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1
Pukiat, Sulada, Nuttapong Ngamphaiboon, Pooja Advani, Julio Chavez, George Deeb, Anjana Elefante, and Francisco J. Hernandez-Ilizaliturri. "BCL-2 Expression at the Time of Diagnosis Affects the Clinical Outcome of Patients with Germinal Center and Non-Germinal Center Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Chemo-Immunotherpy." Blood 116, no. 21 (November 19, 2010): 3130. http://dx.doi.org/10.1182/blood.v116.21.3130.3130.
Abstract:
Abstract Abstract 3130 DLBCL has been recognized as a heterogeneous disease varying in molecular biology and clinical outcome. The use of genetic expression profiling has led to the sub-classification of DLBCL into germinal center B-cell like (GCB) and non-germinal center B cell like (non-GCB) based on the cell of origin of the neoplastic B-cell. Immunohistochemistry (IHC) algorithms had been developed and validated to identify GCB or non-GCB DLBCL. Deregulation of Bcl-2 family member of proteins plays an important role in the development, progression, and prognosis of various subtypes of B-cell neoplasms, including DLBCL. Bcl-2 protein expression is a previously known negative prognostic indicator of clinical outcome in DLBCL treated with antracycline-containing combination chemotherapy (e.g. CHOP) in the past. In the post-rituximab (R) era (e.g. use of upfront R-CHOP), the negative prognostic value of Bcl-2 protein expression needs to be reevaluated to ensure its validity. To study the prognostic value of Bcl-2 in patients with either GCB or non-GCB DLBCL, we retrospectively analyzed differences in progression-free survival (PFS) and overall survival (OS) between Bcl-2+ and Bcl-2- de novo DLBCL (GCB or non-GCB subtypes). Using the RPCI tumor registry and pharmacy database, we identified 201 DLBCL patients treated with equivalent doses of rituximab and anthracycline-based therapy (i.e. R=CHOP or R+DA-EPOCH) at RPCI between 1997 and 2007. Demographic, clinical and pathological characteristics were obtained for each patient. Patients were classified into GCB or non-GCB DLBCL according to the Han's algorithm based on the expression of CD10, Bcl-6 and MUM-1. Bcl-2 was determined by IHC and was available for 101 patients. Using the Han's algorithm, fifty-three patients (26.4%) were classified as GCB, 54 patients (26.9%) non-GCB, and 94 patients (46.8%) could not be classified due to inadequate data/sample. Bcl-2 expression was detected in 67% and 73% of the GCB- and non-GCB DLBCL subtypes respectively. Demographics and clinical characteristics were equally distributed between GCB- and non-GCB DLBCL. Patients received either R+CHOP (90%) or R+DA-EPOCH (10%). The complete response (CR) rate of the entire cohort was 82.6% and no differences were observed between GCB- or non-GCB DLBCL (78.4% vs. 75.5%, P=0.73) or by Bcl-2 expression (+:72.5% vs. -:81.3%, P=0.35]. After a median follow up period of 74 months, significant differences were observed between Bcl-2 positive or negative and GCB or non-GCB DLBCL. GCB-DLBCL had a longer 5-yr PFS and 5-yr OS than non-GCB DLBCL (58.5% vs. 37%, P=0.026; 81.1% vs. 53.7% and, P=0.002; respectively). By itself, Bcl2 over-expression, had a negative impact in PFS (P=0.002) and OS (P=0.001) in R+CHOP/R+DA-EPOCH treated de novo DLBCL. The combined prognostic value of the Han's algorithm and Bcl-2 expression was also evaluated. Bcl-2 expression in the context of both GBC and non-GCB subtypes remains an unfavorable prognostic indicator for overall survival, with a more pronounced influence in the GCB-DLBCL phenotype (See table). Our data supports the predictive value of the Han's algorithm and Bcl-2 expression in DLBCL patients undergoing front-line chemo-immunotherapy. Bcl-2 expression is associated with a poor prognosis in GCB and non-GCB DLBCL. It is possible that intrinsic biological pathways involved in lymphomagenesis and/or “resistance” of these subtypes of DLBCL may play a role in their responsiveness to rituximab-based therapies and could be influenced by the net balance between pro- and anti-apoptotic proteins. Attempts to further delineate the biological heterogeneity of DLBCL may help identify subgroups of patients at high risk of resistance to chemo-immunotherapy and lead to the development of new therapeutic strategies. In conclusion, our data analysis confirms that the DLBCL immunophenotypes based on cell of origin and Bcl-2 status continues to have predictive significance on clinical outcomes in DLBCL in the rituximab era. Differences in clinical outcomes between GCB or non-GCB-DLBCL by Bcl-2 status Median PFS (months) Significance Median OS (months) Significance GCB-DLBCL Bcl-2 (-) NR *P = 0.016 NR *P =0.029 Bcl-2 (+) 39 83 Non-GCB DLBCL Bcl-2 (-) 49.8 NR Bcl-2 (+) 15 48 PFS = Progression free survival, OS = overall survival, GCB = germinal center B-cell, DLBCL = diffuse large B-cell lymphoma. * P values calculated by comparing GCB-DLBCL Bcl-2 (-) to the other groups Disclosures: No relevant conflicts of interest to declare.
2
Tarius, Jenifer Marsela, Hermawan Istiadi, Ika Pawitra Miranti, and Intan Rahmania Eka Dini. "THE CORRELATION BETWEEN CELL OF ORIGIN SUBTYPE WITH OVERALL SURVIVAL OF DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS IN KARIADI GENERAL HOSPITAL SEMARANG." DIPONEGORO MEDICAL JOURNAL (JURNAL KEDOKTERAN DIPONEGORO) 9, no. 3 (May 12, 2020): 252–58. http://dx.doi.org/10.14710/dmj.v9i3.27504.
