Kaplan-Meier survival curves for the four risk groups (L denotes low risk, LI low intermediate risk, HI high intermediate risk, and H high risk). The right panels show death rates during the study period. Only 2031 of the 3273 patients had enough relevant information for classification according to the international index.
The prognostic-factor model was then applied to a validationsample of patients, which contained the remaining patients withcomplete data on the seven specified variables (487 of the 1872patients with complete data) and the other patients with completedata on only the five variables in the final model (159 additionalpatients; total, 646). The model was equally predictive in thevalidation sample, identifying four groups of patients at low,low intermediate, high intermediate, or high risk of death (Figure 1).In the training and validation samples, the risk of deathwas increased primarily in the first three to four years afterdiagnosis (Figure 1, right panels).
Since the training and validation samples had comparable outcomes,we combined these two groups into a single group for furtherdetailed analysis (Figure 1, bottom panels; Table 4, internationalindex, all patients). The four risk groups had distinctly differentrates of complete response, relapse-free survival, and overallsurvival (Table 4). For example, the low-risk group had a complete-responserate of 87 percent and a five-year overall survival of 73 percent,whereas the high-risk group had a complete-response rate ofonly 44 percent and a five-year overall survival of only 26percent (Table 4, international index, all patients).
Table 4. Outcome According to Risk Group Defined by the International Index and the Age-Adjusted International Index.
The Significance of Age in Prognosis
Since the two age groups ( 60 vs. >60 years) had significantlydifferent outcomes (Table 2 and Table 3) and the age limit forpatients treated by most intensive experimental regimens fornon-Hodgkin's lymphoma is 60 years, we also developed an age-adjustedmodel for younger patients -- the age-adjusted internationalindex. Three of the previously identified risk factors -- tumorstage, performance status, and LDH level -- remained independentlysignificant prognostic factors among the patients in the trainingsample who were 60 or younger (885 patients) (Table 3). Sincethe relative risks of death associated with the three risk factorswere comparable (Table 3), a younger patient could also be assignedto a risk group by counting the number of risk factors presentat diagnosis. The age-adjusted international index was similarlypredictive in the training and validation samples (in 885 and389 patients, respectively, or a total of 1274), justifyingour combining these two groups for further analysis (Figure 2;Table 4, age-adjusted index, patients 60). The younger patients( 60 years) were assigned to four risk groups according to thenumber of risk factors at presentation (0, 1, 2, or 3) (Figure 2and Table 4). The younger patients in the low-risk group hada complete-response rate of 92 percent and a five-year overallsurvival of 83 percent, whereas those in the high-risk grouphad a complete-response rate of only 46 percent and a five-yearoverall survival of only 32 percent (Table 4). As was true ofall patients (Table 4, international index, all patients), theincreased risk of death among the younger patients was due toboth a lower complete-response rate and lower relapse-free survivalamong those with complete responses.
Figure 2. Survival among the 1274 Younger Patients ( 60 Years) According to Risk Group Defined by the Age-Adjusted International Index.
The left panel shows the Kaplan-Meier curves for this age group, and the right panel the death rates during the study period. L denotes low risk, LI low intermediate risk, HI high intermediate risk, and H high risk. Only 1274 of the 1931 patients 60 or younger had enough relevant information for classification according to the international index.
To define the differences between the younger and older patientsmore specifically, the two age groups were compared by the age-adjustedinternational index (Table 4). The distribution of the youngerpatients among the four risk groups was similar to the distributionof the older patients among these groups (Table 4). Althoughthe older patients (>60 years) had complete-response ratesthat were similar to or only slightly lower than those of theyounger patients, the older patients with complete responseshad much lower rates of relapse-free survival (Table 4). Thesedata suggested that increased numbers of older patients diedof lymphoma rather than of unrelated causes. Consistent withthis observation was the finding that the older patients alsohad an observed death rate that was substantially higher thanthat of an age-matched cohort (data not shown)24.
