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Glasgow prognostic score is superior to other inflammation-based scores in predicting survival of diffuse large B-cell lymphoma
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Poster Presentations/Experimental Hematology 43 (2015) S51–S106
3044 - THE INTERNATIONAL STAGING SYSTEM PREDICTS OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH R-CHOP Ru Feng Nanfang Hospital, Guangzhou City, Guangdong Province, China The international staging system (ISS), based only on the serum beta-2 microglobulin and serum albumin levels, has always been used to predict survival in multiple myeloma. But its prognostic significance in the diffuse large B-cell lymphoma (DLBCL) patients, especially in those treated with R-CHOP (rituximab, cyclophosphamide, doxorubicinm vincristine and prednisone), remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients in this study. According to ISS there were 90 of 215 (41.9%) patients in stage I group, 98 of 215 (45.6%) in stage II group and 27 of 215 (12.6%) in stage III group. Patients in stage II/ III group correlated with B symptoms, elevated LDH and higher International Prognostic Index (IPI) score (p50.011, p50.019 p50.001, respectively) comparing with those in stage I group. There was no significant difference in gender, age, performance status, number of extranodal sites, stage and cell of origin subtype in different group(pO0.05). ISS showed no significant impact on the overall survival (OS) and event free survival (EFS) in all DLBCL patients (p50.109 and p50.216, respectively) and also those treated with CHOP regimen (p50.906 and p50.972, respectively). However in the cases treated with R-CHOP, ISS could divide patients into different prognostic group (p50.012 and p50.043, respectively). Multivariate analysis revealed that ISS, independent of IPI, indicated different survival in both OS (relative ratio [RR] 2.849; 95% confidence interval [CI], 1.467-5.534, p50.002) and EFS (RR, 1.795; 95% CI, 1.1552.788, p50.009) in DLBCL patients treated with R-CHOP. In conclusion, these date suggest that ISS at diagnosis may allow the identification of a different outcome subgroup in DLBCL patients treated with R-CHOP, but not in those treated with CHOP.
3045 - THE PROGNOSTIC SIGNIFICANCE OF TUMOR-ASSOCIATED MACROPHAGES AND NK CELLS IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH RCHOP Ru Feng Nanfang Hospital, Guangzhou City, Guangdong Province, China Tumor microenvironment has been reported to be associated with both metastatic spread and diminished in some tumors. Tumor-associated macrophages (TAMs) and nature-killer (NK) cells play an important role in the tumor microenvironment. Therefore, we performed this study to investigate the prognostic implications of TAMs including M1 as well as M2 and NK cells in DLBCLs. We reviewed 77 cases of DLBCL diagnosed between June 2004 and October 2012, who treated with R-CHOP. We performed immunohistochemical stains using CD68, CD163 and CD57 to mark M1 macrophages, M2 macrophages and NK cells on paraffin tissue section. The percentage of TAMs was recorded and graded as: 0 if less than 5%, 1 if 5-25%, and 2 if greater than 25% of the total cells present in tumor cells rich nodules were positive for CD68 or CD163. And counting the mean number of the CD57+ cells in 5 fields under high-power magnification (400 times): 0 if less than 5 positive cells；1 if more than 5 positive cells. Of the 77 DLBCL patients treated with R-CHOP, there were 51 males (66.2%). The median percentage for CD68 was 12.8 % ( range, 2.4–50.84), for CD163 was 12.3 % (range, 1.0–39.2). The median counts of CD57 cells were 5 (range, 1.0-78) per unit area. In univariate analysis, an increase in CD68-positive cells was related to improved EFS (grade 0 vs. grade 2, p5 0.036). By contrast, an increased CD163-positive cells were associated with poor OS (grade0 vs grade2, p5 0.033). While, elevated NK cells have no effect on prognosis. Multivariate analysis, an increased CD68 -positive cells was an independent predictors of EFS (HR 0.467, 95%CI 0.236-0.922, P50.028), an decreased CD163-positive cells and lower LDH were independent predictors for OS (HR 2.287, 95%CI 1.043-5.013, P50.039). These results suggest that M1 macrophages might predict favorable clinical outcome and M2 macrophages predict poor outcome. However, the NK cells have no prognostic significance in DLBCL patients treated with RCHOP.
