Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop.

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials.

Assessment of bone marrow response in Waldenström's macroglobulinemia.

In this study we used bone marrow flow cytometry and immunohistochemistry to evaluate response to fludarabine therapy in patients with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma. Responses in serum M protein were typically delayed with a median time to maximum response of 6 months following the completion of therapy (range, 0-18 months). In contrast, bone marrow responses occurred promptly in responding patients such that there were no detectable clonal B cells at the end of therapy in 55% of patients assessed. Persistent monoclonal plasma cells were, however, readily identified by CD138 immunohistochemistry, explaining the persistence of serum M protein in these patients. This simple observation has significant implications for the assessment of responses in WM as well as the design of future therapeutic strategies.

CD52 expression in Waldenstrom's macroglobulinemia: implications for alemtuzumab therapy and response assessment.

The efficacy of monoclonal antibody therapy is determined, at least in part, by the extent to which the target antigen is expressed. This is a complex issue in Waldenstrom's macroglobulinemia (WM) as it is a disorder characterized by plasma cell differentiation and therefore target antigen expression may differ between the B-cell and plasma cell compartments of the disease. In order to assess this in the context of alemtuzumab therapy, the authors used multiparameter flow cytometry to determine CD52 expression in the B-cells and plasma cells of patients with WM. CD52 expression was demonstrable in the B-cells of all cases, with a median of 99% of cells (range, 81%-100%) expressing the antigen compared with the isotype control (n = 47). Antigen density was very similar to that seen in chronic lymphocytic leukemia (median mean fluorescence intensity [MFI], 1249; range, 175-3170). Antigen expression was, however, significantly lower in the plasma cells (median MFI, 235; range, 31-1814) in all but 1 of the cases assessed (n = 21). The clinical significance of this was assessed by examining serial bone marrow samples from patients receiving alemtuzumab as part of an ongoing clinical trial. In 4 of 5 patients, alemtuzumab therapy successfully eradicated clonal B-cells from the bone marrow, but residual plasma cells remained evident in 2 of these patients. The implications of these findings for monoclonal antibody therapy in WM are discussed.