Abstract:
Background: DLBCL is the most common type of NHL in the world. DLBCL based on cell of origin is divided into GCB and non-GCB. The diagnosis of DLBCL has not been routinely done to its cell of origin, and there have not been many studies that discuss the DLBCL subtype and the overall survival of the patients, especially in Kariadi General Hospital. This study aims to determine the correlation of DLBCL cell of origin with the 2-year overall survival of DLBCL patients in Kariadi General Hospital. Methods: This is an observational analytic study of 40 DLBCL patients in Kariadi General Hospital from January to August 2017. The data collection including: age of diagnosis, location, stage and 2-year overall survival. Data analysis used chi square test and Kaplan Meier curve. Results: GCB patients had higher 2-year overall survival than non-GCB subtype significantly (p: 0.047), with a 2-year survival rate of GCB subtype was 66.7% and non-GCB subtype was 31.6%. GCB patients tend to have early stage than non-GCB subtype significantly (p:0.028). Conclusion: DLBCL GCB subtype patients had significantly higher 2-year overall survival therefore it has better prognosis than non-GCB subtype.
3
Gandhi, Shipra, Vishala T. Neppalli, George Deeb, Myron S. Czuczman, and Francisco J. Hernandez-Ilizaliturri. "Distinct CD30 Expression Patterns In Germinal Center B-Cell (GCB) and Non-GCB Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 122, no. 21 (November 15, 2013): 5064. http://dx.doi.org/10.1182/blood.v122.21.5064.5064.
Abstract:
Abstract Background DLBCL is the most common type of non-Hodgkin lymphoma, which demonstrates morphologic, immunophenotypic, molecular, and clinical heterogeneity. Gene expression profiling studies define two molecular subtypes of DLBCL, namely germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Hans' algorithm was developed to provide an immunohistochemical correlation to the molecular subtypes of DLBCL. In the pre and post-rituximab era, ABC subtype of DLBCL is known to demonstrate poor overall survival when compared to GCB subtype. In addition, relapsed or primary refractory DLBCL responds poorly to current therapeutic strategies. These findings underscore the necessity to identify novel therapeutic targets in DLBCL to achieve better clinical outcomes. Recent data suggests that CD30, a member of the tumor necrosis factor receptor family, is a potential therapeutic target in DLBCL. CD30 is widely expressed in classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) thus serving as an attractive target of immunotherapy for cHL and ALCL. In this study we conducted a retrospective evaluation of CD30 expression in GCB and non-GCB DLBCL, treated at our Institution with standard front-line chemo-immunotherapy (i.e. R+CHOP or R+ DA-EPOCH). Materials and Methods We identified 60 patients with confirmed DLBCL for which archived formalin fixed paraffin embedded tissue was available in the form of a tissue micro-array (39 Cases) or diagnostic biopsy material (21 Cases). Immunohistochemical detection of CD30 was performed using routine methods (Biocare #PM031, ready to use aliquots). Demographic, clinical and pharmacological parameters were obtained for each patient. DLBCL cases were subtyped as GCB or non-GCB using immunohistochemistry-based Hans' algorithm. Membranous and Golgi pattern of CD30 expression in the tumor cells was designated as positive. Results 21 patients (48.8%) were classified as GCB, 22 patients (51.2%) non-GCB. CD30 expression was detected in 13.3% of all DLBCL patients. Differences in CD30 expression were noted between GCB- and non-GCB DLBCL. CD30 expression was detected in 9.5% and 23% of the GCB- and non-GCB DLBCL subtypes respectively. Demographics and clinical characteristics were equally distributed between GCB- and non-GCB and between CD30 positive or negative DLBCL. Patients received either R+CHOP (82%) or R+DA-EPOCH (18%). The complete response (CR) rate of the entire cohort was 67% and no differences were observed between GCB- or non-GCB DLBCL. CD30 (+) DLBCL had a higher CR (complete response) rate than CD30 (-) DLBCL (88% vs 63.4%). However, the numbers were too small to reach statistical significance. No significant differences were observed between CD30 (+) or (-) DLBCL in terms of progression free survival (PFS) (CD30[-]37m vs. CD30[+]16.5m, P =0.785) or overall survival (OS) (CD30[-]86m vs. CD30[+]57.4m, P =0.99). In contrast to previously reported by other investigators, there was no difference in the clinical outcome between GCB vs. non-GCB DLBCL treated with R+CHOP or R+DA-EPOCH. Conclusions Our data suggests that CD30 expression is more prevalent in non-GCB DLBCL patients based on our small cohort. While CD30 expression may not confer a prognostic value in newly diagnosed DLBCL (Table 1), routine testing for it may identify a group of patients that may benefit from CD30-targeted therapeutic strategies (i.e. antibody-drug conjugates) in the relapsed/refractory setting. (Research, in part, supported by The Eugene and Connie Corasanti Lymphoma Research Fund) Disclosures: Czuczman: Genetech, Onyx, Celgene, Astellas, Millennium, Mundipharma: Advisory Committees Other. Hernandez-Ilizaliturri:Seattle Genetics: Consultancy, Honoraria.
4
Hayama, Miyuki, Masataka Okamoto, Yuki Hagiwara, Ken Tanae, Mika Kohri, Naoki Takahashi, Tadashi Yoshino, Koichi Ohshima, and Nozomi Niitsu. "Clinical Significance of Immunohistochemical Markers of Diffuse Large B-Cell Lymphoma In the Rituximab Era." Blood 116, no. 21 (November 19, 2010): 1800. http://dx.doi.org/10.1182/blood.v116.21.1800.1800.
