Peter Johnson, MD
2010-01-01
Dr. Johnson
has served on Scientific Advisory Boards for Roche and Genentech.
Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of
molecular relapse after autologous stem cell transplantation in mantle cell
lymphoma. J Clin Oncol.
2009;27:4365-70.
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.
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.
- Dreyling M, Lenz G, Hoster E, et al. Early
consolidation by myeloablative radiochemotherapy followed by autologous stem
cell transplantation in first remission significantly prolongs event-free
survival in mantle-cell lymphoma: results of a prospective randomized trial of
the European MCL Network. Blood. 2005;2677-84.
- Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy
with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone
significantly improves response and time to treatment failure, but not
long-term outcome in patients with previously untreated mantle cell lymphoma:
results of a prospective randomized trial of the German Low Grade Lymphoma
Study Group (GLSG). J Clin Oncol. 2005;1984-92.
- Geisler CG, Kolstad A, Laurell A, et al. Long-term
progression-free survival of mantle cell
lymphomaafterintensivefront-lineimmunochemotherapy with in vivo-purged stem
cell rescue: A nonrandomized phase 2 multicenter study by the Nordic Lymphoma
Group. Blood.2008;112:2687-93.
back to top