Relapse-free Survival among Patients with Complete Responses
If patients with an increased risk of relapse from completeresponse could be identified before relapse, they might be candidatesfor experimental approaches to consolidation therapy, such ashigh-dose chemoradiotherapy with infusion of peripheral-bloodstem cells or bone marrow support. For this reason, we alsoidentified the presenting clinical features most closely associatedwith the risk of relapse from complete response: age ( 60 vs.>60 years: relative risk, 1.80; P<0.001), tumor stage(I or II vs. III or IV: relative risk, 1.79; P<0.001), andserum LDH level ( 1 times normal vs. >1 times normal: relativerisk, 1.47; P<0.001).
International Index and Ann Arbor Stage
Since features other than the Ann Arbor stage were independentlyassociated with overall survival in our analyses (Table 3),a model incorporating these additional features would by definitionbe more predictive than the Ann Arbor classification system.This is illustrated in Figure 3, which shows the survival ofpatients in Ann Arbor stage II, III, and IV according to theirrisk group as defined by the international index.
Figure 3. Survival among 1880 Patients in Ann Arbor Stages II, III, and IV, According to Risk Group Defined by the International Index.
L denotes low risk, LI low intermediate risk, HI high intermediate risk, and H high risk. Values for these groups are also shown in Table 4. Only one patient in stage II was at high risk, and that group is therefore not shown. Only 1881 of 3025 patients in stages II through IV had enough relevant information for classification according to the international index.
Discussion
The goal of our project was to develop a system for classifyingpatients with aggressive non-Hodgkin's lymphoma according touniversally recognized clinical features. The resulting modelapplicable to all these patients (the international index) incorporatesclinical features that reflect the growth and invasive potentialof the tumor (tumor stage, serum LDH level, and number of extranodaldisease sites), the patient's response to the tumor (performancestatus), and the patient's ability to tolerate intensive therapy(age and performance status). The simplified model for youngerpatients (the age-adjusted international index) uses a subgroupof these clinical features (tumor stage, LDH level, and performancestatus). Both models identified four risk groups of patientsbased on both the rate of complete response and the rate ofrelapse from complete response. The size of the study populationand the diversity of the referring institutions and study centershelped ensure that the international index and the age-adjustedindex were derived from a broadly representative group. Sincerecent studies indicate that unselected patients with aggressivenon-Hodgkin's lymphoma who are treated with first-, second-,and third-generation chemotherapy regimens have comparable outcomes,25,26,27the variety of regimens that contained doxorubicin in our studyis unlikely to have influenced the analysis. Furthermore, theinternational index was equally predictive of survival in tworecent series of over 2000 patients treated with intensive third-generationregimens25 (and unpublished data).
We developed separate models -- one for all patients (the internationalindex) and one for younger patients (the age-adjusted internationalindex) -- because the two models may be applicable in differentsettings. In trials that include patients of all ages, the internationalindex, not restricted according to age, would be more useful.However, in trials of more intensive experimental approachesthat are targeted to younger patients, the age-adjusted indexcould be used.
We retained four risk groups of patients defined by the internationalindex and the age-adjusted index because physicians and investigatorsmay collapse these risk groups differently, depending on theirobjectives. For example, if the goal is to compare the typesof patients who are being treated in specific trials, the relativenumbers of patients in all four risk groups should be noted.If the objective is to identify candidates for experimentaltherapy -- patients whose predicted five-year survival is lessthan 50 percent with standard regimens -- it would be reasonableto include patients identified as being at high, high intermediate,and perhaps even low intermediate risk according to the internationalindex (Table 4). However, when experimental approaches are specificallydesigned for younger patients ( 60 years), the target populationmight be patients at high intermediate and high risk as definedby the age-adjusted international index (Table 4). It is importantthat the target population of a "high-risk" protocol be accuratelydefined because the results of an experimental approach maybe as dependent on the definition of high risk as on the regimenitself28,29. Furthermore, therapeutic approaches should be comparedin appropriate, age-matched populations because younger patientsgenerally have more favorable outcomes.