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Abstract Abstract 1800 Rituximab combination chemotherapy has significantly improved the treatment outcome of diffuse large B-cell lymphoma (DLBCL). Therefore, the prognostic factors of DLBCL in the rituximab era are different from previously reported prognostic factors. Biological prognostic markers have been analyzed to help understand the biologic basis of treatment outcome. Hans, et al. reported that patients with non-germinal center B-cell like (GCB)-type DLBCL had a significantly poorer prognosis than those with GCB-type DLBCL in the pre-rituximab era. In patients who received rituximab combination chemotherapy, there is a report that did not find a difference in survival ratio between those with GCB DLBCL or non-GCB DLBCL. On the other hand, there was a report that found a difference in survival ratio between patients with GCB DLBCL and those with non-GCB DLBCL. In the present study, we compared the prognostic factors of DLBCL between patients who received CHOP-like chemotherapy and those who received rituximab combined with CHOP-like therapy. The subjects were 204 DLBCL patients who underwent rituximab + CHOP-like therapy and in whom markers could be analyzed. We evaluated CD5, CD10, BCL2, BCL6, and MUM1 expression by immunohistochemistry. One hundred forty-six DLBCL patients who underwent CHOP-like therapy were assumed as historical controls. The median age was 52 years in both groups. In the R-CHOP-like and CHOP-like groups, patients with stage III or IV disease comprised 75% and 67%, respectively, patients with performance status3a2 comprised 28% and 20%, respectively, and patients with serum LDH >normal comprised 60% and 77%, respectively. There were no significant differences in clinical characteristics between the CHOP-like group and R-CHOP-like group. BCL2 was positive in 85(63%) of the 134 patients who received the R-CHOP-like regimen and in 66 (46%) of the 142 patients who received the CHOP-like regimen. When the 202 patients who received the R-CHOP-like regimen were divided into the GCB group and the non-GCB group, the GCB group consisted of 92 patients (46%) and the non-GCB group consisted of 110 patients. The relationships between immunohistological markers and outcome among the patients with DLBCL who received CHOP-like therapy were studied. CD5, CD10, and BCL6 had no prognostic impact on 5-year overall survival (OS) and progression-free survival (PFS) rates. When the patients were divided into the GCB DLBCL and non-GCB DLBCL groups, the 5-year OS of the GCB group was 78% and that of the non-GCB group was 57% (p<0.05). The 5-year PFS of the GCB group was 73% and that of the non-GCB group was 52% (p<0.05). The 5-year OS rate of the BCL2-positive and -negative groups was 61% and 74%, respectively (p<0.05). The 5-year PFS rate of the BCL2-positive and -negative groups was 55% and 70%, respectively (p<0.05). Thus, among patients who received the CHOP-like regimen, the BCL2-positive group showed significantly poorer prognosis than the BCL2-negative group. Next, the effect of rituximab with chemotherapy was examined. CD5, CD10, BCL2, BCL6, and MUM-1 had no prognostic impact on 5-year OS and PFS rates. When the patients were divided into the GCB DLBCL (n=92) and non-GCB DLBCL (n=110) groups, the 5-year OS of the GCB group was 74% and that of the non-GCB group was 75%, showing no significant difference. The 5-year PFS of the GCB group was 71% and the 5-year PFS of the non-GCB group was 69%, showing no significant difference. In the rituximab era, BCL2, MUM1 and non-GCB were not prognostic factors. As to reports on patients with DLBCL who received rituximab combination chemotherapy, there was a report in which the cases were separated into the GCB-type DLBCL and non-GCB-type DLBCL groups and compared. Fu, et al. reported that the survival of patients with GCB-type DLBCL was still superior to that of patients with non-GCB-type DLBCL in the rituximab era. However, other reports did not find a difference in survival ratio between those with GCB-type DLBCL or non-GCB-type DLBCL. In conclusion, the finding of improved OS and PFS with the addition of rituximab indicates that new biomarkers should be studied. Disclosures: No relevant conflicts of interest to declare.
5
Kharchenko, Yevgeniya, Tatyana Semiglazova, Anna Artemeva, Galina Kireeva, I. Polyatskin, Ilya Zyuzgin, Larisa Filatova, Yuliya Chudinovskikh, Margarita Motalkina, and Yuliya Oleynik. "PROGNOSTIC IMPACT OF IMMUNOHISTOCHEMICAL AND MOLECULAR GENETIC MARKERS IN DIFFUSE LARGE B-CELL LYMPHOMA." Problems in oncology 66, no. 1 (January 1, 2020): 79–89. http://dx.doi.org/10.37469/0507-3758-2020-66-1-79-89.
