Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma

Abstract

We conducted a randomized trial to compare the intensive conventional chemotherapy regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) with standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in previously untreated patients with poor-risk aggressive lymphoma. Patients aged 61 to 69 years who had aggressive non-Hodgkin lymphoma with at least one prognostic factor of the age-adjusted international prognostic index (IPI) were included. ACVBP consisted of an induction phase of intensified chemotherapy and central nervous system (CNS) prophylaxis followed by a sequential consolidation phase. Of the 708 patients registered for the study, 635 were eligible. The rate of complete response was 58% in the ACVBP group and 56% in the CHOP group (P ‫؍‬ .5). Treatmentrelated death occurred in 13% of the ACVBP group and 7% of the CHOP group (P ‫؍‬ .014). At 5 years, the event-free survival was 39% in the ACVBP group and 29% in the CHOP group (P ‫؍‬ .005). The overall survival was significantly longer for patients treated with ACVBP, at 5 years it was 46% compared with 38% for patients treated with CHOP (P ‫؍‬ .036). CNS progressions or relapses were more frequent in the CHOP group (P ‫؍‬ .004). Despite 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 survival and overall survival. IntroductionThe incidence of non-Hodgkin lymphoma, especially that of aggressive histology, is steadily increasing. 1 However, during the last 30 years, improvement in treatment outcome remained modest 2 and less than 50% of the patients with aggressive lymphoma are cured.The standard treatment used since the 1970s is the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy regimen, 3 delivering 8 cycles at a 3-week interval in advanced disease. Subsequently, new combinations including additional non-cross-reacting drugs such as methotrexate, bleomycin, or cytarabine have been proposed. [4][5][6] However, multicenter randomized trials failed to demonstrate any survival advantage of these second-and third-generation regimens over the standard CHOP. 7,8 Since 1980, the Groupe d'Etudes des Lymphomes (GELA) has developed a chemotherapy schedule, the ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen, which consisted of an induction phase of 4 cycles of intensified CHOP with central nervous system (CNS) prophylaxis followed by a sequential consolidation phase. 9,10 In a previous study, the comparison of this regimen with m-BACOD (cyclophosphamide, doxorubicin, vincristine, bleomycin, methotrexate, and dexamethasone), a third-generation regimen, in patients with low-risk aggressive lymphoma, showed that ACVBP could be beneficial for patients with more advanced disease. 11 Therefore, in 1993, the GELA initiated a phase 3 study comparing ACVBP to CHOP in patients with poor-prognosis aggressive lymphoma. We restricted this trial to...

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial

“…ACVBP improves results over CHOP in comparative trials assessing patients with localised diff use large B-cell lymphoma 8 and patients with more advanced disease. 9 The association of rituximab with ACVBP in patients younger than 60 years with an ageadjusted International Prognostic Index score of 1, as in our trial, seems to improve progression-free survival from 81% at 2 years 22 to 90%.…”

“…The induction phase is associated with noticeable haematological toxic eff ects, which is why the regimen is only used in patients younger than 60 years. 9 Most patients experience substantial neutropenia between day 9 and day 13 of each cycle, with a substantial proportion (39%) having a febrile episode despite the use of growth factor. However, our trial and previous ones involving the ACVBP regimen 25 have shown that lifethreatening complications related to treatment are uncommon in a population of patients younger than 60 years with good performance status.…”

“…Two randomised studies done in the so-called prerituximab era showed that the intensifi ed doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone chemotherapy regimen (ACVBP) with subsequent sequential consolidation, compared with standard CHOP, can improve the outcome both in low-risk 8 and high-risk 9 groups of patients, according to the International Prognostic Index for aggressive lymphoma. 10 Similarly, the Deutsche Studiengruppe Hochmaligne Non-HodgkinLymphome 11 showed that the addition of etoposide to CHOP improves the event-free survival of patients younger than 60 years with aggressive lymph oma.…”

High frequency of neurolymphomatosis as a relapse disease of intravascular large B‐cell lymphoma

“…Similar observations have been made in patients with CNS relapse of aggressive non-Hodgkin lymphoma. 33,34 Recently, Gan et al 35 reported 4 patients who had diffuse large B-cell lymphomas that were complicated by the presence of NL. It is noteworthy that all NL occurred as recurrent disease during or shortly after those patients completed chemotherapy, as observed in our patients.…”

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

“…IT methotrexate has been most commonly used historically, 12 but evidence of benefit has been equivocal, with no protective benefit observed in 2 large randomized controlled treatment trials of DLBCL. 2,11,[13][14][15] By contrast, the combination of systemic and IT methotrexate has demonstrated effective reduction in CNS recurrence in DLBCL, 16 suggesting that intravenous methotrexate may be primarily responsible for the risk reduction; however, the protective benefit of intravenous high-dose methotrexate without concurrent IT chemotherapy has never been formally evaluated. In the current study, we present what to the best of our knowledge is the first report of high-dose systemic methotrexate combined with standard chemoimmunotherapy to decrease CNS recurrence in high-risk DLBCL patients.…”