Best Treatment of Aggressive Non-Hodgkin’s Lymphoma: A French Perspective

Aggressive lymphomas comprise at least four different types of lymphoma: diffuse large B-cell lymphoma (DBLCL), peripheral T-cell lymphomas (PTCL), Burkitt lymphoma, and lymphoblastic lymphoma. Lymphoblastic lymphoma is a rare subtype in adult patients and is currently treated as acute lymphoblastic leukemia, so it will not be considered in this article. Burkitt lymphoma occurs mostly in pediatric patients, but infrequently in adult patients outside of human immunodeficiency virus infection or the posttransplant setting. It poses special problems because of its aggressiveness, particularly in elderly patients. Whereas the treatment of DLBCL has completely changed in recent years with the combination of rituximab(Drug information on rituximab) (Rituxan) with chemotherapy, no similar immunochemotherapy exists for PTCL and hence the outcome for these patients still needs to be improved. Since 1984, the Groupe d'Etude des Lymphomes de l'Adulte (GELA) has run several studies on aggressive lymphomas that have contributed to the advances made for thetreatment of these patients and to defining the standard care. A summary of principal studies will be presented here with conclusions regarding their implications for the future. Choice of Treatment Since 1987, the GELA has based the choice of treatment on the presence or absence of prognostic factors. Before the description of the International Prognostic Index (IPI),[1] weused the parameters largely used around the world, not differing much from the IPI.[2] Since 1993, as shown in Figure 1, we based all our prospective studies on (1) age and (2) an ageadjusted IPI score, based on the following parameters: stage III/IV, serum lactate dehydrogenase (LDH) level, and performance status. Stage was never considered as a determinant parameter for deciding treatment, but because stage is part of the parameters defining the IPI, patients with localized stage represent a large portion of good-risk patients as defined by the age-adjusted IPI (score 0 or 1). Until the incorporation of rituximab into the treatment of patients with B-cell lymphoma, patients with B-cell and T-cell lymphoma were given the same chemotherapy regimens. In subgroup analyses, the GELA has never found a difference in response to treatment, progression-free survival, or overall survival for any particular location (mediastinal, gastrointestinal, nodal, or extranodal), so all these patients were included in the same studies without any stratification according to involved site (although patients with central nervous system lymphoma were usually excluded from these studies). It was the same for the different histologic entities within the large group of diffuse large B-cell lymphoma. Currently, gene profiling for choosing the treatment of patients is not applicable in prospective studies because the results of such an assay should be obtained within a few days before starting treatment for most patients.[3] The ACVBP Regimen In 1984, some hematologists and oncologists from France and Belgium decided to work together on prospective studies for patients with lymphoma and founded what would become the GELA a few years later. The first attempt at cooperation was based on the LNH84 study[4]-a prospective study where all patients were treated with ACVBP (doxorubicin [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide), vindesine, bleomycin(Drug information on bleomycin), prednisone(Drug information on prednisone)), a dose-dense and dose-intense CHOP (cyclosphosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone)-likeregimen, followed by sequential consolidation (Figure 2). Because this regimen yielded a high response rate and a 5-year progression- free survival rate of more than 50%, it was chosen as the standard regimen to which others would be compared in subsequent randomized studies. Figure 3 shows the overall survival of patients treated with the ACVBP regimen in the successive randomized studies where it was used as the standard arm. More than 3,000 patients were included in these four studies. It shows the reproducibility of the results obtained with this regimen over time and the fact that 5-year survival rate is over 50% in unselected patients. A long-term follow- up has proven its absence of longterm toxicity, particularly a low secondary risk for myelodysplastic syndromes or acute leukemia.