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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2826-2834 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.032 Prognostic Factors in Patients With Aggressive Non-Hodgkin's Lymphoma Treated by Front-Line Autotransplantation After Complete Remission: A Cohort Study by the Groupe d'Etude des Lymphomes de l'AdulteFrom the Groupe d'Etude des Lymphomes de l'Adulte, Hôpital Saint Louis, Paris, France Address reprint requests to Nicolas Mounier, MD, PhD, Service d'Onco-Hématologie, INSERM ERM0220, Hôpital Saint Louis, AP-MP, 1 Avenue Claude Vellefaux, 75010, Paris, France; e-mail: nicolas.mounier{at}sls.ap-hop-paris.fr
PURPOSE: Improved survival has been observed in aggressive non-Hodgkin's lymphoma (NHL) patients with adverse prognostic factors when autotransplantation (ASCT) was performed after complete remission. However, there is no agreement on the prognostic factors for patients treated with ASCT. We aimed to estimate the prognostic effect of clinical and biologic variables on relapse and survival rates by pooling the data from two trials. PATIENTS AND METHODS: Of the patients treated in the LNH87 and LNH93 trials, 330 under age 60 years achieved complete remission after high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone, and received consolidative ASCT; 16% of patients had T-cell NHL. The International Prognostic Index (IPI) score was 0 for 11%, 1 for 23%, 2 for 51%, and 3 for 15%. Univariate and Cox multivariate survival analyses were retrospectively performed on this population. RESULTS: Overall survival was 75 ± 5% at 5 years and disease-free survival (DFS) 67 ± 5%. For T-cell NHL, these scores were 54% and 44%, respectively. The IPI score had no prognostic value and only the following parameters adversely affected overall survival and DFS (P < .05): marrow involvement; more than one extranodal site; histology (nonanaplastic T-cell v others); and type of anthracycline (mitoxantrone v doxorubicin, for DFS only). CONCLUSION: These results suggest that ASCT can prevent relapse in patients with adverse IPI factors. However, patients presenting with a nonanaplastic T-cell phenotype, more than one extranodal site, or marrow involvement still have a higher risk of relapse. These factors should be taken into account when designing post-ASCT maintenance studies.
Aggressive non-Hodgkin's lymphomas (NHL) are highly chemotherapy-sensitive malignancies. Treatment with conventional combination chemotherapy produces complete remission (CR) rates of 50% to 70%, and disease-free survival (DFS) rates of approximately 50%.1-3 More intensive third generation regimens did not prove to be better than the standard CHOP regimen, consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone.4 However, most of those regimens were designed before the use of hematopoietic growth factor or high-dose chemotherapy (HDT) with autologous stem-cell transplantation (ASCT) and did not comprise high-dose intensive treatment. ASCT is the treatment of choice for patients with relapsed aggressive NHL still responding to salvage chemotherapy,5 but whether ASCT has a role as front-line therapy is still a matter of debate.6 The authors of randomized phase III studies maintained that such an approach was beneficial at least by preventing disease progression in patients who had achieved CR after induction.7-11 By contrast, other randomized trials of abbreviated induction therapy followed by early ASCT gave non significant results.12-14 Different criteria for patient selection and dose-intensity chemotherapy might explain such discrepancies, but there is evidence that ASCT might be useful in certain selected cases. The probability of being cured by the initial treatment depends on the presence or absence of adverse prognostic factors such as age, performance status, tumor stage, the lactate dehydrogenase level (LDH) and the number of sites of extranodal disease. These factors are included in the International Prognostic Index (IPI).15 However, the clinical factors of the IPI are likely to be surrogate markers of the intrinsic molecular heterogeneity in NHL, as shown by recent developments of DNA microarrays, a genome-wide approach to predicting NHL treatment outcome.16-18 Nevertheless, when the IPI was applied to randomized trials, a failure-free and overall survival benefit from ASCT was demonstrated for high-/intermediate-risk and high-risk patients but not for low-risk patients.7,8,10,11 This led to the general feeling among clinicians that young patients at high or intermediate risk who responded to full course CHOP-like chemotherapy would benefit from consolidation by ASCT. To establish whether or not ASCT reduces the IPI-associated relapse rate for patients achieving CR and to determine the prognostic factors, we compared patient characteristics to clinical outcome in a cohort of patients from the two trials conducted by Groupe d'Etude des Lymphomes de l'Adulte (GELA), which combined high-dose CHOP induction (adriamycin, cyclophosphamide, vindesine, bleomycin; ACVB) and front-line consolidative ASCT.