3046 - GLASGOW PROGNOSTIC SCORE IS SUPERIOR TO OTHER INFLAMMATION-BASED SCORES IN PREDICTING SURVIVAL OF DIFFUSE LARGE B-CELL LYMPHOMA Ru Feng Nanfang Hospital, Guangzhou City, Guangdong Province, China Inflammation-based prognostic scores, such as the glasgow prognostic score (GPS), prognostic index(PI), prognostic nutritional index(PNI), neutrophil lymphocyte ratio(NLR), platelet lymphocyte ratio(PLR) was related to survival in many solid tumors. Recent study showed that GPS can be used to predict outcome in diffuse large B-cell lymphoma(DLBCL). However other inflammation related scores had not been reported in DLBCL, and it also remained unknown which of them was more useful to evaluate the survival in DLBCL. In this retrospective study, a number of 252 newly diagnosed and histologically proven DLBCL patients from January 2003 to December 2014 were included. An elevated GPS, PI, NLR, PNI and PLR were all associated with decreased overall survival(p50.000, p50.000, p50.006, p50.001 and p50.001, respectively) and event-free survival (p50.000, p50.000, p50.011, p50.001 and p50.009, respectively) in univariate analysis. Multivariate analysis indicated that GPS(RR51.768, 95%CI51.043-3.000, p50.034) remained an independent prognostic predictor in DLBCL. The area under the curve of GPS (0.735, 95%CI50.645-0.824) was greater than that of PI(0.710, 95%CI50.6210.799), PNI(0.600, 95%CI50.517-0.683), NLR(0.572, 95%CI50.503-0.642), and PLR(0.599, 95%CI50.510-0.689) by Harrell’s C-statistics. Especially in the DLBCL patients treated with R-CHOP, GPS also remained the most powerful inflammationbased prognostic score when comparing with PI, NLR, PNI and PLR (p50.004, p50.000, respectively for OS and EFS). In conclusion, these results indicate that Inflammation-based prognostic scores such as GPS, PI, NLR, PNI and PLR can be used to evaluate the outcome in DLBCL patients. Among them, GPS is the most powerful tool in predicting survival in DLBCL patients, even in the rituximab era. Key words: diffuse large B-cell lymphoma, glasgow prognostic score, inflammationbased prognostic scores
3047 - REJUVENATION OF AGED HEMATOPOIETIC STEM CELLS BY RESTORING THE ASYMMETRY OF DIVISION M.Carolina Florian1, Kalpana Nattamai2, Karin Soller1, Gina Marka1, Yi Zheng2, and Hartmut Geiger1,2 1 University of Ulm, Ulm, Germany; 2Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Hematopoietic stem cell (HSC) function declines upon aging and it is associated with impaired hematopoiesis in the elderly. Previously we showed a causative role for increased activity of the small RhoGTPase Cdc42 in cell polarity establishment and aging of HSCs. Treatment of aged HSCs with a Cdc42-specific inhibitor (CASIN) restores polarity in quiescent cells together with improving function upon transplantation assays. Here we report that the polarity status in quiescent HSCs is correlated with the mode and outcome of HSC division. Young HSCs, when quiescent, are mostly polar and when induced to cycle show an asymmetric mode of division in that the two nascent daughter cells inherit different amount of Cdc42, AcH4K16, AcH4K12 and Numb. Quiescent aged HSCs are apolar and upon cycling divide symmetrically Cdc42, AcH4K16, AcH4K12 and Numb in nascent daughter cells. Importantly, in aged CASIN-treated HSCs the mode of division reverts to asymmetric, similarly to young HSCs. The outcome of division assayed by paired cell-daughter assays with the CAFC (cobblestone area forming cell) assay as a readout in vitro and single daughter cell pair transplants in vivo indicates consistently a prevalence of asymmetric fates for young daughter cells, with one cell committed to differentiation and one preserving stem cell potential. In agreement with the immunofluorescence data, the divisional outcome of aged HSCs correlated with a symmetric mode of division, as daughter cell pairs presented with a striking prevalence of symmetric self-renewing outcomes both in vitro and in vivo. In summary, we present here as a novel concept that the increased activity of Cdc42 upon aging in HSCs alters not only the polarity of quiescent HSCs but also the balance of symmetric vs. asymmetric stem cell divisions. Decreasing Cdc42 activity levels via CASIN restores both the mode and outcome of divisions of aged HSCs to those measured in young HSCs.