[5] Good-Risk Patients Patients with a score of 0 or 1 on the age-adjusted IPI have either localized or disseminated disease with a normal LDH level and good performance status. As shown in Figure 1,the GELA has chosen for a long time to propose different treatment for this group of patients and to stratify between those with no adverse prognostic factors (score of 0 on the age-adjusted IPI) and those with one prognostic factor (score of 1 on the age-adjusted IPI). One of the reasons for this choice was the decision of the GELA to evaluate the benefit of radiotherapy in patients with localized disease. Previously, few randomized studies had tested this benefit. The principal study that merged patients with adverse parameters (age and LDH level) on the IPI concluded the superiority of three cycles of CHOP followed by local radiotherapy over chemotherapy alone with eight cycles of CHOP.[6] Another study with a longer follow- up that compared radiotherapy or nothing in patients treated with CHOP did not show any benefit in favor of the radiotherapy.[7] Because our previous LNH87.1 study of good-risk patients had shown a benefit for the ACVBP regimen over the m-BACOD (methotrexate, bleomycin, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], dexametha-sone, leucovorin) regimen[8] (a CHOP-like regimen that was thought to be superior to CHOP at the time), ACVBP was chosen as the comparator to CHOP plus radiotherapy in our LNH93-1 study.[9] This study accrued previously untreated patients < 61 years with localized stage I/II aggressive lymphoma and no adverse prognostic factors on the age-adjusted IPI. Patients were randomly assigned to receive either three cycles of CHOP plus involved-field radiotherapy (329 patients) or chemotherapy alone using ACVBP with a sequential consolidation regimen (318 patients). With a median followup of 7.7 years, event-free and overall survival were significantly longer in the chemotherapy-alone group (P < .001 and P = .001, respectively). The 5-year estimates for event-free survival were 82% (95% confidence interval [CI] = 78%-87%) for patients receiving chemotherapy alone and 74% (95% CI = 69%-78%) for patients treated with CHOP plus radiotherapy. The 5-year estimates for overall survival were 90% (95% CI = 87%-93%) and 81% (95% CI = 77%- 86%), respectively. In a multivariateanalysis, event-free and overall survival were affected by treatment arm, independent of stage and tumor bulk. This study demonstrated that chemotherapy alone with three cycles of ACVBP followed by sequential consolidation is superior to three cycles of CHOP plus radiotherapy for the treatment of low-risk localized lymphoma in patients younger than 61 years old (Figure 4). The GELA has run another study in elderly patients, also testing the benefit of radiotherapy. In this LNH93-4 study, patients older than 60 years were randomized to either four cycles of CHOP or four cycles of CHOP plus involved-field radiotherapy. Patients had localized stage I or II disease without any adverse prognostic factors according to the ageadjusted IPI. Preliminary results[10] showed that complete response at the end of treatment, event-free survival, and overall survival rates were similar in both groups. An updated final analysis will be submitted this year. The results of these two studies allowed us to conclude that radiation therapy did not add any advantage over chemotherapy alone in patients with localized lymphoma. Following these two studies the GELA dropped radiation therapy for the treatment of patients with localized aggressive lymphoma. In young adult patients, the GELA is currently testing the efficacy of R-ACVBP (ACVBP plus rituximab) compared to ACVBP. In elderly patients, the current recommendation is to treat them with six cycles of R-CHOP (CHOP plus rituximab). This recommendation is based on results that were obtained with R-CHOP in the LNH98-5 study of elderly patients, both with low- and high-risk disease (see below). Elderly Patients Classically, elderly patients are defined by an age greater than 60 years. They represent 50% of patients with aggressive lymphoma. A subgroup of patients older than 80 has currently to be defined because the strategy in these very old patients is probably different from the standard in elderly patients. The first GELA trial was run in1987 (LNH87-4). It compared, in 453 patients older than 69 years, CVP (cyclophosphamide, vincristine, prednisone) to CTVP, a CHOP-like regimen where doxorubicin was replaced with pirarubicin(Drug information on pirarubicin) (THP-adriamycin)- an anthracycline that was thought to be associated with less cardiotoxicity in 1987.