Nicol Macpherson

PURPOSE: For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC). METHODS: We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with "B" symptoms or bulky [> 10 cm] disease) DLBCL. RESULTS: A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P = .002) and overall survival (risk ratio, 0.40; 95% CI, 0.27 to 0.61, P < .0001) were significantly improved in the postrituximab group. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of progression-free survival (risk ratio, 0.59; 95% CI, 0.41 to 0.85; P = .005) and overall survival (risk ratio, 0.43; 95% CI, 0.29 to 0.66; P < .001). The benefit of treatment in the postrituximab era was present regardless of age. CONCLUSION: The addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL patients of all ages in the province of BC.

INTRODUCTION: Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels. METHODS: The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1. RESULTS: In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes. CONCLUSIONS: ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.

PURPOSE: To correlate cytogenetic abnormalities with clinical presentation and outcome in Burkitt-like, small noncleaved non-Burkitt's lymphoma (SNC-NB). PATIENTS AND METHODS: Thirty-nine patients with SNC-NB lymphoma and a clonal karyotype were evaluated between January 1989 and January 1996. All were from British Columbia, Canada, underwent uniform clinical staging, and were treated on investigational protocols by a small group of clinicians. RESULTS: Three groups of patients were identified by clonal karyotype on cytogenetic analysis: (1) those with a c-myc translocation (n = 11); (2) those with dual translocation of c-myc and bcl-2 (n = 13); and (3) those with other cytogenetic abnormalities (n = 15). The c-myc group was younger, presented with earlier stage de nova disease, and had a better clinical prognostic factor profile. The dual-translocation and other groups were older and presented in advanced stage with poorer prognostic features, and a larger proportion of the dual-translocation group patients had transformed from previously diagnosed follicular lymphoma. The median overall survival (OS) time for all patients was 5 months. The median OS time for the dual-translocation group was only 2.5 months, as compared with 7 months and 8 months for the c-myc and other group, respectively (P < .001). There were no survivors beyond 7 months among the dual-translocation group, as opposed to 32% and 25% 2-year OS rates in the c-myc and other group. CONCLUSION: SNC-NB lymphoma is a clinically and cytogenetically heterogenous disease. Dual translocation of c-myc and bcl-2 is characterized by a rapid clinical course and extremely poor outcome. This latter entity may represent the most clinically aggressive lymphoma thus far characterized and warrants intensive investigational treatment where feasible.