Patients The patients studied for prognostic factors after ASCT were entered in two prospective multicentric trials conducted by the GELA between October 1987 and September 1998: LNH-87 (n = 916) and LNH-93 (n = 718).7,8,12,19 The trials were approved by our institutional review board and informed consent was obtained from all participants in accordance with the declaration of Helsinki.
The LNH-87 Trial
The LNH-93 Trial The interim analysis conducted after the first part of the trial showed negative results for the shortened induction arm with ASCT compared to the results of the ACVB arm with sequential conolidation. Consequently, the Data and Safety Monitoring Committee recommended that the randomization be stopped on September 15, 1995 (n = 370).12 In the second part of the trial, patients should be treated as in the LNH 87 trial, with full course induction—four cycles of ACVB followed in patients achieving CR by consolidative HDT with the CBV or BEAM regimen (carmustine 300 mg/m2, etoposide 800 mg/m2, aracytine 800 mg/m2, and melphalan 140 mg/m2)—and then ASCT with peripheral stem cells collected after three or four cycles of ACVB (n = 348).19 Only this group of 348 patients was included in the present analysis.
Staging and Follow-Up Tumor responses were assessed after the four cycles of ACVB or NCVB were classified according to the International Workshop criteria20 as follows: CR—the disappearance of all the lesions and radiologic or biologic abnormalities observed at diagnosis and the absence of new lesions. In particular, the spleen must not be palpable and the bone marrow biopsy must be cleared; Unconfirmed complete response (CRu)—CR, but the persistence of some radiologic abnormalities (ie, a residual lymph node mass greater than 1.5 cm in greatest transverse diameter) whose size had regressed by at least 75%. Individual nodes that were previously confluent must have regressed by more than 75% in their sum of the products of the greatest diameters; partial response (PR)—the regression of all measurable lesions by more than 50%, the disappearance of non measurable lesions, the absence of new lesion, and no increase in the size of other nodes, liver, or spleen; stable disease—less than PR, but not progressive disease; and progressive disease—the appearance of new lesions, or growth of any previously identified abnormal node by more than 50% from nadir in the sum of the products of the greatest diameters. Follow-up procedures included physical examination every 3 months for the first 2 years, then every 6 months for 3 years, and then annually. Thoracic and abdominal CT scans were performed every 6 months during the first 2 years and then at the discretion of the treating physician. Histologic slides were reviewed by two independent GELA pathologists for 80% of the study population, and lymphomas were reclassified according to the WHO classification.21 Agreement for discordant cases was reached using a two-headed microscope.
Patient Selection
Statistical Methods We checked for the effects of prognostic factors on outcome due to sampling fluctuation using multivariate analysis of survival. A Cox model regression was fitted, which included the age adjusted-IPI (aa-IPI) risk factors and patient and treatment characteristics as explanatory variables.23 The interactions between risk factors were also included in the model. Continuous biologic variables were dichotomized by applying the standard split-sample approach.24 The resulting thresholds were checked by including cubic smoothing splines in the risk function of the Cox model.25 To incorporate model selection uncertainty into the inference, we used the bootstrap method, which allows resampling with replacement to be generated from the original population.26 When the bootstrap with model selection was applied separately to each re-sample (10,000 replications), it allowed us to estimate parameters and generate robust confidence intervals without basing our analysis on a single selected model. Differences between the results of comparative tests were considered significant if the two-sided P value was less than .05. All statistical analyses were performed using SAS 8.2 (SAS Institute, Cary, NC) and Splus 2000 (MathSoft, Cambridge, MA) software.