[11] Most patients had clinically aggressive disease, with 30% having one adverse prognostic parameter as defined by the IPI and 53% having two or three. Death during chemotherapy occurred in 16% and 21% of the patients in the CVP and CTVP arms, respectively (not significant). Forty percent of the patients reached complete remission: 47% for CTVP and 32% for CVP (P = .0001). Median time to treatment failure was 7 months for CTVP compared to 5 months for CVP (P < .05). Median overall survival was 13 months in both groups, yet 5-year survival was 26% with CTVP compared to 19% for CVP (P < .05), lymphoma being the primary cause of death. We concluded from this study that (1) that longer survival was associated with reaching complete remission at the end of the treatment; (2) a CHOP-like regimen was not associated with higher toxicity, even in patients older than 80 years; (3) long-term survival was better with a CHOP-like regimen; and (4) overall results were not satisfactory, with only one-fourth of the patients alive 5 years after their diagnosis of lymphoma. Our second trial addressed patients 60 to 70 years old with poor-risk aggressive lymphoma and compared classic CHOP to ACVBP followed by sequential consolidation (LNH93-5 study).[12] Complete remission rates were 58% in the ACVBP group and 56% in the CHOP group (P = .5). Treatment-related death occurred in 13% of the ACVBP group and 7% of the CHOP group (P = .014). At 5 years, event-free survival was 39% in the ACVBP group and 29% in the CHOP group (P = .005). Overall survival was significantly longer for patientstreated with ACVBP: at 5 years it was 46% compared with 38% for patients treated with CHOP (P = .036). Thus, despite a higher toxicity, the ACVBP regimen, used as first-line treatment for patients with poor-risk aggressive lymphoma, is superior to standard CHOP with regard to both event-free and overall survival. However, although survival was better than in our previous study, it was inferior to 50% at 5 years. It appears that ACVBP cannot be used in patients over 65 years because of its toxicity. After the demonstration of the activity of rituximab as a single agent in relapsing patients with DLBCL,[13] the GELA decided to run a study evaluating the benefit of the combination of rituximab and CHOP in elderly patients (LNH98-5 study).[14,15] Previously untreated DLBCL patients aged 60 to 80 years were randomly assigned to receive either eight cycles of CHOP (197 patients) every 3 weeks or CHOP plus rituximab given on day 1 of each cycle (R-CHOP, 202 patients). Patient characteristics were similar in both groups. Median age was 69 years, 20% of patients had poor performance status, 64% had stage IV disease, 66% had elevated LDH levels, and 60% had a poor-risk age-adjusted IPI score (2 or 3). Complete remission rates were significantly higher with R-CHOP (76%, compared to 63% with CHOP; P = .005). With a median follow-up of 2 years, the R-CHOP regimen was associated with significant prolongation of event-free survival (P < .001) and overall survival (P = .007), compared to standard CHOP therapy. Thus, the addition of rituximab to standard CHOP significantly decreased the risk of treatment failure and death (risk ratio 0.58 and 0.64, respectively). Clinically relevant toxicity was not significantly greater with R-CHOP. These results were recently updated with a median follow-up of 5 years.[15] The number of events is clearly superior in the CHOP arm, with nearly half of the patients without event at 5 years in the R-CHOP arm compared to 28% in the CHOP arm (Table 1). Event-free survival, progression-free survival, disease-free survival, and overall survival remainedstatistically significant in favor of the combination of CHOP plus rituximab, with P values of .00002, < .00001, .00031, and .0073, respectively (Figure 5). Both patients with low- or high-risk lymphoma according to the age-adjusted IPI have longer survival if treated with the combination (Figure 6). No long-term toxicity appeared to be associated with this R-CHOP combination. So, the combination of rituximab plus CHOP leads to significant improvement in the outcome of elderly patients with DLBCL, with significant survival benefit maintained over a 5-year follow-up. Because of this improvement R-CHOP became the standard for treating patients with DLBCL not only