If it were possible to identify patients who enter completeremission but are at increased risk of subsequent relapse, suchpatients might be candidates for intensive experimental consolidationtherapy. However, in our study, the clinical features that correlatedwith an increased risk of relapse were also associated witha decreased likelihood of obtaining an initial complete remission.Therefore, therapeutic approaches to patients at high risk mustbe directed toward increasing the low rates of initial completeresponses as well as toward improving the durability of thoseresponses.
Although the international index was specifically developedto predict outcome in patients with aggressive non-Hodgkin'slymphoma, it may also have prognostic value in patients withlymphoma that is histologically more indolent. Recent studiesindicate that a prognostic-factor model developed for patientswith aggressive non-Hodgkin's lymphoma also predicted survivalin a small series of patients with follicular lymphoma,30 andthat the international index predicted survival in a largerseries of similar patients (unpublished data).
Finally, it is important to recognize that the clinical prognosticfeatures incorporated in the international index are, in part,surrogate variables that reflect the biologic heterogeneityof aggressive non-Hodgkin's lymphoma. As additional featuressuch as serologic variables (beta2-microglobulin level31), indexesof tumor-cell proliferation (expression of Ki-67 antigen32 andincorporation of tritiated thymidine33), karyotypic abnormalities,34,35,36,37and aberrant adhesion-molecule38,39 and oncogene40 expressionare evaluated in larger numbers of patients, the biologic heterogeneityof this disease may be better understood. In the meantime, clinicalprognostic-factor models such as the international index andthe age-adjusted index can be used to identify specific riskgroups and to compare different therapeutic approaches.
Supported in part by the Arntraud C. Arlinger Fund.
We are indebted to Jane Russell, Mia Donnelly, Stacey Cohen,and Sharon Cassidy of the Dana-Farber Cancer Institute QualityControl Center for assistance with data management; to JaneWeeks, M.D., for thoughtful review of the manuscript; and toDonna Favreau and Judy Nahas for assistance in the preparationof the manuscript.
Source Information
The following persons are members of the International Non-Hodgkin's Lymphoma Prognostic Factors Project: M.A. Shipp (Dana-Farber Cancer Institute and Harvard Medical School, Boston) and D.P. Harrington (Dana-Farber Cancer Institute and Harvard Medical School, Boston; Eastern Cooperative Oncology Group, Denver), chairpersons; J.R. Anderson (Nebraska Lymphoma Study Group, Omaha; Cancer and Leukemia Group B, Lebanon, N.H.); J.O. Armitage (Nebraska Lymphoma Study Group, Omaha); G. Bonadonna (Istituto Nazionale Tumori, Milan, Italy); G. Brittinger (Bundesministerium fur Forschung und Technologie Study, Essen, Germany); F. Cabanillas (M.D. Anderson Cancer Center, Houston); G.P. Canellos (Dana-Farber Cancer Institute and Harvard Medical School, Boston); B. Coiffier (Groupe d'Etude des Lymphomes de l'Adulte, Paris); J.M. Connors (British Columbia Cancer Agency, Vancouver); R.A. Cowan and D. Crowther (Manchester Lymphoma Group, Manchester, United Kingdom); S. Dahlberg (Southwest Oncology Group, San Antonio, Tex.); M. Engelhard (Bundesministerium fur Forschung und Technologie Study, Essen, Germany); R.I. Fisher (Southwest Oncology Group, San Antonio, Tex.); C. Gisselbrecht (Groupe d'Etude des Lymphomes de l'Adulte, Paris); S.J. Horning (Stanford University, Stanford, Calif.); E. Lepage (Groupe d'Etude des Lymphomes de l'Adulte, Paris); T.A. Lister (St. Bartholomew's Hospital, London); J.H. Meerwaldt (Lymphoma Cooperative Group, European Organisation for Research on Treatment of Cancer, Brussels, Belgium); E. Montserrat (Hospital Clinic i Provincial de Barcelona, Barcelona, Spain); N.I. Nissen (Finsen Institute, Copenhagen, Denmark); M.M. Oken (Eastern Cooperative Oncology Group, Denver); B.A. Peterson (Cancer and Leukemia Group B, Lebanon, N.H.); C. Tondini (Istituto Nazionale Tumori, Milan, Italy); W.A. Velasquez (M.D. Anderson Cancer Center, Houston); and B.Y. Yeap (Dana-Farber Cancer Institute and Harvard Medical School, Boston; Eastern Cooperative Oncology Group, Denver).
