Response: BCL6 and outcome in diffuse large B-cell lymphoma: a work in progress

In patients with a median age of 69 years, we believe the results reported by Winter et al¹  in patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R-CHOP) followed by maintenance rituximab for BCL6⁺ diffuse large B-cell lymphoma (DLBCL) will indeed be difficult to improve upon; the 2-year failure-free survival (FFS) for this specific subgroup was 82%. Dunleavy et al are contending that these results are an overestimation since they include only the patients that had a complete or partial response to induction therapy; however, this is not the case. The subset of patients enrolled in E4494 for the analysis by Winter et al¹  was selected on the basis of the following: Southwest Oncology Group (SWOG)/Eastern Cooperative Oncology Group (ECOG) patients, tissue availability, and staining for BCL6. We agree, however, if one focuses on the patients treated with R-CHOP and analyzes the data by intent to treat, excluding the use of maintenance rituximab, then the results offer only a modest improvement over CHOP chemotherapy; the 3-year FFS is approximately 40% as suggested by Dunleavy et al. However, it is not valid to compare this study with that of the National Cancer Institute (NCI) single-center phase 2 study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), where FFS is 88% with all the well-known problems with selection bias in a small single-center trial involving a much younger patient population. If these study populations could be well balanced, a small difference in outcome would require a large randomized study to establish the superiority of either R-CHOP-21 with or without maintenance or DA-EPOCH-R. One may be able to look at this subgroup in the ongoing Cancer and Leukemia Group B (CALGB) phase 3 trial comparing R-CHOP-21 and DA-EPOCH-R, but we would predict that any improvement in this elderly cohort will be small.

We agree with Dunleavy et al that the BCL6^+/− division in the Winter et al paper¹  likely was at best a rough surrogate for cell of origin. BCL6 expression is seen in both germinal center (GC) and non-GC lymphoma, though more common in the former. Immunohistochemistry (IHC) classification of the samples with CD10, BCL6, MUM1, and possibly FOX P1 would provide a better definition of cell of origin. It would be interesting to see if the correlation of outcome was more closely related to cell of origin or BCL6 expression. Without these data, it is difficult to know if the benefit of rituximab was related to cell of origin or more specifically to BCL6 expression. Without these data, it is premature to speculate on the mechanisms by which rituximab may be acting in these tumors.

We agree that rituximab may not be needed in all subsets of DLBCL. However, before the practicing oncologist eliminates rituximab from the treatment of newly diagnosed DLBCL, we need to be certain that we can prospectively identify the patients who will not benefit from rituximab.