within the GELA, but also around the world. Currently, the GELA is testing whether giving R-CHOP every 2 weeks might increase response rate and prolong response, particularly in patients with poor-risk lymphoma. The feasibility of administering such dose-dense chemotherapy to elderly patients with a high age-adjusted IPI score and concomitant diseases is questioned but not known. We are also testing whether treating and preventing anemia (that is, maintaining a hemoglobin level of 13 g/dL) in these patients may render them able to tolerate the dose-dense regimen. Young Patients With Intermediate-Risk DLBCL According to the age-adjusted IPI, these patients have one adverse prognostic factor, usually disseminated stage or high LDH level. In these patients, we demonstrated that ACVBP plus consolidation chemotherapy was superior to m-BACOD.[8] In the subsequent LNH98-2B study, we tried to improve on ACVBP by defining the subgroup of patients with worst prognosis on the basis of the expression of bcl-2 protein.[ 16] Patients without bcl-2 protein expression were treated with ACVBP plus sequential chemotherapy, and those with bcl-2 protein expression were treated with ACVBP followed by autologous transplant with the CBV-mitoxantrone regimen.[17] From 1999 to 2002, 272 low/inter-mediate-risk patients (age-adjusted IPI score of 1) entered the trial and presented either with bcl-2 protein overexpression (151) or without (121). There was no difference in initial characteristics and complete remission rates between bcl-2 protein positive and negative patients (78% and 82%,respectively, P = .38). Although patients not expressing bcl-2 protein retained a longer 2-year overall survival than patients expressing bcl-2 protein (95% vs 86%, P = .01), 2-year eventfree survival and 2-year disease-free survival did not differ significantly (84% vs 79%, P = .33; and 89% vs87%, P = .94, respectively). The lack of difference in eventfree and disease-free survival between patients expressing bcl-2 protein who received high-dose therapy (HDT) and patients not expressing bcl-2 protein treated with conventional consolidation suggested that HDT may overcome the adverse prognostic value of bcl-2 protein expression in low/intermediate- risk patients who achieved complete remission or unconfirmed complete remission. Because elderly patients with intermediate- risk DLCBL responded optimally when treated with the combination of rituximab and CHOP in the above-cited LNH98-5 study, the GELA has decided to conduct a study comparing R-CHOP with R-ACVBP in nonelderly patients with intermediate risk to see whether the combination of rituximab with a dose-dense and dose-intense chemotherapy may further increase response rate and outcome. This study is currently ongoing. The German lymphoma group has recently shown in these patients that R-CHOP or R-CHOP-like regimens do better than the same chemotherapy regimen without rituximab (the MabThera International Trial Group [MInT] study).[18] So, outside a clinical study, R-CHOP might be the recommended regimen. Young Patients With Poor-Risk DLBCL These patients defined by an ageadjusted IPI score of 2 or 3 and age younger than 60 years have the worst outcome. Some of them are truly refractory to chemotherapy-that is, progressed during treatment-and others relapsed soon after the end of treatment. All GELA attempts to modify the chemotherapy regimen to decrease the number of patients who progressed during treatment have failed; the best complete remission rate, around 65%, was reached with ACVBP. The GELA also worked on decreasing the relapse rate with more success. The first study, LNH87-2, compared standard consolidation after four cycles of ACVBP with a CBV (cyclophospamide, carmustine(Drug information on carmustine) [BiCNU], etoposide(Drug information on etoposide) [VePesid]) high-dose regimen followed by autologous transplant (HDT).[19] With a median follow- up of 8 years, and in the population of 236 randomized patients, HDT was superior to sequential chemotherapy: disease-free survival rates of 55% (95% CI = 46%- 64%) and 39% (95% CI = 30%-48%), respectively. The 8-year overall survival rate was significantly superior in the HDT arm (64%; 95% CI = 55%-73%) compared with the sequential chemotherapy arm (49%; 95% CI = 39%-59%). On the basis of this analysis and of the results of the subsequent LNH93-2 study,[20] we hypothesized that HDT benefits patients at higher risk who first achieve complete remission after induction treatment. A randomized study by another French group has recently confirmed our results.