Low Immunoglobulin G and Low Lymphocyte-Monocyte Ratio at the End of Treatment Predict Early Progression in Diffuse Large B-Cell Lymphoma

Introduction

The outcome of diffuse large B-cell lymphoma (DLBCL) has improved with rituximab-containing immunochemotherapy. However, some patients with DLBCL experience relapse or disease progression. Particularly, early progressive disease (EPD) influences dismal prognosis. Immunoglobulin G (IgG), absolute lymphocyte (ALC) and lymphocyte-monocyte ratio (LMR) are candidates for host immune biomarkers and reportedly influence the prognosis of DLBCL. We performed a retrospective analysis to identify the key factors affecting EPD in DLBCL patients.

Patients and Methods

Patients newly diagnosed with DLBCL at our institution between January 2015 and December 2021 were evaluated. All patients were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In this study, EPD was defined as progression within 12 months from the date of initial treatment. We surveyed the correlation between EPD and characteristics (age >60 years, performance status [PS] ≥2, international prognostic index [IPI] ≥3, serum albumin [Alb] ≤3.5 g/dl, and lactate dehydrogenase [LDH] >upper limit normal [ULN]) and immune biomarkers (IgG, ALC, and LMR) at the time of diagnosis and at the end of treatment (EOT). We analyzed I) comparison of immune biomarkers between groups; Group1: EPD, Group2: late PD, Group3: no PD, II) factors related to EPD, and III) progression-free survival (PFS) and overall survival (OS) between patients with EPD factors. Statistical analyses of patient characteristics were performed using Fisher's exact test, Student's t-test, or Mann-Whitney U test. Comparison of immune biomarkers between the Group1-3 was conducted using the Kruskal-Wallis test. The optimal cutoff of immune biomarkers for EPD was calculated using receiver operating characteristic (ROC) analysis. Factors affecting EPD were evaluated using Gray's test and the Fine-Gray proportional hazard model. Survival was calculated using the Kaplan-Meier method, and statistical analyses were performed using the log-rank test.

Results

Among 263 patients, 104 experienced relapse/progression (including 66 with EPD), with a median follow-up of 41 months (range 3-106 months). The median age of the EPD group was 71.5 years (range: 43-85 years). Twenty-five (37.9%) patients had PS ≥2, 39 (59.1%) had Alb ≤3.5 g/dl, 56 (84.8%) had LDH >ULN, and 45 (68.2%) had IPI ≥3. The median IgG, EOT-IgG, ALC, EOT-ALC, LMR, and EOT-LMR in the EPD group were 1145 mg/dl, 685 mg/dl, 1100 /μl, 800 /μl, 2.4 and 2.0, respectively. Regarding the comparison of immune biomarkers between the Group1-3, only EOT-IgG was significantly different (median 685 mg/dl [Group1] vs. 735 mg/dl [Group2] vs. 831 mg/dl [Group3], p<0.001). Based on ROC analysis, the cutoff values of immune biomarkers for EPD were determined as follows: IgG 1150 mg/dl, EOT-IgG 780 mg/dl, ALC 1100 /μl, EOT-ALC 600 /μl, LMR 3.0, and EOT-LMR 1.5. By multivariate analysis, EOT-IgG ≤780 mg/dl (hazard ratio [HR]: 2.52, 95% confidence interval [95%CI]: 1.44−4.39, p=0.0012), LDH >ULN (HR: 2.31, 95%CI: 1.13−4.75, p=0.023), EOT-LMR ≤1.5 (HR: 3.15, 95%CI: 1.89−5.24, p<0.001), and PS ≥2 (HR: 1.85, 95%CI: 1.01−3.40, p=0.046) were associated with EPD. Next, we divided patients into three groups according to the total number of risk factors (low EOT-IgG, high LDH, low EOT-LMR, and poor PS); 0-1 (low), 2 (intermediate), and 3-4 (high). A high proportion of advanced-stage (81.5% vs. 49.8%, p<0.001) and extranodal lesions ≥2 (42.3% vs. 15.8%, p<0.001) were observed in the high-risk group. PFS and OS were significantly different between the low-, intermediate-, and high-risk groups (3-year PFS: 80.3% vs. 53.2% vs. 28.4%, p<0.001 and 3-year OS: 95.6% vs. 75.1% vs. 51.2%, p<0.001, respectively).

Discussion and Conclusion

Low IgG levels and low LMR at EOT may be influenced by aggressive disease status and reflect the suppression of tumor immunity. A high tumor burden reportedly promotes inflammatory cytokines such as interleukin (IL)-9 and IL-10, which are associated with regulatory T cells and are involved in the immunosuppressive state (Feng LL, 2011; Ji H, 2018). Another report indicated that a high degree of M2 macrophage is correlated with lymphopenia and residual lymphoma cells after chemotherapy (Jones K, 2015). In conclusion, our study suggests that a poor immune environment predicts early progression and poor prognosis in patients with DLBCL.

Kawashima:Ono Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; AstraZeneca K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi K.K.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; SymBio Pharmaceuticals Limited: Honoraria; Nippon Kayaku Co.,Ltd.: Honoraria; TAIHO Phamaceutical Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Genmab K.K.: Honoraria. Suzuki:Bristol Myers Squibb: Honoraria; Sanofi: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Gunji:Bristol-Myers Squibb K.K.: Honoraria; AbbVie Inc.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Asahi Kasei Pharma Corp.: Honoraria; AstraZeneca K.K.: Honoraria; Sanofi K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria. Nishiwaki:Nippon Shinyaku CO., LTD.: Honoraria; Abbvie Inc.: Honoraria; Chugai Pharmaceutical CO., LTD.: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Pfizer Inc.: Honoraria. Dobashi:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc: Research Funding; AbbVie GK.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AstraZeneca K.K.: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Novartis Pharma K.K.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd: Research Funding; Amgen K.K.: Speakers Bureau. Yano:Ono Pharma: Speakers Bureau; Janssen: Speakers Bureau; Eisai: Speakers Bureau; Astrazeneca: Speakers Bureau; Pfizer Japan: Speakers Bureau; Kyowa KIRIN: Speakers Bureau; Kyowa KIRIN: Research Funding; Sumitomo Pharma: Research Funding; TAIHO Phamaceutical Co., Ltd.: Research Funding; Icon Japan: Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Novartis Japan: Research Funding; Takeda: Research Funding; Syneos Health: Research Funding; Mebix: Research Funding; Abbvie: Research Funding; MSD: Research Funding; Japan Airlines: Research Funding; Takeda: Speakers Bureau; MSD: Speakers Bureau; Astellas Japan: Speakers Bureau; Daiichisankyo: Speakers Bureau; Abbvie: Speakers Bureau; Novartis Japan: Speakers Bureau; Chugai Pharmaceutical Co.,Ltd.: Speakers Bureau; Nippon shinyaku: Speakers Bureau; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Asahikasei Pharma: Research Funding; Dainippon Pharmaceutical: Research Funding; Kissei: Research Funding; Daiichisankyo: Research Funding; Teijin pharma limited: Research Funding; Eli Lilly Japan K.K: Research Funding; SymBio: Speakers Bureau.