Emergence of New lesions upon Treatment failure is an Independent, Negative Prognostic Factor for Patients with Primary Refractory DLBCL
Authors: Yamauchi Nobuhiko , Koba Yusuke , Ochi Yotaro , Kazuma Yasuhiro , Nagahata Yosuke , Ono Yuichiro , Hiramoto Nobuhiro , Tabata Sumie , Yonetani Noboru , Matsushita Akiko , Hashimoto Hisako , Imai Yukihiro , Ishikawa Takayuki 
Published: November 2019

Abstract
<Introduction>Diffuse large B-cell lymphoma (DLBCL) has an aggressive clinical course and, even in the R-CHOP era, about 10-20% of DLBCL patients (pts) show primary refractory disease. For pts with primary refractory disease, salvage chemotherapy with or without stem cell transplantation (SCT) is generally performed, but even with this treatment, less than half of the pts survive. To elucidate the pts population who require innovative therapy, we retrospectively analyzed the risk factors that lead to an unsuccessful outcome of primary refractory DLBCL.
<Patients and Methods>DLBCL pts who received R-CHOP with curative intent were included. Pts with primary mediastinal large B-cell lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma and iatrogenic immunodeficiency-associated lymphoproliferative disorders were excluded. In this study, primary refractory disease was defined as disease progression during first-line immuno-chemotherapy or recurrence within 3 months after completion of the first-line therapy. The primary endpoint was overall survival (OS) after treatment failure, which was assessed using the Kaplan-Meier method. The log-rank test and Cox regression analysis were used to assess the prognostic values of each clinical variable.
<Results>From January, 2004 to December, 2013, 440 DLBCL pts were referred to our institute. Among them, 60 pts (20 females and 40 males) were considered to have primary refractory disease (55 with progressive disease and 5 with early relapse). At the time of treatment failure, the median age was 72 (range, 31–90) and 44 pts (73%) showed advanced stage (stage IIIor more) disease. Nineteen (32%) had an ECOG performance status (PS) of 2 or more, and 23 (38%) had a high IPI score. In 31 pts, disease progression was observed at novel sites that had not been detected during the initial evaluation; patients with these sites were designated as "new lesion pts". The remaining 29 pts displayed regrowth of known lesions and were designated as "regrowth pts". Among new lesion pts, 29 displayed extranodal disease. After disease progression, 52 pts received salvage chemotherapy or radiotherapy, and 21 pts achieved a clinical response. Among the 24 patients less than 70 years old, 11 received autologous or allogeneic stem cell transplantation (SCT). After a median follow-up time of 17 months (range, 1–81 months), 39 pts had died of lymphoma. The 1-year OS rate (1y-OS) was 38.8% [95% confidence interval (CI), 25.5-51.8%].Univariate analysis using clinical variables at the time of treatment failure revealed that new lesion pts or patients with an IPI score >3 had a poor 1y-OS rate (p<0.05). The presence of CNS involvement or bulky disease at treatment failure had no effect on OS. In addition, progressive disease before the 4th course of R-CHOP or at a CHOP dose intensity less than half of that actually prescribed had no negative impact on OS. After adjusting for IPI score using multivariate analysis, new lesion pts had an independent, poor prognostic factor for OS (HR, 3.11; 95%CI, 1.34-7.23; p=0.008). The unadjusted 1y-OS of new lesion pts was 11.4% (95% CI, 2.9-26.3%), which was significantly lower than that of regrowth pts, who had a 1y-OS of 65.8% (95% CI, 43.9-80.8%) (HR, 4.4; 95% CI, 2.1-9.3; log-rank, p<0.001). Of 31 new lesion pts, six achieved a clinical response after salvage chemotherapy, but the remission durations were short. Five patients who received SCT died of lymphoma.
<Conclusion>Primary refractory DLBCL pts with new lesions, most of which were extranodal sites, have an extremely poor outcome. Disease progression at novel extranodal sites may indicate that the disease has chemotherapy-resistant characteristics. Routine approaches using platinum- or cytarabine-based salvage chemotherapy followed by SCT rarely overcome the progressive nature of the disease, and a novel treatment strategy is required.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.