[21] To build on these results, the GELA is currently testing two hypotheses. The first is derived from the results obtained in the LNH98-5 study: we now include rituximab in the ACVBP regimen to try to decrease progressions during treatment. As the LNH98-5 and MInT studies have shown that rituximab combined with CHOP increases the complete remission rate and decreases the progression rate, we are confident that we might decrease the progression rate in this group of really poor prognosis patients; however, we do not know if this effect will be observed as well in the case of dose-dense and dose-intense chemotherapy. The second hypothesis tries to further decrease the relapse rate in these patients. To that end, we are currently testing rituximab therapy after autologous transplant.[22] In the first interim analysis on 211 patients who received HDT, 170 were randomized after hematologic recovery to receive either rituximab (n = 90) or nothing (n = 80). With a median follow-up of 13 months, 2-year event-free survival does not yet significantly differ betweenthe two groups (rituximab 80% vs nothing 70%, P = .15). An updated analysis of these patients is pending. The GELA approach in these highrisk patients does combine everything that is possible: rituximab combined with a dose-dense and dose-intense chemotherapy, intensification with autologous transplant, and maintenance with rituximab. If this approach dose not succeed in improving outcome for these patients, the solution may only come from new drugs not yet available for the treatment of lymphoma patients. Patients With T-Cell Lymphoma During the first studies run by the GELA, patients with peripheral T-cell lymphoma (PTCL) and anaplastic large cell lymphoma (ALCL) were included within the same studies as patients with DLBCL. However, with rituximab being part of the treatment for DLBCL patients, patients with T-cell lymphoma are now treated in separate studies. As others, the GELA demonstrated that patients with PTCL have a poorer outcome than patients with DLBCL, particularly in cases of disseminated disease or poor-risk score on the age-adjusted IPI.[23] However, our various attempts to find a better regimen with higher efficacy in PTCL have failed. Patients with ALCL have a better outcome than those with PTCL, and ACVBP provided a very good overall survival rate in these patients.[23] Patients with non-anaplastic PTCL have a worse outcome after HDT with autologous transplant than patients with DLBCL.[20] Currently the GELA has no randomized study ongoing for these patients, but it recommended a dose-dense and dose-intense chemotherapy such as ACVBP for young patients and CHOP or DHAP (dexamethasone, high-dose cytarabine(Drug information on cytarabine) [Ara-C], cisplatin(Drug information on cisplatin) [Platinol]) for elderly patients. Very Old Patients With DLBCL Patients over 80 years old represent a growing group, and more than 50% of them have DLBCL. However,classic treatments are not generally feasible because of one or several concomitant diseases and deteriorated body functions. Single-agent chemotherapy is associated with very poor outcome (C. Thieblemont, personal communication) and more standard chemotherapy should be tested. The GELA is currently conducting a study with adapted R-CHOP in these patients. "Adapted" means that doses of doxorubicin, cyclophosphamide, and vincristine are reduced for the first cycle (25 mg/m², 400 mg/m², and 1 mg/m², respectively) and may be increased for further cycles if tolerance is good. With the addition of rituximab, we hope to have a significant number of complete responses and to prolong the survival of these patients without harming them. Conclusions During the past 20 years, the GELA has conducted several successive randomized studies in patients with DLBCL and successfully built on each study to improve the outcome of these patients. Major improvements made during these studies were (1) the description of benefit associated with a dose-dense and dose-intense regimen, ACVBP; (2) the interest in intensification with high-dose therapy for patients in complete remission and poor-risk lymphoma; (3) the improvement of results by combining rituximab with chemotherapy. However, more studies have to be conducted to improve the outcome of patients with truly refractory lymphoma, T-cell lymphoma patients, and very old patients.