Peripheral Blood B-Cell Recovery in Patients With Non-Hodgkin’s Lymphoma Treated With Rituximab Does Not Correlate With Onset of Disease Progression

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.

Click here to read Dr. Bruce Cheson's commentary on this abstract.