Address reprint requests to Dr. Margaret A. Shipp at the Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115.
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(2008). Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era. Blood
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[Abstract][Full Text]
Mead, G. M., Barrans, S. L., Qian, W., Walewski, J., Radford, J. A., Wolf, M., Clawson, S. M., Stenning, S. P., Yule, C. L., Jack, A. S., on behalf of the UK National Cancer Research Insti,
(2008). A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood
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International T-Cell Lymphoma Project,
(2008). International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes. JCO
26: 4124-4130
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Sacchi, S., Marcheselli, L., Bari, A., Marcheselli, R., Pozzi, S., Gobbi, P. G., Angrilli, F., Brugiatelli, M., Musto, P., Federico, M.
(2008). Second malignancies after treatment of diffuse large B-cell non-Hodgkin's lymphoma: a GISL cohort study. haematol
93: 1335-1342
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Kim, T. M., Lee, S. -Y., Jeon, Y. K., Ryoo, B. -Y., Cho, G. J., Hong, Y. S., Kim, H. J., Kim, S.-Y., Kim, C. S., Kim, S., Kim, J. S., Sohn, S. K., Song, H. H., Lee, J. L., Kang, Y. K., Yim, C. Y., Lee, W. S., Yuh, Y. J., Kim, C. W., Heo, D. S., for the Lymphoma Subcommittee of the Korean Cancer,
(2008). Clinical heterogeneity of extranodal NK/T-cell lymphoma, nasal type: a national survey of the Korean Cancer Study Group. Ann Oncol
19: 1477-1484
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Yamaguchi, M., Nakamura, N., Suzuki, R., Kagami, Y., Okamoto, M., Ichinohasama, R., Yoshino, T., Suzumiya, J., Murase, T., Miura, I., Ohshima, K., Nishikori, M., Tamaru, J.-i., Taniwaki, M., Hirano, M., Morishima, Y., Ueda, R., Shiku, H., Nakamura, S.
(2008). De novo CD5+ diffuse large B-cell lymphoma: results of a detailed clinicopathological review in 120 patients. haematol
93: 1195-1202
[Abstract][Full Text]
Tarella, C., Zanni, M., Magni, M., Benedetti, F., Patti, C., Barbui, T., Pileri, A., Boccadoro, M., Ciceri, F., Gallamini, A., Cortelazzo, S., Majolino, I., Mirto, S., Corradini, P., Passera, R., Pizzolo, G., Gianni, A. M., Rambaldi, A.
(2008). Rituximab Improves the Efficacy of High-Dose Chemotherapy With Autograft for High-Risk Follicular and Diffuse Large B-Cell Lymphoma: A Multicenter Gruppo Italiano Terapie Innnovative nei Linfomi Survey. JCO
26: 3166-3175
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Shimada, K., Matsue, K., Yamamoto, K., Murase, T., Ichikawa, N., Okamoto, M., Niitsu, N., Kosugi, H., Tsukamoto, N., Miwa, H., Asaoku, H., Kikuchi, A., Matsumoto, M., Saburi, Y., Masaki, Y., Yamaguchi, M., Nakamura, S., Naoe, T., Kinoshita, T.