Abstract:
Aim: To identify incidence and prognostic impact of different IHC and molecular genetic markers in Diffuse Large B-cell lymphoma. Methods: We analyzed 215 patients with DLBCL who received treatment from 2008 to 2016. We assess expression of different IHC markers, defined DLBCL to GCB and non-GCB subtypes by Hans-algorithm and performed FISH to evaluate MyC, BcL2 and BCL6 translocations. Results: Median follow-up was 29 months. Non-GCB DLBCL were identified in 44 pts (62,9%), GCB-subtype in 26 pts (37,1%). Median PFS in non-GCB DlBCL was 46,0 months, in GCB DLBCL median PFS and 75% quartile was not reached (p=0,171). Traslocations of MYC, BCL2 and BCL6 were found in 10/48 pts (20,8%). Double expression of c-myc and bcl-2 was identified in 21 of 71 пациентов (29,6%). СD5-expression were determined in 19/55 (34,5%), CD30+ DLBCL - in 24/66 pts (36,4%). In pts with DLBCL without CD-10 expression PFS was 6,0 months, in group with CD 10 expression median of PFS was not reached (р=0,122). Pts with CD 10 expression had lower risk of relapse compared to those without expression (р=0,049). Absence of CD 10 expression was negative prognostic factor for PFS in multivariate analysis (р=0,015). Conclusion: Patients with DLBCL and GCB subtype have tendency to better prognosis in PFS rates and lower risk of relapse compared to non-GCB subtype. Dividing to GCB or non-GCB subtypes in DLBCL and assessment of different IHC markers can potentially determine DLBCL with worse prognosis.
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Adhi Pangarsa, Eko, Desta Nur Ewika Ardini, Daniel Rizky, Kevin Tandarto, Hermawan Istiadi, Dik Puspasari, Budi Setiawan, et al. "The association of Hypoxia-Inducible Factor-2α (HIF-2α) overexpression score with Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (Non-GCB) subtypes of Diffuse Large B-cell Lymphoma (DLBCL)." Bali Medical Journal 12, no. 3 (August 22, 2023): 2456–62. http://dx.doi.org/10.15562/bmj.v12i3.4521.
Abstract:
Link of Video Abstract: https://www.youtube.com/watch?v=KF58IGGdWmc Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. It is classified into homogeneous subtypes, namely Germinal Center B-Cell Like (GCB) and Non-Germinal Center B-Cell Like (GCB), with the latter associated with worse survival outcomes. Increased expression of Hypoxia-Inducible Factor-2α (HIF-2α) is often observed in DLBCL and has been correlated with enhanced angiogenesis, suggesting its potential as a prognostic factor in managing DLBCL. The study evaluates the association between HIF-2α overexpression and the GCB and non-GCB subtypes of DLBCL. Methods: This cross-sectional study utilized samples from DLBCL patients at Dr. Kariadi Semarang Hospital between January and December 2021. Immunohistochemistry was performed on the samples to determine the DLBCL subtypes and assess the presence of HIF-2α. HIF-2α was evaluated by immunohistochemistry based on its distribution and intensity. The Kruskal-Wallis test was used to find the association between HIF-2α expression and the GCB and non-GCB subtypes of DLBCL. Furthermore, Spearman's rank correlation test explored the correlation between all numeric variables. Results: A total of 30 subjects were included in this study, with 7 samples of GCB subtype (23.3%) and 23 samples of non-GCB subtype (76.6%). Kruskal-Wallis test showed no association between HIF-2α expression and the subtypes of DLBCL (p=0.812). Spearman's rho correlation test indicated no correlation between HIF-2α overexpression score with NCCN IPI score in GCB (r=0.219; p=0.637) and non-GCB (r=-0.194; p=0.386). Conclusion: There was no association between HIF-2α expression and GCB and non-GCB subtypes of DLBCL. Additionally, no correlation was found between HIF-2α overexpression and NCCN IPI score.
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Mishima, Yuko, Masahiro Yokoyama, Noriko Nishimura, Kyoko Ueda, Tadahiro Gunji, Hideaki Nitta, Yoshiharu Kusano, et al. "R-CHOP Therapy Cannot Overcome CD5 Positive Non-GCB Subtype of DLBCL." Blood 126, no. 23 (December 3, 2015): 1507. http://dx.doi.org/10.1182/blood.v126.23.1507.1507.
Abstract:
Abstract Introduction: There are various poor prognosis factors in diffuse large B cell lymphoma (DLBCL). CD5 positive (CD5+) is estimated as one of the poor prognosis markers in DLBCL. CD5+ DLBCL is completely distinguished from CLL or Mantle cell lymphoma, and de Novo CD5+ DLBCL is related to a high incidence of cytogenetic abnormalities of 8p21 and 11q13. In many cases, CD5+ DLBCL is associated with an aggressive clinical status and advanced stages. Several chromosomal studies have demonstrated the gene expression was similar to non-GCB type of DLBCL. In the clinical phase, it is easy to express chemo-resistance and CNS invasion. However, the clear characterization and mechanisms of chemo-resistance have not been demonstrated yet. In this study, we examined our previous CD5+ DLBCL patients in our institute, then evaluated the prognosis and clinical characteristics regarding GCB or non GCB type. Methods: We studied 372 newly diagnosed DLBCL patients including 42 cases of CD5+ from 2005 to 2015 in our institution retrospectively. The pathological diagnoses were performed with immunohistochemical analysis by two or three hematological pathologists. CD5 expression was evaluated by immunohistostaining and flowcytometry, then cyclin D1 positive cases were excluded. GCB or non-GCB subtype was evaluated with CD10, bcl-6, and MUM-1 of immunohistostaining. The clinical stage of patients and evaluation of the effect of the therapy were performed using PET-CT scan. The statistical analyses were performed by Dr. SPSS II. Results: In all our treated patients, 350 DLBCL patients (female;161) and 41 CD5+ patients (female 22) could be evaluated. 192 patients were GCB type and 158 patients were non-GCB type. The median age was 64.5 yrs (25-86 yrs) and the median follow up time was 45 months (1-133 months). All patients were treated by rituximab-CHOP (R-CHOP) therapy. CR rate of CD5- DLBCL was 94.2% and CD5+ was 73.1% respectively (p =0.0093). 