Clinical Trial Information: Bendamustine-Rituximab (B-R) (BRIGHT Study)

Trial Information: 436 patients will be randomized to receive either Bendamustine-Rituximab (B-R), or conventional therapy (R-CHOP or R-CVP). This is an international Phase III trial intended to compare the effectiveness of bendamustine with a conventional alkalating agent/anthracycline-based regimen, CHOP (cyclophosphamide, vincristine, prednisone, and doxorubicin) or CVP (cyclophosphamide, vincristine, and prednisone).

This study is recruiting people with follicular lymphoma, mantle call lymphoma, Waldenstrom macroglobulinemia, and marginal zone B-cell lymphomas. This is for patients eligible for first-line treatment, i.e. previously untreated and having one or more criteria for treatment (B symptoms, bulky disease, etc.).

Clinical Trial Information: Ofatumumab versus Rituximab

Trial Information: This is a Phase III comparative clinical trial of rituximab (Rituxan) and ofatumumab (Arzerra) monotherapy in follicular lymphoma patients who have relapsed following prior therapy with rituximab. 516 patients will be recruited and randomized to rituximab or ofatumumab, in both cases four weekly treatments followed by an additional treatment every two months, for eight months. Patients must have relapsed following a prior chemotherapy regimen that included rituximab.

Rituximab Maintenance: New PRIMA Trial Data

The Lancet's Online First section has released a new set of data from the major Primary Rituximab and Maintenance Study (PRIMA), a massive analysis of over 1200 patients in 25 countries. Rituximab maintenance is a common strategy for converting some partial responses to complete remission, and in others delaying disease progression, following initial treatment. It usually lasts two years and involves about 6-12 additional cycles of therapy. Cancer Care Ontario, for instance, funds eight maintenance doses over two years, or one every three months.

Once again, the PRIMA data show impressive progression-free survival statistics for follicular lymphoma patients -- meaning patients who, following treatment have both survived and experienced no further disease growth. 1217 patients were enrolled on the PRIMA study; after initial therapy with one of several rituximab-based regimens (R-CHOP, R-CVP, or R-FCM, which contains fludarabine), 1019 people with a detectable response were randomized to either untreated observation or to 2 years of rituximab maintenance.

The short-term benefits of rituximab maintenance are now very apparent. After the 2-year maintenance cycle was complete, 72% of patients were still in complete remission, compared with just over 50% in the untreated arm. Three years out, 75% of maintenance patients still had not experienced disease progression, compared with just 58% in the untreated group. This confirms other studies which suggest that rituximab maintenance cuts the relapse rate roughly in half over the short term.

What PRIMA can't yet answer is the increasingly urgent question of whether rituximab maintenance actually affects overall survival. Overall (long-term) survival statistics are a serious problem in indolent lymphoma research, because the natural history of the disease is already long enough that it can't easily be evaluated in a single trial. So far, the PRIMA data suggests no significant impact on overall survival. However, this may reflect the fact that 2- and 3-year survival statistics for follicular lymphoma are already so high that it is difficult to detect improvement. If benefits do exist, it may take a number of years for them to become apparent in the data.

Research Highlights: Week of December 20, 2010

Beyond my own ramblings, here is an overview of some of the published work that may be of interest to people living with lymphoma, over the past week. I'm skipping over the recent material from ASH, which is of interest in itself. More on that later, perhaps, but there were plenty of interesting papers there, too. Here I look at the December 16 issue of Blood, the December 20 issue of the Journal of Clinical Oncology, December 2010 issues of the British Journal of Cancer, CA, Clinical Lymphoma, Myeloma & Leukemia, Lancet Oncology, and Leukemia & Lymphoma (as dense as always).

Treatment Options: Maintenance Treatment with Rituximab

Rituximab maintenance therapy typically involves multiple doses of rituximab given over a two-year period, such as at three-month intervals (for a total of eight doses in addition to whatever was given in initial treatment).

People who undergo rituximab maintenance have already responded to initial treatment. The premise behind the additional maintenance doses is that it may convert some partial responses into deeper (even complete) remissions, and that it should delay disease progression or relapse, since patients rarely relapse until at least after the maintenance round is complete.

The most important major clinical trial evidence supporting rituximab maintenance is an international study known as the PRIMA study (Primary Rituximab and Maintenance). PRIMA recruited over 1200 patients in 25 countries. 1019 people responded after initial treatment including rituximab (R-CHOP, R-CVP, or R-FCM) and then went on to the maintenance round. After three-years, progression-free survival was 75% in the maintenance arm, compared with 58% in the observation arm (who received no further treatment prior to progression).

Other studies have provided similar findings. The German Low-Grade Lymphoma Study Group reported in 2006 that the median progression-free survival after R-FCM was 16 months without maintenance, and had not reached the median in its maintenance arm.

Currently, the main question to be resolved is whether rituximab maintenance provides a genuine benefit in terms of overall survival. Indolent lymphoma life expectancies are long enough that overall survival studies take considerable amounts of time to complete. However, it is at least possible that the up-front benefit of maintenance is countered by greater resistance to therapy if and when relapse does occur, later on. Long-term studies are needed to confirm the benefits of rituximab maintenance.

Bendamustine Continues to Impress

This month, some new trial data came available that continues to illustrate the advantages of the "new" alkylating agent bendamustine (Treanda). Bendamustine is a nitrogen mustard agent that was developed in East Germany in the 1960s. Despite being a very old communist drug, it is now a very new capitalist drug, with the price tag and brand name to boot. It's effective enough that there are now a number of trials looking at whether bendamustine can stand in for the more conventional chemotherapy regimens like CHOP (in combination, of course, with new drugs of choice like rituximab).

In Canada, there are currently five ongoing clinical trials involving bendamustine that are looking for test subjects with lymphoma. These include an ofatumumab trial in refractory patients (bendamustine versus O-B), a GA101 study in refractory patients (bendamustine versus B-GA101) the major BRIGHT Study for new patients (B-R going head to head with the older standbys, R-CHOP and R-CVP). A sixth trial is looking at bendamustine in childhood leukemia patients.

An End to "Watch & Wait"?

"Watch & Wait" has got to be one of the stupidest phrases in medical history, guaranteed to provoke anxiety as much as any other response. The rationale is the same for all indolent lymphomas, like follicular lymphoma: decades ago, studies demonstrated that chemotherapy would have more or less the same effect whether it was started immediately upon diagnosis, or delayed until a later date when troubling symptoms developed or tumours grew to an unacceptable size. Since then, every new therapy is evaluated as a potential end to the watch and wait era.

Which brings us to Rituxan (rituximab), certainly the most important lymphoma drug of the last decade. One of the most important studies to emerge from the ASH conference in December 2010, judging from the flourish of congratulatory press coverage, is one claiming that rituximab is better with immediate, up-front treatment. So far, I'm just not buying it.