Patient Characteristics The study population of 330 patients consisted of 197 males and 133 females. The median age was 39 years (range, 16 to 60 years). Main hematologic characteristics are shown in Table 1. The cohort included 249 patients (75%) with B-cell NHL (B NHL); of these patients, 1.5% exhibited follicular large cells, 55% diffuse B large cells, 15% Burkitt or Burkitt-like cells, and 2.5% immunoblastic cells. There were 52 cases (16%) with T-cell NHL (T NHL); of these patients, 4% exhibited lymphoblastic subtype, 5% peripheral T-cells, and 7% exhibited anaplastic subtype. In 29 cases (9%), large-cell NHL could not be otherwise classified, because of the lack of an immunohistochemical study. Two thirds of the study population consisted of high-risk patients with an aa-IPI above 1. However, in the LNH-93 trial, only patients with an IPI score more than 1 could be included. Of the total study population of 330, 160 patients (48%) had mediastinal localizations, only 50 (15%) had gastrointestinal involvement, and 12 (4%) had meningeal or cranial nerve involvement.
Treatment characteristics are shown in Table 2. The anthracycline was doxorubicin for 246 patients and mitoxantrone for 84 patients. The theoretical dose-intensities of the ACVB regimen for doxorubicin, mitoxantrone, and cyclophosphamide were 37.5 mg/m2/wk, 6 mg/m2/wk, and 600 mg/m2/wk, respectively, for the first three cycles. The median received dose of doxorubicin, mitoxantrone, and cyclophosphamide were 34.9 mg/m2/wk, 5.2 mg/m2/wk, and 546 mg/m2/wk, respectively (ie, 93%, 87%, and 91% of the designed dose). The dose-intensity for doxorubicin was better in the LNH-93 trial because of the systematic use of granulocyte colony-stimulating factor. Three hundred fourteen (95%) patients received intrathecal methotrexate prophylaxis during the induction phase. Two hundred two patients (61%) achieved CR and 128 patients (39%) achieved CRu. The CBV conditioning regimen was given to 243 patients (74%) and the BEAM regimen to 79 patients (24%). The source of stem cells was bone marrow for 201 patients (61%) and peripheral blood stem cells (PBSC) for 129 patients (39%).
Univariate Analysis The stopping date of the present analysis was set at January 1, 2002. For the entire population, the median follow-up was 6.5 years (range, 0.5 to 12.1 years). For the LNH-93 trial, the median follow-up was 2.25 years (range, 0.5 to 4.5 years) and for the LNH-87 trial, it was 8.5 years (range, 3.8 to 12.1 years). A total of 80 deaths occurred, three of them transplant-related. One hundred four patients relapsed. For four of the six patients who died without relapsing, the cause of death was known: one accident, one cardiac event, and two infections. The two-year OS was estimated at 82% ± 5% in the LNH-87 trial, and 81.5% ± 7% in the LNH-93 trial. As these estimates were identical, we pooled the data for the two cohorts, which led us to estimate 2-year OS at 82% ± 4% and 5-year OS at 75% ± 5% (Fig 1). The 2-year DFS was 72.5% ± 6% for LNH-87 and 74% ± 8% for LNH-93, leading to pooled estimations of 73.5% ± 5% for 2-year DFS and 67% ± 5% for 5-year DFS.
The association between main patient characteristics and survival calculated by univariate analysis (Table 3) showed that aa-IPI (0 to 1 [n = 108] v 2 to 3 [n = 211]) had no prognostic value (5-year OS, 76% v 74%; P = .48; and DFS, 65% v 66%; P = .67; Fig 2). There was also no significant difference between two and three adverse IPI factors (5-year OS, 76% v 67%; P = .28; and DFS, 69% v 58%; P = .38). To investigate the impact of other covariates, we first studied the categoric variables and then the continuous variables. Of the categoric variables, marrow involvement, one or more extranodal sites, the type of anthracycline (mitoxantrone v doxorubicin), and histologic subtype had a significant adverse effect.
Neither the conditioning regimen nor the source of stem cell had a significant effect on OS (82% v 81% at 2 years, P = .4 for CBV versus BEAM; and 82% v 82%, P = .61 for marrow v PBSC) or DFS (73% v 73% at 2 years, P = .5 for CBV versus BEAM; and 72% v 74%, P = .22 for marrow v PBSC). For the continuous covariates, the smoothing spline curves, which estimate the functional form of their prognostic value (Fig 3), show how the relative risk (RR) of mortality changes as the continuous covariates vary. For chemotherapy dose-intensity and age, the RR curve was monotonic, which enabled us to determine a single cut-off point to categorize the covariate. For dose-intensity, the RR curve decreased as the dose-intensity rose (best cut-off point estimated at 85%). On the other hand, for age, RR increased as the patient grew older (best cut-off point estimated at 35 years). Therefore, according to this categorization, age  35 years, anthracycline dose-intensity below 85%, and cyclophosphamide dose-intensity below 85% had a significant adverse effect.
