While the results of treatment for germinal center lymphomas have been steadily improving, the natural history of mantle cell lymphoma (MCL) has been more difficult to influence, and the median survival has remained three to five years in most series. Trial data suggest that cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is probably not optimal, and indeed there is little evidence to support the use of anthracyclines. Maintenance interferon and high-dose therapy in first remission have been tested, but, in general, relapse is the rule and overall survival is not different.1 The addition of rituximab to CHOP improves response rates and time-to-progression, but not long-term outcome.2 However, there was encouragement from the Nordic Lymphoma Group, which treated patients under age 66 with an intensified R-CHOP regimen incorporating high-dose cytarabine, followed by myeloablative therapy in first remission and rescue with autologous peripheral blood progenitor cells.3 The overall response rate of 96
percent, six-year survival of 70 percent, and progression-free survival of 66 percent among 160 patients was unusually good, particularly since no recurrences were reported beyond six years, hinting at some possible cures. This follow-up paper from the same group analyzes the results of rituximab given pre-emptively after high-dose therapy in this series.
MCL is characterized by overexpression of the cell cycle regulator cyclin D1 resulting from an (11;14) translocation between the immunoglobulin heavy chain and CYCLIN-D1 (BCL-1) genes. This characteristic may explain the frequent acquisition of resistance to chemotherapy and also serves as a potential marker of low-level disease, using polymerase chain reaction (PCR) technologies.
This study looked at the effects of giving four doses of rituximab at weekly intervals after autografting at the time when molecular relapse was detected by PCR. In 16 of the 26 treated patients continued remission was achieved, although in five cases a repeat administration was required to control the disease. In the remaining 10 cases, the disease relapsed clinically, despite an initial molecular response in six. A further 38 patients had continuing molecular remission after high-dose therapy and were not given rituximab; 33 of them remained in clinical remission.
In Brief
Various attempts have been made to use molecular detection of recurrent lymphoma to guide therapy, and to date none has given definitive evidence of an advantage. This study builds upon the impressive clinical results of the Nordic Group with MCL and suggests that, at the least, it is possible to lower the number of lymphoma cells below the threshold of detection with pre-emptive rituximab. How influential this might be on the eventual outcome is hard to say, but the overall figure of 16/26 in reasonably durable remission after molecular relapse is encouraging. A major difficulty of this approach is clearly its generalizability; of 148 patients who received high-dose therapy, only 78 had PCR-detectable disease in the original bone marrow, which is why so few actually came to receive pre-emptive rituximab. To test this approach in a randomized trial, it will be essential to derive molecular markers from involved lymph nodes as well as bone marrow; this is certainly an approach to consider for future trials. The alternative strategy of giving all patients rituximab after high-dose therapy would clearly be much easier to do in practice.
From this series we would predict that around half the patients treated this way would receive the antibody unnecessarily.
References
Competing Interests
Dr. Johnson has served on scientific advisory boards for Roche and Genentech.
