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.

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.

Maintenance Treatment: Interferon-alpha

Interferon-alpha (IFN alfa) is an older cytokine drug used to fight various cancers. It is not a standard first-line drug in lymphoma at this point, but older trials did evaluate interferon alpha, including in a maintenance role. Today, maintenance therapy, when used, is usually based on rituximab (Rituxan, MabThera).

A 2010 Italian review of previous trials argued that IFN alfa might have some impact on overall survival in follicular lymphoma, but only when added to combination chemotherapy, and only at the cost of greater toxic side effects.

Published Trials

P. Baldo et al. "Interferon-alpha for Maintenance of Follicular Lymphoma." Cochrane Database Systematic Reviews (2010).