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

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 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 peripheral blood as well as in lymph nodes, bone marrow, and extranodal lesions. Stem cells, pre-pre B cells, plasma cells, and dendritic cells are not affected. B cells in peripheral blood are generally undetectable for about 6 months, when recovery begins. The B-cell count enters the normal range in about 9 months. B-cell depletion has not been associated with an increase in infections. It has been speculated that rituximab responders may relapse around the time of B-cell recovery, and that this recovery could be a surrogate marker for relapse.

We have analyzed the database of our 166 patients in a phase III study to determine the correlation between peripheral blood B-cell recovery (fluorescence-activated cell sorting [FACS] assay for CD19-positive cells) and change in tumor bulk (sum of the products of the perpendicular diameters of all measurable lesions [SPD]), bcl-2 clearance (polymerase chain reaction [PCR] assay), and rituximab serum levels. In this study, patients with relapsed or refractory low-grade or follicular NHL received single-agent rituximab at 375 mg/m2 every week ´ 4. The response rate was 48% and the median progression-free survival was 13.2 months.

The SPD initially drops in parallel with the CD19-positive cell count, and the median SPD for responders continues to drop beyond 6 and up until 12 months, despite the increasing number of normal peripheral blood B cells. 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 vs CD19-positive) regardless of bcl-2 status. No apparent correlation between B-cell recovery and molecular relapse was noted.

Immediately following the first infusion, the CD19-positive cell count falls and the rituximab concentration-time curve rises as accumulation of the antibody occurs up to the fourth infusion. Then, serum levels drop and are negligible after 6 months when the CD19-positive cell count starts to rise. The SPD, however, continues to fall up until 12 months. In this clinical trial, we have also observed that some patients relapse while still B-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 between B-cell recovery and SPD, bcl-2, or serum levels that would indicate that it could be a surrogate marker for relapse. It is more likely that normal B cells are recovering from the stem cell pool and that the NHL cells are following a different, and certainly not parallel, course.

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

 
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