Poster Presentations/Experimental Hematology 43 (2015) S51–S106
3044 - THE INTERNATIONAL STAGING SYSTEM PREDICTS OUTCOME IN DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH R-CHOP Ru Feng Nanfang Hospital, Guangzhou City, Guangdong Province, China The international staging system (ISS), based only on the serum beta-2 microglobulin and serum albumin levels, has always been used to predict survival in multiple myeloma. But its prognostic significance in the diffuse large B-cell lymphoma (DLBCL) patients, especially in those treated with R-CHOP (rituximab, cyclophosphamide, doxorubicinm vincristine and prednisone), remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients in this study. According to ISS there were 90 of 215 (41.9%) patients in stage I group, 98 of 215 (45.6%) in stage II group and 27 of 215 (12.6%) in stage III group. Patients in stage II/ III group correlated with B symptoms, elevated LDH and higher International Prognostic Index (IPI) score (p50.011, p50.019 p50.001, respectively) comparing with those in stage I group. There was no significant difference in gender, age, performance status, number of extranodal sites, stage and cell of origin subtype in different group(pO0.05). ISS showed no significant impact on the overall survival (OS) and event free survival (EFS) in all DLBCL patients (p50.109 and p50.216, respectively) and also those treated with CHOP regimen (p50.906 and p50.972, respectively). However in the cases treated with R-CHOP, ISS could divide patients into different prognostic group (p50.012 and p50.043, respectively). Multivariate analysis revealed that ISS, independent of IPI, indicated different survival in both OS (relative ratio [RR] 2.849; 95% confidence interval [CI], 1.467-5.534, p50.002) and EFS (RR, 1.795; 95% CI, 1.1552.788, p50.009) in DLBCL patients treated with R-CHOP. In conclusion, these date suggest that ISS at diagnosis may allow the identification of a different outcome subgroup in DLBCL patients treated with R-CHOP, but not in those treated with CHOP.
3045 - THE PROGNOSTIC SIGNIFICANCE OF TUMOR-ASSOCIATED MACROPHAGES AND NK CELLS IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH RCHOP Ru Feng Nanfang Hospital, Guangzhou City, Guangdong Province, China Tumor microenvironment has been reported to be associated with both metastatic spread and diminished in some tumors. Tumor-associated macrophages (TAMs) and nature-killer (NK) cells play an important role in the tumor microenvironment. Therefore, we performed this study to investigate the prognostic implications of TAMs including M1 as well as M2 and NK cells in DLBCLs. We reviewed 77 cases of DLBCL diagnosed between June 2004 and October 2012, who treated with R-CHOP. We performed immunohistochemical stains using CD68, CD163 and CD57 to mark M1 macrophages, M2 macrophages and NK cells on paraffin tissue section. The percentage of TAMs was recorded and graded as: 0 if less than 5%, 1 if 5-25%, and 2 if greater than 25% of the total cells present in tumor cells rich nodules were positive for CD68 or CD163. And counting the mean number of the CD57+ cells in 5 fields under high-power magnification (400 times): 0 if less than 5 positive cells；1 if more than 5 positive cells. Of the 77 DLBCL patients treated with R-CHOP, there were 51 males (66.2%). The median percentage for CD68 was 12.8 % ( range, 2.4–50.84), for CD163 was 12.3 % (range, 1.0–39.2). The median counts of CD57 cells were 5 (range, 1.0-78) per unit area. In univariate analysis, an increase in CD68-positive cells was related to improved EFS (grade 0 vs. grade 2, p5 0.036). By contrast, an increased CD163-positive cells were associated with poor OS (grade0 vs grade2, p5 0.033). While, elevated NK cells have no effect on prognosis. Multivariate analysis, an increased CD68 -positive cells was an independent predictors of EFS (HR 0.467, 95%CI 0.236-0.922, P50.028), an decreased CD163-positive cells and lower LDH were independent predictors for OS (HR 2.287, 95%CI 1.043-5.013, P50.039). These results suggest that M1 macrophages might predict favorable clinical outcome and M2 macrophages predict poor outcome. However, the NK cells have no prognostic significance in DLBCL patients treated with RCHOP.