3.5-year event free survival (EFS) was 79.16% and 52.20% (p <0.0001) and overall survival (OS) was 85.82% and 54.35 %(p <0.0001) (CD5- and CD5+ respectively). In CD5+ DLBCL, GCB type was 11 (36.6%) and non-GCB type was 30 (63.3%). In the non-GCB type of CD5+ cases, IPI low (L) and low intermediate (LI) was 86.6% (18 and 8 each) and high intermediate (HI) was 13.3% (4/30). CR of GCB type in CD5+ was 81.8% and relapse rate was 22.2% compared with CR of non-GCB in CD5+ was 70.0% and relapse rate was 52.4% respectively. All HI cases of non-GCB type could not get CR and died within 6 months. 3.5-year EFS of CD5+ DLBCL according to GCB and non-GCB were 81.82% and 40.6% (p =0.1214) and OS was 90.9% and 40.05% (p =0.0154), respectively. 3.5-year EFS of CD5- DLBCL according to GCB and non-GCB were 82.12% and 69.23% (p =0.0173), and OS of CD5- was 88.51% (GCB) and 82.12%(non-GCB) (p =0.0061) respectively. Discussion: CD5+ showed poor prognosis in our treated DLBCL, however, GCB type of CD5+ had similar OS and EFS as CD5- DLBCL. Non-GCB type of CD5+ demonstrated significantly poor prognosis compared to GCB subtype or CD5- DLBCL. The clinical status of CD5+ cases have been generally reported as having aggressive status, however, in our CD5+ of non-GCBcases, IPI L and LI were 86%. In spite of many populations of L and LI of IPI, the prognosis was poor. From these results, it suggested that it is not necessary to estimate CD5+ of GCB subtype as poor prognosis in R-CHOP therapy, however, CD5+ non-GCB type indicated independent poor prognosis factors in DLBCL. Additionally, R-CHOP therapy could induce CR at once in IPI L and LI cases, however it could not contribute to good prognoses. We should investigate other treatment strategies for improving outcomes of CD5+ non-GCB subtype of DLBCL. Disclosures Mishima: Chugai Pharmaceutical CO., LTD.: Consultancy. Yokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.
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Chavez, Julio, Mark Walsh, Francisco J. Hernandez-Ilizaliturri, Anjana Elefante, and Myron S. Czuczman. "Classification of Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) According to the Han's Criteria Defines Two Groups of Patients with Different Clinical Outcomes Following Systemic Rituximab-Multi Agent Anthracycline-Based Therapy." Blood 114, no. 22 (November 20, 2009): 623. http://dx.doi.org/10.1182/blood.v114.22.623.623.
Abstract:
Abstract Abstract 623 Gene expression profiling has successfully distinguished three subtypes of DLBCL with different biology and response to treatment: 1) germinal center B-cell (GCB); and 2) non-germinal center lymphomas, that include: activated B-cell-like (ABC) and Type 3 subtypes. Currently, immunohistochemical (IHC) analysis of lymphoma biopsy specimens appear to be a more widely applicable methodology (i.e. compared to gene microarray analysis) to use in order to differentiate between subtypes of DLBCL. While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy as a front line treatment of DLBCL is beyond dispute, it also requires a re-evaluation of previously accepted biomarkers of response to CHOP or CHOP-like chemotherapy alone. The predictive value of “IHC–defined” GCB phenotype in rituximab-chemotherapy-treated patients continues to be controversial, as retrospective studies have reported conflicting results. In an attempt to define the predictive value of using the Han's algorithm in newly diagnosed DLBCL patients undergoing frontline immunochemotherapy, we retrospectively analyzed differences in progression free survival (PFS) and overall survival (OS) between patients with GCB and non-GCB DLBCL treated with equivalent doses of rituximab and anthracycline-based therapy at our institution. Using the tumor registry and the pharmacy database, we identified patients with DLBCL treated at our Institution between 2000 and 2008. Demographic, clinical, pharmacologic and pathological characteristics were obtained for each patient. Patients were classified into GCB or non-GCB DLBCL according to the Han's algorithm based on the expression of CD10, Bcl-6 and MUM-1 in the large cell component of the tumor specimen. Cumulative doses of rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O), etoposide (E,; when used) and prednisone (P) were calculated for each patient, as well as the number of cycles, dose delays, and growth factor use. A total of 192 patients were included in the study. The average age was 58.65 years (F/M:73/119). Using the Hans algorithm, n=55 (28.6%) and n=57 (29.7%) were classified as non-GCB or GCB, respectively. Inadequate information was availabel to classify 80 patients (undetermined group). Clinical indictors such as clinical demographics, international prognostic index (IPI) score, extra-nodal disease, performance status, Ann Arbor stage, therapy delays, cumulative rituximab and chemotherapy doses were not significantly different between groups (non-GCB, GCB, and undetermined DLBCL). The majority of patients received R+CHOP (90%) or R+ dose adjusted–EPOCH. On follow-up, a total of 42 (21.8%) patients relapsed or were found to have primary-refractory disease. The complete remission rate to front-line therapy was 81% for the entire cohort of patients and was not different between patients with GCB or non-GCB DLBCL. On the other hand, significant differences in PFS and OS were observed between patients with non-GCB versus GCB DLBCL. The 5-year progression free survival (PFS) and overall survival (OS) were significantly better in the GCB DLBCL subtype (75.4% vs. 56.4%, p=0.017 and 84.2% vs. 70.9 %, p=0.037; respectively). As no differences in clinical parameters, CR rate, or rituximab-chemotherapy dose/schedule were observed between non-GCB and GCB DLBCL patients, it is possible that intrinsic biological pathways involved in lymphomagenesis and/or “resistance” of these subtypes of DLBCL may play a role in their responsiveness to rituximab-based immunochemoimmunotherapy. In summary, our data suggest that the Hans algorithm can predict the clinical outcome of patients with DLBCL undergoing front-line therapy with R-chemotherapy. Patients with non-GCB DLBCL while having a comparable initial complete response rate to R+CHOP had a shorter PFS and OS than GCB DLBCL patients. Non-GCB DLBCL represents a subgroup of DLBCL for which innovative therapeutic strategies targeting key regulatory pathways in the induction and/or maintenance setting are needed in an attempt to prolong PFS and improve OS. Disclosures: No relevant conflicts of interest to declare.