(2008). Retrospective Analysis of Intravascular Large B-Cell Lymphoma Treated With Rituximab-Containing Chemotherapy As Reported by the IVL Study Group in Japan. JCO
26: 3189-3195
[Abstract][Full Text]
Savage, K. J., Harris, N. L., Vose, J. M., Ullrich, F., Jaffe, E. S., Connors, J. M., Rimsza, L., Pileri, S. A., Chhanabhai, M., Gascoyne, R. D., Armitage, J. O., Weisenburger, D. D., for the International Peripheral T-Cell Lymphoma P,
(2008). ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood
111: 5496-5504
[Abstract][Full Text]
Khouri, I. F., McLaughlin, P., Saliba, R. M., Hosing, C., Korbling, M., Lee, M. S., Medeiros, L. J., Fayad, L., Samaniego, F., Alousi, A., Anderlini, P., Couriel, D., de Lima, M., Giralt, S., Neelapu, S. S., Ueno, N. T., Samuels, B. I., Hagemeister, F., Kwak, L. W., Champlin, R. E.
(2008). Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood
111: 5530-5536
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Malumbres, R., Chen, J., Tibshirani, R., Johnson, N. A., Sehn, L. H., Natkunam, Y., Briones, J., Advani, R., Connors, J. M., Byrne, G. E., Levy, R., Gascoyne, R. D., Lossos, I. S.
(2008). Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. Blood
111: 5509-5514
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Wilson, W. H., Dunleavy, K., Pittaluga, S., Hegde, U., Grant, N., Steinberg, S. M., Raffeld, M., Gutierrez, M., Chabner, B. A., Staudt, L., Jaffe, E. S., Janik, J. E.
(2008). 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. JCO
26: 2717-2724
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Persky, D. O., Unger, J. M., Spier, C. M., Stea, B., LeBlanc, M., McCarty, M. J., Rimsza, L. M., Fisher, R. I., Miller, T. P.
(2008). Phase II Study of Rituximab Plus Three Cycles of CHOP and Involved-Field Radiotherapy for Patients With Limited-Stage Aggressive B-Cell Lymphoma: Southwest Oncology Group Study 0014. JCO
26: 2258-2263
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Mercadal, S., Briones, J., Xicoy, B., Pedro, C., Escoda, L., Estany, C., Camos, M., Colomo, L., Espinosa, I., Martinez, S., Ribera, J.M., Martino, R., Gutierrez-Garcia, G., Montserrat, E., Lopez-Guillermo, A., On behalf of the Grup per l'Estudi dels Limfomes d,
(2008). Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann Oncol
19: 958-963
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Dierlamm, J., Murga Penas, E. M., Bentink, S., Wessendorf, S., Berger, H., Hummel, M., Klapper, W., Lenze, D., Rosenwald, A., Haralambieva, E., Ott, G., Cogliatti, S. B., Moller, P., Schwaenen, C., Stein, H., Loffler, M., Spang, R., Trumper, L., Siebert, R., for the Deutsche Krebshilfe Network Project "Molec,
(2008). Gain of chromosome region 18q21 including the MALT1 gene is associated with the activated B-cell-like gene expression subtype and increased BCL2 gene dosage and protein expression in diffuse large B-cell lymphoma. haematol
93: 688-696
[Abstract][Full Text]
Mourad, N., Mounier, N., Briere, J., Raffoux, E., Delmer, A., Feller, A., Meijer, C. J. L. M., Emile, J.-F., Bouabdallah, R., Bosly, A., Diebold, J., Haioun, C., Coiffier, B., Gisselbrecht, C., Gaulard, P.
(2008). Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Blood
111: 4463-4470
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Canellos, G. P.
(2008). What Constitutes "Improved Prognosis"?. JCO
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[Full Text]
Ladetto, M., De Marco, F., Benedetti, F., Vitolo, U., Patti, C., Rambaldi, A., Pulsoni, A., Musso, M., Liberati, A. M., Olivieri, A., Gallamini, A., Pogliani, E., Scalabrini, D. R., Callea, V., Di Raimondo, F., Pavone, V., Tucci, A., Cortelazzo, S., Levis, A., Boccadoro, M., Majolino, I., Pileri, A., Gianni, A. M., Passera, R., Corradini, P., Tarella, C., for Gruppo Italiano Trapianto di Midollo Osseo (GI,
(2008). Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood
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[Abstract][Full Text]
Ziepert, M., Schmits, R., Trumper, L., Pfreundschuh, M., Loeffler, M., On behalf of the German High-Grade Non-Hodgkin's L,
(2008). Prognostic factors for hematotoxicity of chemotherapy in aggressive non-Hodgkin's lymphoma. Ann Oncol
19: 752-762
[Abstract][Full Text]
Thieblemont, C., Grossoeuvre, A., Houot, R., Broussais-Guillaumont, F., Salles, G., Traulle, C., Espinouse, D., Coiffier, B.