Multivariate Analysis On the basis of the results of the univariate analysis, six pretreatment characteristics were included in the multivariate analysis (ie, age 35 years, marrow involvement, number of extranodal sites 1, type of anthracycline [mitoxantrone v doxorubicin], anthracycline dose-intensity below 85%, cyclophosphamide dose-intensity below 85%, and histology [nonanaplastic T NHL v other types]). The histology was classified according to nonanaplastic T NHL versus others because, as shown in Table 3, BNHL and anaplastic T NHL exhibited the same survival, in contrast to the low survival for nonanaplastic T NHL. In multivariate analysis, only the following characteristics retained prognostic value for OS and DFS: marrow involvement, extra-nodal sites, and histology. Table 4 shows that these last two characteristics had the strongest predictive value, with the highest RR and bootstrap selection frequency. Marrow involvement had an intermediate prognostic value, with bootstrap selection frequency below 70%. The type of anthracycline had a prognostic value for DFS but not for OS.
The report of the International Consensus Conference on ASCT in aggressive NHL indicated that only for patients achieving CR/CRu should front-line ASCT be given, and that only a subset of this population would benefit from this treatment.6 At present, pending the completion of molecular response profile studies, the clinical factors of the IPI are still used to identify patients at increased risk of standard treatment failure for whom experimental therapy would be appropriate.27 Some of these factors, such as the LDH level and number of extranodal sites or stage, define the aggressive potential of the tumor. Others, such as the ECOG performance status or age help to evaluate the patient's response to the disease. Although most deaths among aggressive NHL patients occur within 2 years of diagnosis, a small percentage occurs after that time.28 In previous multivariate analyses, predictive models were developed using a Cox model for the entire follow-up period (ie, from diagnosis to death).7-10 However, the prognostic factors are not necessarily the same for the short-term (ie, during the treatment period) and during later follow-up (ie, after the consolidation treatment).28,29 Therefore, the main purpose of the present study was to establish whether the adverse effect of the IPI clinical factors can be overcome by ASCT when it is given to CR patients as consolidation treatment. Another aim was to identify patients at increased risk of relapse after ASCT for whom maintenance therapy would be appropriate. The number of patients (n = 330) and the diversity of the 30 study centers made the study population broadly representative. Furthermore, to obtain a homogeneous group and counteract the difference between the effects of chemotherapy regimens, we only included patients younger than 60 years treated by ACVB type regimen. The main interest of the present study was to focus only on patients who achieved CR or CRu and underwent to HDT with ASCT. Although this was a selected study population, the aim of the study was to identify precisely the prognostic factors after ASCT. OS and DFS were the only end points, because cause-specific survival could not be assessed with our database. Patients came from two trials with different follow-up periods, but as treatment and survival were the same for the common follow-up period, we thought it reasonable to pool the data for prognostic factor analysis. In accordance with conventional procedure, we limited the problems associated with selection of variables by fitting our predictive model to a random sample of the data, using the bootstrap method. However, the results still need an external validation because new prognostic factors retrospectively analyzed have to be tested in a new prospective randomized phase III clinical trial to actually prove their merits. Three main findings resulted from the present study. Firstly, it showed that the aa-IPI prognostic factors (LDH level, stage, and ECOG status) had no prognostic value in this population of CR patients. Extranodal and marrow involvement were retained as independent prognostic factors. We confirmed that the prognostic factors are not the same throughout the disease, especially between the induction and consolidation periods. Secondly, we confirmed the results of studies showing that B-cell aggressive NHL or anaplastic large-cell lymphoma have better outcomes than control T NHL.30,31 In future studies, other features, such as the molecular genomic profile, should be incorporated into a multivariate regression analysis for long-term survival.27 Lastly, the type and dose-intensity of chemotherapy induction played a crucial role, as in other hematologic diseases in which consolidation treatment helps to prevent relapse. Here, we showed that the substitution of mitoxantrone for doxorubicin in our standard ACVB induction regimen and the loss of dose-intensity during the induction led to a higher rate of relapse after ASCT. This data confirmed the results of previous studies; however, due to the retrospective analysis, it does not prove that ASCT is superior to alternative therapies for patients who achieved a CR. In addition, the CR rate is only 65% for patients with adverse prognostic factors, and needs to improve. For B-cell lymphoma, rituximab combined with chemotherapy is likely to improve the CR rate and will be used in future trials with ASCT.32 In conclusion, the results of this cohort study suggest that ASCT is able to prevent relapse in responding patients with adverse aa-IPI factors. However, this data demonstrate that patients presenting with a T-cell phenotype or more than one extranodal site still had a higher risk of relapse after ASCT. To design new studies, these two factors should be taken into account, particularly when intensive or expensive procedures like immunotherapy are proposed.
