Rituximab retherapy in patients with relapsed aggr

Authors: Andrea Borgerding Justin Hasenkamp Bertram Glaß Gerald Wulf Lorenz Trümper

Publish Date: 2009/09/02

Volume: 89, Issue: 3, Pages: 283-289

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Abstract

Neither effective salvage regimens nor the outcome and response to retherapy with rituximab containing chemotherapy have been defined for rituximab pretreated patients with relapsing aggressive lymphoma We report here a singlecentre retrospective outcome analysis of secondline immunochemotherapy with rituximab In 28 patients with relapsed or refractory diffuse large B cell lymphomas firstline immunochemotherapy had induced objective responses in 18 patients Nine of 28 patients responded to rituximab containing salvage therapy leading to a median overall survival of 243 days after start of second immunochemotherapy Longterm disease free survivors 1260 and 949 days were restricted to the group of twelve patients that had received allogeneic stem cell transplantation as consolidation therapy In 21 patients with relapsed mantle cell lymphomas MCL 19 patients had reached remissions with firstline therapy Of those 16 patients experienced responses to salvage therapy with a median overall survival of 226 days Noteworthy none of patients with initial nonresponding disease reached a remission with second immunochemotherapy Seven patients with MCL stayed free from progression after highdose therapy with autologous or allogeneic stem cell transplantation in two and five cases respectively In summary responses to repeated immunotherapy with rituximab were observed in approximately one third and two thirds of initially responding patients with aggressive B cell lymphoma and mantle cell lymphoma respectively but not in primarily refractory disease Lasting remissions were achieved only by highdose chemotherapy with stem cell transplantationThe addition of the monoclonal antiCD20 antibody rituximab to standard chemotherapy regimens significantly improved treatment results for patients with aggressive B cell nonHodgkin lymphoma increasing response rates as well as progression free and overall survival of patients in all prognostic subgroups 1 2 3 4 Approximately one third of patients with diffuse large B cell lymphoma DLBCL however experience relapse of disease 3 4 5 and treatment of such patients remains a major problem For patients who had not received initial immunochemotherapy ICT with rituximabcontaining regimens several studies showed that the addition of rituximab increased the response rates to salvage protocols such as dexamethasone highdose cytarabine and cisplatin DHAP 6 ifosfamide carboplatin and etoposide ICE 7 or gemcitabine/oxaliplatin 8 allowing to proceed to highdose consolidation followed by stem cell transplantation The PARMA trial established highdose chemotherapy with autologous stem cell transplantation as the standard approach for patients with chemosensitive relapsed lymphoma disease 9 Recently Martin et al reported a series of 163 patients with aggressive B cell lymphoma confirming the role of intensified ICT in the relapse situation however also documenting a significantly worse outcome for those 94 patients who had relapsed following initial rituximabcontaining regimens 10 Overall data on outcome after repeated rituximab therapy for patients in relapse after initial ICT are still scarce and the optimal strategy to achieve consolidation of second remission is currently unknown reviewed in 11 Similarly in mantle cell lymphoma MCL several studies have documented the value of ICT with rituximab to improve response rates progression free and overall survival 11 Approaches combining rituximab with highdose chemotherapy regimens including methotrexate and cytarabine with and without stem cell support led to further improvements of treatment results still leaving however a significant proportion of patients to relapse 12 13 14 Again patients were found to experience significant benefit from the addition of rituximab to salvage protocols 15 and data for patients in the situation of relapsed disease following initial rituximab exposure are scarce We report here a retrospective analysis from a lymphoma referral centre analysing patients with aggressive lymphomas failing from firstline immunochemotherapy with RCHOPlike regimens rituximab cyclophosphamide adriamycin vincristine and prednisone This analysis was conducted to expand the data on the response rate to secondline ICT and longterm remissions with any therapy after failure of initial immunochemotherapyOn the basis of ICD10 coding C83 and C851 we identified 51 lymphoma patients treated between December 2002 and May 2008 at the University Medicine Goettingen Germany Included were subjects with histopathologically confirmed diagnosis of DLBCL and MCL at age 18 years that received salvage/retherapy with at least one cycle of rituximab due to primarily refractory or relapsed lymphoma after firstline immunochemotherapy with rituximab Patients with primary central nervous system involvement CD20 negative B cell lymphomas maintenance therapy with Rituximab for MCL patients within trials and absence of progression or refractory disease were ineligible Patients were included independent from a participation in clinical trials This retrospective analysis of treatment was submitted to the ethics committee of the University Medicine of Goettingen Germany and no objections were raisedData acquisition comprised information concerning time of diagnosis age at diagnosis gender stage of disease according to the Ann Arbor classification B symptoms Eastern Cooperative Oncology Group performance status bone marrow involvement lactate dehydrogenase summarised in the International Payment Instruction IPI applied first immunochemotherapy and response to firstline therapy complete remission/partial remission CR/PR vs stable disease/progressive disease SD/PD number of given rituximab cycles in firstline therapy time to progression and relapse after first ICT respectively Further information included highdose therapy including autologous and allogeneic stem cell transplantation matched and mismatched related vs unrelated donors date of last to follow up status of disease at last follow up as well as death Progression free survival was defined as the interval between start of initial or second immunochemotherapy and death or lymphoma progression whichever occurred first Response was defined as CR/PR in imaging meaning a reduction of tumour load more than 50 in volume after therapy regardless of the duration nonresponse therefore was progressive disease/no change or reduction of tumour load less than 50 Patients who died without documentation of progression were considered to have had tumour progression on the date of death unless documented evidence indicated that no progression occurred Data acquisition was based on recorded patient files and survival information acquired from public registration office Unavailable data were censoredProgressionfree survival was calculated from the date of diagnosis to documented disease progression observations were censored on the date the patient was last known to be alive or for patients dying as a result of causes unrelated to lymphoma or treatment at the date of death Overall survival was calculated from the date of diagnosis or the start of second immunochemotherapy until death as a result of any cause or date last known alive The times to event distributions were estimated using the Kaplan–Meier method All statistics were calculated using Statistica 8 software

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