(2008). Non-Hodgkin's lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome. Ann Oncol
19: 774-779
[Abstract][Full Text]
Zinzani, P. L., Tani, M., Fanti, S., Stefoni, V., Musuraca, G., Castellucci, P., Marchi, E., Farsad, M., Fina, M., Pellegrini, C., Alinari, L., Derenzini, E., de Vivo, A., Bacci, F., Pileri, S., Baccarani, M.
(2008). A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients. Ann Oncol
19: 769-773
[Abstract][Full Text]
Pfreundschuh, M., Zwick, C., Zeynalova, S., Duhrsen, U., Pfluger, K.-H., Vrieling, T., Mesters, R., Mergenthaler, H.-G., Einsele, H., Bentz, M., Lengfelder, E., Trumper, L., Rube, C., Schmitz, N., Loeffler, M., On behalf of the German High-Grade Non-Hodgkin's L,
(2008). Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: II. Results of the randomized high-CHOEP trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Ann Oncol
19: 545-552
[Abstract][Full Text]
Overman, M. J., Feng, L., Pro, B., McLaughlin, P., Hess, M., Samaniego, F., Younes, A., Romaguera, J. E., Hagemeister, F. B., Kwak, L., Cabanillas, F., Rodriguez, M. A., Fayad, L. E.
(2008). The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma. Ann Oncol
19: 553-559
[Abstract][Full Text]
Morel, P., Gaulard, P., Gisselbrecht, C., Ferme, C., Salles, G., Tilly, H., Briere, J., Copin, M. C., Lederlin, P., Hermine, O., Theate, I., Haioun, C., Mounier, N.
(2008). Autologous stem-cell transplantation as consolidation therapy for diffuse large B-cell lymphoma patients with overexpression of bcl-2 protein. Results of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trial LNH98-B2. Ann Oncol
19: 560-565
[Abstract][Full Text]
Trumper, L., Zwick, C., Ziepert, M., Hohloch, K., Schmits, R., Mohren, M., Liersch, R., Bentz, M., Graeven, U., Wruck, U., Hoffmann, M., Metzner, B., Hasenclever, D., Loeffler, M., Pfreundschuh, M., On behalf of the German High-Grade Non-Hodgkin's L,
(2008). Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: I. A randomized dose escalation and feasibility study with bi- and tri-weekly regimens. Ann Oncol
19: 538-544
[Abstract][Full Text]
10 cm), III, or IV. Performance status was assessed according to the Eastern Cooperative Oncology Group scale, in which 0 indicated that the patient had no symptoms; 1, the patient had symptoms but was ambulatory; 2, the patient was bedridden less than half the day; 3, the patient was bedridden half the day or longer; and 4, the patient was chronically bedridden and required assistance with the activities of daily living. Performance status was classified as 0 or 1 (the patient was ambulatory) or 2, 3, or 4 (the patient was not ambulatory) (equivalent Karnofsky scores, 
70). B symptoms were defined as recurrent fever (temperature, >38.3 °C [101 °F]), night sweats, or the loss of more than 10 percent of body weight. The recorded sites of extranodal lymphomatous involvement included the bone marrow, gastrointestinal tract, liver, lung, central nervous system, and other sites; the numbers of extranodal disease sites were recorded as 0, 1, or more than 1. Splenic involvement was also recorded. The largest dimension of the largest site of bulky disease was measured and reported as being less than 10 cm or as 10 cm or more. The serum LDH level was expressed as the ratio of the measured value to the upper limit of the normal range reported in the laboratory of each participating institution. 
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