9
Van Meerten, Tom, Renee Bouwstra, Yuan He, de Boer Janneke, Hilde Kooistra, Rudolf Fehrmann, Emanuele Ammatuna, Gerwin Huls, and Edwin Bremer. "CD47 Expression Defines the Efficacy of Rituximab in Non-Germinal Center B-Cell (non-GCB) Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 132, Supplement 1 (November 29, 2018): 2852. http://dx.doi.org/10.1182/blood-2018-99-114561.
Abstract:
Abstract CD47 is an immune-checkpoint protein that binds SIRPa on immune cells to deliver an inhibitory "don't eat me" signal. CD47 is a prominent new target in B-cell malignancies, in which CD47 antibody in combination with the CD20 antibody rituximab (R) is explored in clinical trials. Addition of R to CHOP chemotherapy significantly improves survival of patients with DLBCL, but how CD47 expression contributes to this positive impact of R on patient outcome is currently unclear. Especially in the context of the different cell-of-origin DLBCL subtypes (Germinal Center B-cell (GCB) vs non-GCB DLBCL). We therefore investigated the impact of CD47 expression on rituximab efficacy. We first studied a clinically well annotated transcriptome cohort of 939 DLBCL patients treated with either CHOP or R-CHOP, and we validated these findings in functional in vitro assays. Our analyses showed that overall survival (OS) for patients with high CD47 expression (i.e. above median) is worse compared to patients with low CD47 expression (i.e. below median) after R-CHOP (p=0.001), but not after CHOP treatment (p=0.645). Correspondingly, patients with low CD47 expression benefited most from addition of R to CHOP (HR=0.32, CI:[0.21-0.50], p<0.0001). Non--GCB patients showed a worse survival compared to GCB DLBCL patients after R-CHOP treatment (p<0.0001). Interestingly, with respect to COO classification, high expression of CD47 impacted the OS in non-GCB R-CHOP-treated patients (HR=1.9, CI:[1.14-3.26], p=0.013) but not in GCB DLBCL patients (HR=1.16, CI:[0.68-1.99], p=0.58). Importantly, high CD47 expression was found to determine the worse overall survival of non-GCB versus GCB patients (p=0.0006). No difference in OS was observed between GCB and non-GCB-patients with low CD47 expression (p=0.7662). Pro-phagocytic receptors expressed on DLBCL, i.e. SLAMF7, did not determine outcome upon R-CHOP treatment. In multivariate analysis, high CD47 expression remained significantly associated with poor survival only in non-GCB-patients. We further investigated this differential impact of CD47 in non-GCB and GCB subtypes in vitro. Non-GCB and GCB DLBCL cell lines (n=6) were mixed with allogeneic M1 macrophages and treated with a CD47 blocking antibody, which comprises human IgG4. Results confirmed that macrophage-mediated phagocytosis by R was augmented with CD47-blocking antibody only in non-GCB DLBCL cell lines, and not in GCB DLBCL cell lines. Also, CD47 blocking co-treatment also increased the number of tumor cells ingested per macrophage, with a clear significant increase in phagocytic index in non-GCB cells, but not in GCB DLBCL cells (p=0.001). In conclusion, the patient benefit of addition of R to CHOP is limited by CD47 specifically in non-GCB patients. In addition, we confirmed that CD47-blocking only augmented rituximab-mediated phagocytosis in non-GCB cell-lines. Together, these data suggest that especially non-GCB DLBCL patients with a currently worse prognosis may benefit from CD47-targeted therapy combined with rituximab. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Niitsu, Nozomi, Naoki Takahashi, Tadashi Yoshino, Masataka Okamoto, and Shigeo Nakamura. "Prognostic Significance of EBV Association in Diffuse Large B-Cell Lymphoma in the Rituximab Era." Blood 126, no. 23 (December 3, 2015): 3911. http://dx.doi.org/10.1182/blood.v126.23.3911.3911.