The following clinicians actively participated in the LNH-87 and LNH 93-trial: N. Albin, C. Allard, M. Aoudjane, D. Assouline, M. Attal, B. Audhuy, M. Azagury, J.C. Barats, C. Beaumont, E. Baumelou, P. Biron, M. Blanc, D. Bordessoulle, R. Bouabdallah, C. Bouleuc, P. Bourquard, P. Bourquelot, F. Boué, O. Boulat, P. Brice, J. Brière, G. Brun, D. Caillot, O. Casasnovas, P. Carde, S. Castaigne, S. Chèze, B. Christian, P. Colin, C. Collet, T. Conroy, T. Cosnard, B. Corront, H. Curé, A. Delmer, V. Delwail, L. Detourmignies, A. Devidas, H. Dombret, J.F. Dor, C. Doyen, F. Dreyfus, S. Dront, G. Dupont, B. Dupriez, J.C. Eisenmann, M. Fabbro, C. Fermé, G. Fillet, M. Flesch, C. Fruchart, J. Gabarre, C. Haioun, R. Herbrecht, O. Hermine, A. Huyn, F. Huguet, M. Janvier, E. Jourdan, J.M. Karsenti, Y. Kerneis, F. Kohser, V. Leblond, P. Lederlin, S. Lefort, P. Lenain, G. Lepeu, S. Lepretre, X. Levaltier, A. Le Rol, G. Marit, C. Martin, F. Mayer, C. Nouvel, P. Morel, M. Moriceau, J.N. Munck, G. Nedellec, F. Offner, J.M. Pavlovitch, I. Plantier, P.Y. Péaud, A.M. Peny, J. Pico, C. Platini, J.P. Pollet, B. Quesnel, O. Reman, B. Richard, R. Riou, P. Rodon, B. Salles, G. Salles, C. Sarazin, D. Schlaifer, C. Sebban, M. Simon, P. Solal-Céligny, J.J. Sotto, A. Stamatoullas, C. Soussain, G. Tertian, A. Thyss, J.D. Tigaud, G. Tobelem, P. Travade, A. Van Hoof, A. Zaniboni, J.M. Zini. The following members of the Groupe d'Etudes des Lymphomes de l'Adulte performed the histological review: T. Molina, J. Brière, J. Diebold, B. Fabiani, P. Gaulard, C. Guettier, T. Petrella, L. Xerri.
The authors indicated no potential conflicts of interest.
We thank Mathilde Dreyfus for editing the English and Sylvie Corre for expert secretarial assistance. We also thank the editor and referees for helpful comments and suggestions.
Supported in part by research funding from the Ministère de la Sante (PHRC-AOM 95061) and from the Délégation à la Recherche Clinique de l'Assistance Publique-Hôpitaux de Paris to the Groupe d'Etude des Lymphomes de l'Adulte. This study was presented in part at the 8th Annual Meeting of the European Haematology Association, June 12-15, 2003, Lyon, France, and at the 45th Annual Meeting of the American Society of Hematology, December 5-9, 2003, San Diego, CA. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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32. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 Submitted December 3, 2003; accepted April 23, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 and Fisher's exact tests. DFS was measured from the date of graft to that of disease progression, relapse, or death from any cause or to the stopping date. Overall survival (OS) was measured from the date of graft to either death from any cause or the stopping date. When the latter date was not reached, the data were censored at the date of the last follow-up evaluation. Survival functions were estimated by the Kaplan-Meier method and compared by the log-rank test.