3046 - GLASGOW PROGNOSTIC SCORE IS SUPERIOR TO OTHER INFLAMMATION-BASED SCORES IN PREDICTING SURVIVAL OF DIFFUSE LARGE B-CELL LYMPHOMA Ru Feng Nanfang Hospital, Guangzhou City, Guangdong Province, China Inflammation-based prognostic scores, such as the glasgow prognostic score (GPS), prognostic index(PI), prognostic nutritional index(PNI), neutrophil lymphocyte ratio(NLR), platelet lymphocyte ratio(PLR) was related to survival in many solid tumors. Recent study showed that GPS can be used to predict outcome in diffuse large B-cell lymphoma(DLBCL). However other inflammation related scores had not been reported in DLBCL, and it also remained unknown which of them was more useful to evaluate the survival in DLBCL. In this retrospective study, a number of 252 newly diagnosed and histologically proven DLBCL patients from January 2003 to December 2014 were included. An elevated GPS, PI, NLR, PNI and PLR were all associated with decreased overall survival(p50.000, p50.000, p50.006, p50.001 and p50.001, respectively) and event-free survival (p50.000, p50.000, p50.011, p50.001 and p50.009, respectively) in univariate analysis. Multivariate analysis indicated that GPS(RR51.768, 95%CI51.043-3.000, p50.034) remained an independent prognostic predictor in DLBCL. The area under the curve of GPS (0.735, 95%CI50.645-0.824) was greater than that of PI(0.710, 95%CI50.6210.799), PNI(0.600, 95%CI50.517-0.683), NLR(0.572, 95%CI50.503-0.642), and PLR(0.599, 95%CI50.510-0.689) by Harrell’s C-statistics. Especially in the DLBCL patients treated with R-CHOP, GPS also remained the most powerful inflammationbased prognostic score when comparing with PI, NLR, PNI and PLR (p50.004, p50.000, respectively for OS and EFS). In conclusion, these results indicate that Inflammation-based prognostic scores such as GPS, PI, NLR, PNI and PLR can be used to evaluate the outcome in DLBCL patients. Among them, GPS is the most powerful tool in predicting survival in DLBCL patients, even in the rituximab era. Key words: diffuse large B-cell lymphoma, glasgow prognostic score, inflammationbased prognostic scores
3047 - REJUVENATION OF AGED HEMATOPOIETIC STEM CELLS BY RESTORING THE ASYMMETRY OF DIVISION M.Carolina Florian1, Kalpana Nattamai2, Karin Soller1, Gina Marka1, Yi Zheng2, and Hartmut Geiger1,2 1 University of Ulm, Ulm, Germany; 2Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Hematopoietic stem cell (HSC) function declines upon aging and it is associated with impaired hematopoiesis in the elderly. Previously we showed a causative role for increased activity of the small RhoGTPase Cdc42 in cell polarity establishment and aging of HSCs. Treatment of aged HSCs with a Cdc42-specific inhibitor (CASIN) restores polarity in quiescent cells together with improving function upon transplantation assays. Here we report that the polarity status in quiescent HSCs is correlated with the mode and outcome of HSC division. Young HSCs, when quiescent, are mostly polar and when induced to cycle show an asymmetric mode of division in that the two nascent daughter cells inherit different amount of Cdc42, AcH4K16, AcH4K12 and Numb. Quiescent aged HSCs are apolar and upon cycling divide symmetrically Cdc42, AcH4K16, AcH4K12 and Numb in nascent daughter cells. Importantly, in aged CASIN-treated HSCs the mode of division reverts to asymmetric, similarly to young HSCs. The outcome of division assayed by paired cell-daughter assays with the CAFC (cobblestone area forming cell) assay as a readout in vitro and single daughter cell pair transplants in vivo indicates consistently a prevalence of asymmetric fates for young daughter cells, with one cell committed to differentiation and one preserving stem cell potential. In agreement with the immunofluorescence data, the divisional outcome of aged HSCs correlated with a symmetric mode of division, as daughter cell pairs presented with a striking prevalence of symmetric self-renewing outcomes both in vitro and in vivo. In summary, we present here as a novel concept that the increased activity of Cdc42 upon aging in HSCs alters not only the polarity of quiescent HSCs but also the balance of symmetric vs. asymmetric stem cell divisions. Decreasing Cdc42 activity levels via CASIN restores both the mode and outcome of divisions of aged HSCs to those measured in young HSCs.