Rituximab in relapsed aggressive lymphoma: play it again, Sam?

In 1976 McKelvey et al. published their results with a new chemotherapy combination consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) [1]. At the time, with 50–70% of patients achieving remissions even in advanced stages, this was considered a breakthrough in the treatment of aggressive lymphoma. CHOP remained the gold standard in aggressive lymphoma until the landmark trial of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and subsequent studies of the German High-Grade Lymphoma Study Group confirmed the superior cure rate after the introduction of combined immunochemotherapy implementing the CD20-specific antibody rituximab [2,3]. Similarly, a number of randomized trials detected a prolonged overall survival also in first-line therapy of follicular lymphoma [4].

This advantage has also been recently confirmed in relapsed aggressive and indolent lymphoma, but almost none of these initial reports included patients pretreated with rituximab in first-line therapy. So far, only one prospective study trial has shown the advantage of a rituximab-containing salvage regimen in relapsed aggressive lymphoma, with the vast majority of patients being rituximab-naive, whereas in follicular lymphoma, a small subgroup analysis of a randomized trial suggested a similar benefit of a rituximab-containing salvage regimen also in rituximab-pretreated patients [5,6].

However, these studies do not represent today's scene. Almost all patients with either aggressive or indolent lymphoma are currently treated with combined immunochemotherapy, at least in the Western world. Accordingly, the rate of rituximab-pretreated patients with relapsed lymphoma has been constantly growing over the last decade. For patients with relapsed aggressive lymphoma who already received rituximab in first-line therapy, data on salvage regimens are still sparse, but significantly lower response rates have been reported in recent publications [7,8].

In this issue of Leukemia and Lymphoma, Johnston et al. address this question in 178 patients with relapsed diffuse large B-cell or indolent lymphoma who had previously received a rituximab-containing first-line regimen and were subsequently salvaged with either rituximab monotherapy or rituximab in combination with chemotherapy [9]. The overall response rate was 66%, as compared to 81% in first-line therapy. Whereas the median progression-free survival in follicular lymphoma was still quite reasonable (19.2 months), the results in diffuse large cell lymphoma were much less impressive and somewhat sobering, with a median progression-free survival of only 8.4 months, although in a case–control comparison these data were not significantly worse compared to a historic rituximab-naive patient cohort with relapsed lymphoma.

As a randomized study will probably never be performed due to its questionable ethical aspects, we are in fact forced to consider our clinical decisions based on such retrospective studies. In follicular lymphoma the results of salvage therapy may be further improved by the addition of rituximab maintenance. In contrast, in diffuse large B-cell lymphoma, the observed duration of remission was much shorter, supporting the assumption that relapses after a rituximab-containing first-line therapy tend to have a more aggressive course than in rituximab-naive patients [7,8]. So, how should we address this patient population?

New antibodies, including types I and II anti-CD20 targeted compounds, are currently under investigation with promising results, but until now no clear superiority has been proven. Radioimmunotherapy achieves high response rates in rituximab-refractory follicular lymphoma, but its role in diffuse large B-cell lymphoma remains unclear. New molecular approaches, including immunomodulatory compounds (lenalidomide) and proteasome inhibitors (bortezomib), may have the potential to specifically improve the outcome of patients with the activated B-cell (ABC) type of diffuse large B-cell lymphoma, and may finally allow a molecularly guided therapeutic stratification [10].

However, in this respect, it still seems common sense to argue that, in contrast to indolent lymphoma, you should try as hard as possible to overcome aggressive lymphoma with your first punch.