Abstract:
Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases in terms of morphology, immunohistochemistry and molecular features. The prognostic factors of DLBCL in the rituximab era are different from previously reported prognostic factors. Hans, et al. reported that patients with non-germinal center B-cell like (GCB)-type DLBCL had a significantly poorer prognosis than those with GCB-type DLBCL in the pre-rituximab era. In patients who received rituximab combination chemotherapy, there is a report that did not find a difference in survival ratio between those with GCB DLBCL or non-GCB DLBCL. On the other hand, there was a report that found a difference in survival ratio between patients with GCB DLBCL and those with non-GCB DLBCL. In addition, the previously reported that patients with Epstein-Barr virus (EBV)-positive DLBCL had a significantly poorer prognosis than those with EBV-negative DLBCL in the pre-rituximab era. In the present study, we considered the prognostic factors of DLBCL patients who received rituximab combined chemotherapy. Patients and Methods: The subjects were 209 DLBCL patients in whom immunohistochemical markers (CD20, CD5, CD10, BCL-2, BCL-6, MUM-1) could be analyzed. In addition, 86 patients were examined EBV-encoded RNA (EBER) in situ hybridization. Pathologic evaluation of the materials from each patient was performedat several central review meetings by six hematopathologists in the ALTSG pathology review board. Patients were treated with cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, and prednisolone (CyclOBEAP) regimen or CHOP regimen. Rituximab was administered to all patients. One hundred forty-six DLBCL patients who underwent CHOP-like therapy were assumed as historical controls. The median follow-up period was 69 months (range, 46-88months). Results: In the R-chemotherapy and CHOP-like groups, patients with stage III or IV disease comprised 57% and 67%, respectively, patients with performance status≧2 comprised 32% and 23%, respectively, and patients with serum LDH >normal comprised 61% and 69%, respectively. There were no significant differences in clinical characteristics between the R-chemotherapy group and CHOP-like group. BCL2 was positive in 72 (55%) of the 131 patients who received the R-chemotherapy and in 71 (50%) of the 142 patients who received the CHOP-like regimen. When the 209 patients who received the R- chemotherapy group were divided into the GCB group and the non-GCB group, the GCB group consisted of 74 patients (35%) and the non-GCB group consisted of 135 patients. The relationships between immunohistological markers and outcome among the patients with DLBCL who received CHOP-like therapy were studied. CD5, CD10, and BCL6 had no prognostic impact on 5-year overall survival (OS) and progression-free survival (PFS) rates. When the patients were divided into the GCB DLBCL and non-GCB DLBCL groups, the 5-year PFS of the GCB group was 78% and that of the non-GCB group was 48% (p=0.0008). Next, the effect of rituximab with chemotherapy was examined. CD5, CD10, BCL2, BCL6, and MUM-1 had no prognostic impact on 5-year OS and PFS rates. When the patients were divided into the GCB DLBCL (n=74) and non-GCB DLBCL (n=135) groups, the 4-year PFS of the GCB group was 79% and that of the non-GCB group was 73%, showing no significant difference. We also evaluated the significance of EBER expression among patients by incorporating the EBV-positive DLBCL (n=14) and EBV-negative DLBCL (n=72).There were no significant differences in immunophenotyping analysis between the EBV-positive DLBCL and EBV-negative DLBCL. As for EBER expression in DLBCL, the 4-year PFS of the EBER-positive group was 37% and that of the EBER-negative group was 75% (P=0.007), indicating that the EBER-positive group showed significantly poorer prognosis. The 4-year OS of the EBER-positive group was 50% and the EBER-negative group was 86% (P=0.0005). Conclusions: The EBER may be an important prognostic factor in patients with DLBCL who underwent R-chemotherapy therapy. Disclosures No relevant conflicts of interest to declare.
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Alam, SM Mahbubul, and Ahmed Khaled. "Immunophenotypic characteristics of Diffuse Large Bcell Lymphoma." Bioresearch Communications 8, no. 1 (December 26, 2021): 1049–52. http://dx.doi.org/10.3329/brc.v8i1.57043.
Abstract:
Introduction: Immunohistochemistry (IHC) is essential in the diagnostic workup of Diffuse Large B cell lymphoma (DLBCL). Determination of biological heterogenicity of Diffuse Large B-cell Lymphoma (DLBCL) is critical to institute precise treatment and predict prognosis. IHC confirms B cell phenotypes, reflects molecular subtype based on cell of origin and determines other immunophenotypic characteristics. Methods and Material: All cases of DLBCL diagnosed in 2020 (Jan-Dec) in histopathology department of Evercare Hospital Dhaka were included in this study. Histopathological sections were stained with CD20, CD3, CD5, CD30, BCL2, BCL6, CD10, MUM1, MYC, Ki67 and other markers. Hans algorithm was applied to classify DLBCL cases into germinal center B-cell (GCB) or Non-GCB. Results: Out of 64 DLBCL cases, 21 (24%) of DLBCL were GCB, while 76% (43 cases) were non-GCB subtypes. 30% cases of DLBCL showed double expression for MYC and BCL2. Fewer cases were immunoreactive for CD5 and CD30. Conclusion: This first study at Dhaka with wide range of antibody to characterize the Immunophenotypic features of DLBCL. The main finding of this study is the identification of non-germinal center B-cell (non-GCB) as the major immunophenotype of DLBCL. This may be an enabler for further studies to observe the clinical outcome of different subtypes of GCB and Non-GCB. Bioresearch Commu. 8(1): 1049-1052, 2022 (January)
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Nooruddin, Zohra, Zenggang Pan, Lilyana Gross, Weitzenkamp David, Bradley M. Haverkos, Daniel A. Pollyea, Jonathan A. Gutman, et al. "Post-Transplant Diffuse Large B Cell Lymphoma with Non Germinal Center B-Cell Subtype Frequently Lacks Programmed Cell Death Ligand (PD-L1) Overexpression Which May Influence Overall Outcomes." Blood 128, no. 22 (December 2, 2016): 3054. http://dx.doi.org/10.1182/blood.v128.22.3054.3054.
