Rituximab (Rituxan) is a chimeric monoclonal antibody that targets the CD20 anti-gen on normal and malignant non-Hodgkin’s lymphoma (NHL) cells. It has been shown to produce immediate, severe, and specific B-cell depletion in
Rituximab (Rituxan) is a chimericmonoclonal antibody that targets the CD20 anti-gen on normal and malignantnon-Hodgkin’s lymphoma (NHL) cells. It has been shown to produce immediate,severe, and specific B-cell depletion in peripheral blood as well as in lymphnodes, bone marrow, and extranodal lesions. Stem cells, pre-pre B cells, plasmacells, and dendritic cells are not affected. B cells in peripheral blood aregenerally undetectable for about 6 months, when recovery begins. The B-cellcount enters the normal range in about 9 months. B-cell depletion has not beenassociated with an increase in infections. It has been speculated that rituximabresponders may relapse around the time of B-cell recovery, and that thisrecovery could be a surrogate marker for relapse.
We have analyzed the database of our 166 patients in a phaseIII study to determine the correlation between peripheral blood B-cell recovery(fluorescence-activated cell sorting [FACS] assay for CD19-positive cells) andchange in tumor bulk (sum of the products of the perpendicular diameters of allmeasurable lesions [SPD]), bcl-2 clearance (polymerase chain reaction [PCR]assay), and rituximab serum levels. In this study, patients with relapsed orrefractory low-grade or follicular NHL received single-agent rituximab at 375mg/m2 every week ´ 4. The response rate was 48% and the median progression-freesurvival was 13.2 months.
The SPD initially drops in parallel with the CD19-positivecell count, and the median SPD for responders continues to drop beyond 6 and upuntil 12 months, despite the increasing number of normal peripheral blood Bcells. This is true for all responders(n = 76) and for a selected cohort with FACS and SPD data up until 12 months (n= 28). Baseline bcl-2-positive patients exhibit a similar pattern (SPD vsCD19-positive) regardless of bcl-2 status. No apparent correlation betweenB-cell recovery and molecular relapse was noted.
Immediately following the first infusion, the CD19-positivecell count falls and the rituximab concentration-time curve rises asaccumulation of the antibody occurs up to the fourth infusion. Then, serumlevels drop and are negligible after 6 months when the CD19-positive cell countstarts to rise. The SPD, however, continues to fall up until 12 months. In thisclinical trial, we have also observed that some patients relapse while stillB-cell-depleted, whereas others have prolonged remissions (4 or more years)long after their peripheral blood B-cell recovery has occurred.
CONCLUSION: We conclude that there is no correlation betweenB-cell recovery and SPD, bcl-2, or serum levels that would indicate that itcould be a surrogate marker for relapse. It is more likely that normal B cellsare recovering from the stem cell pool and that the NHL cells are following adifferent, and certainly not parallel, course.