Matched Pair Analysis Comparing the Outcomes of Primary Breast and Nodal Diffuse Large B Cell Lymphoma In Patients Treated with R-Chop; Consortium for Improving Survival of Lymphoma (CISL) Study.

The addition of rituximab to standard chemotherapy has substantially improved the survival in patients with diffuse large B cell lymphoma (DLBCL). Previous studies in the pre-rituximab era have identified the worse outcomes in primary extranodal DLBCL compared with nodal DLBCL. However, there have been reported conflicting datas about outcomes of primary extranodal DLBCL compared with nodal DLBCL in the rituximab era. Primary breast DLBCL is one of the extremely rare extranodal lymphoma. As in other primary extranodal lymphoma, few clinical studies have been reported for investigating the efficacy of rituximab in patients with primary breast DLBCL. For clarifying this, a large randomized trial comparing survival in patients with primary breast DLBCL is required. However, the rarity of primary breast DLBCL makes large trial virtually difficult in single center or study group. Additionally, retrospective studies for evaluating the role of rituximab in primary breast DLBCL had bias according to the difference of treatment period between CHOP and R-CHOP era. Thus, to investigate the impact of rituximab in primary breast DLBCL, we performed a matched pair analysis following strict matching criteria in patients with primary breast and nodal DLBCL treated with R-CHOP.

Primary breast DLBCL patients treated with R-CHOP was identified from 11 hospitals in Korea between May 2004 and August 2009. The eligibility criteria included: (1) histologically confirmed DLBCL, (2) Ann Arbor stage I or II of primary breast DLBCL, defined as isolated breast involvement with or without nodal disease, (3) received front-line treatment with R-CHOP. Each primary breast DLBCL patient was matched to three nodal DLBCL patients treated with R-CHOP during the same period from the data registry of Korean Lymphoma Working Party. The patients were matched for 5 known prognostic factors: age (<60 vs. ≥60), Ann Arbor stage (I vs. II), Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0-1 vs. 2–3), serum LDH level (normal vs. elevated), and B symptom (absent vs. present). All factors should be matched between the four matched patients.

Twenty-five patients with primary breast DLBCL were identified. The median age at diagnosis was 56 (range, 21–79) years and all patients were female. The Ann Arbor stage was I in 13 patients (52%) and II in 12 patients (48%). ECOG PS was 0 or 1 in 23 patients (92%), B symptom was present in 1 patient (4%), and serum LDH level was elevated in 9 patients (36%). Thus, stage-modified international prognostic index (IPI) was 0 or 1 in 20 patients (80%). Eight patients (32%) were received 3 or 4 cycles of R-CHOP followed by involved field radiotherapy and 17 patients (68%) were treated with 6 to 8 cycles of R-CHOP. After matching process, stage-modified IPI, treatment strategy, radiation dose, and follow-up duration as well as 5 matching factors were not significantly different between primary breast and nodal DLBCL groups. With a median follow-up of 34.3 (range, 4.4–76.2) months, 3-year progression-free survival (PFS; 70.0% [59.9-80.1] vs. 85.2% [79.9-90.5], p=0.145) and overall survival (OS; 82.2% [72.6-92.8] vs. 90.0% [86.0-94.0], p=0.528) was not statistically different between primary breast and nodal DLBCL groups. In multivariate analysis, 2 or 3 risk factors of stage-modified IPI were independent prognostic factor for worse PFS (hazard ratio [HR], 3.18; 95% CI, 1.22–8.30) and OS (HR, 4.88; 95% CI, 1.55–15.33). Comparing 3-year cumulative incidence of progression between primary breast and nodal DLBCL, extranodal progression in the breast or central nervous system (CNS) was significantly higher in the primary breast DLBCL than nodal DLBCL (23.6 ± 9.3% vs. 1.4 ± 1.3%, p<0.001, respectively).

In the post rituximab era, the survival outcomes of primary breast DLBCL were not significantly inferior to those of nodal DLBCL. These results suggest adding rituximab improve survival in primary breast DLBCL as in nodal DLBCL, so that the results provide evidence to add rituximab in this rare extranodal DLBCL. However, even including rituximab, extranodal progression in the breast or CNS was observed still high. Thus, further larger studies of international collaboration to confirm these results are warranted.

No relevant conflicts of interest to declare.