Abstract:
Abstract Background : Post Transplant Lymphoproliferative disorder (PTLD) represents a distinct and rare complication following solid organ transplantation (SOT). Insight into the biology of this disorder is limited to retrospective reviews and case series. In one of the first reports for post-transplant Diffuse Large B cell Lymphoma (PT-DLBCL) cases, we demonstrated a higher incidence and improved outcomes in PT-DLBCL non-germinal center B-cell (non-GCB) subtype compared to PT-DLBCL germinal center B-cell (GCB) Subtype. Published data suggests immunocompetent DLBCL non-GCB subtypes are less common and fare worse than immunocompetent GCB DLBCL. The reason for this unexpected finding in our PT-DLBCL pts is not fully understood. Recently Kiyasu and colleagues demonstrated that PD-L1 overexpression was significantly associated with non-GCB DLBCL, EBV virus positivity and poor prognosis in immunocompetent DLBCL samples. Therefore based on this we hypothesized that PT-DLBCL non-GCB subtype may have negative PD-L1 overexpression thus possibly accounting for improved outcomes compared to their immunocompetent counterparts. Hence we sought to test PD-L1 expression in our samples with PT-DLBCL. Methods: With IRB approval, we retrospectively identified PT- DLBCL patients treated at the University of Colorado between Jan 1989 to April 2015. We retrieved formalin fixed paraffin embedded PT-DLBCL tissue specimens and determined cell of origin by the Hans Algorithm. We assessed PD-L1 expression by immunohistochemistry. PD-L1 positive PT-DLBCL was defined as 30% of more of the lymphoma cells showing distinct membranous and or cytoplasmic staining. In addition EBER-ISH was performed to assess EBV status. Results: 86 adult SOT pts with PTLD were treated at our institution. 75 of 86 pts (87%) had monomorphic histology. Among monomorphic PTLD, 64% (48 of 75) had DLBCL. The median age at transplantation was 49.5 yrs (5-74 yrs). Median time from SOT to PTLD was 37 mos (1.4-499). The most common transplanted organ included kidney (40%), liver (38%), lung (13%) and heart (9%). 31% had early PTLD (<12mos of SOT) and 69% had late PTLD (>12mos of SOT). 60% were EBV positive. 77% with early PTLD and 49% with late PTLD were EBV positive. Due to a paucity of archived tissue blocks, IHC staining was applied to 32/48 samples with DLBCL. Non-GCB subtype was identified in 75% (24/32) samples and GCB subtype in 25% (8/32) samples. Of the 48 pts with PT-DLBCL histology, PD-L1 stain was performed on 18 samples. Of the 18 PT-DLBCL samples, 77% (14/18) had non-GCB subtype and 16% (3/18) had GCB subtype. PD-L1 expression was negative in 78% (11/14) and positive in 22% (3/14) of non-GCB DLBCL samples. PD-L1 expression was negative in 100% (3/3) of GCB DLBCL samples. The sample size was too small to effectively describe the survival experience of pt subsets. Using Fisher's exact test we found no evidence to support an association between EBV Status and PDL1 expression (p-value 0.316). Conclusions: We previously reported in our consecutive series of PTLD after SOT an increased incidence and improved survival in pts with PT-DLBCL non-GCB subtype (ASH 2015) compared to PT-DLBCL GCB subtype. The reason for this is not fully understood. However, our limited series reveals that a majority of pts with PT- DLBCL non-GCB subtype was negative for PD-L1 overexpression. This might explain the improved outcomes in the PT-DLBCL non-GCB population. Despite a small sample size it is also interesting to note that 100% pts with PT-DLBCL GCB subtype were negative for PD-L1 overexpression. In the era of immunotherapy further studies in larger patient cohorts are warranted in order to understand the unique biology and outcomes of PT-DLBCL since it may have therapeutic implications. Disclosures Pollyea: Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member. Kamdar:Seattle Genetics: Speakers Bureau.
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Slimani, Yasmine, Fouzia Hali, and Fatima-Zohra El Fatoiki. "Triple-negative diffuse large B-cell lymphoma: A distinct entity." Our Dermatology Online 12, no. 4 (October 19, 2021): 427–29. http://dx.doi.org/10.7241/ourd.20214.17.
Abstract:
The Hans algorithm categorizes the diffuse large B-cell lymphoma (DLBCL) into two major subtypes: the germinal center B-cell-like (GCB) DLBCL and the non-GCB DLBCL. This classification is based on three immunohistochemical markers: CD10, BCL6, and MUM1. The non-GCB subtype is associated with lower overall survival (OS) and progression-free survival (PFS) rates compared to the GCB. DLBCL without positive staining for these three markers (CD10–, BCL6–, MUM1–), also called a triple negative or TN, are classified as the non-GCB subtype. However, they show different clinical characteristics and better prognosis than others assigned to the same cell-of-origin group. Herein, we report a case of a TN non-GCB DLBCL with a complete response after R-CHOP therapy. Together with previous reports of TN non-GCB DLBCLs, our case might depreciate the prognostic value of the Hans algorithm, which was already controversial in the literature, especially in the chemoimmunotherapy era.
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Lossos, Izidore S., XiaoQing Lu, Feiying Ding, Manuel Rosado, Ash A. Alizadeh, and Hovav Nechushtan. "Distinct IL-4 Intracellular Signaling in Germinal Center B-Cell like and Activated B-Cell like Diffuse Large B-Cell Lymphoma: Novel Opportunities for Therapeutic Interventions." Blood 104, no. 11 (November 16, 2004): 244. http://dx.doi.org/10.1182/blood.v104.11.244.244.
Abstract:
Abstract Gene expression profiling studies sub-classified diffuse large B-cell lymphomas (DLBCL) into two clinically distinct types: germinal center B cell (GCB)-like and activated B-cell (ABC)-like tumors, characterized by long and short survival, respectively. At least two markers of the GCB-phenotype - BCL6 and HGAL - are IL-4 target genes whose high expression independently predicts better overall survival. Gene expression analysis of DLBCL also demonstrated higher levels of mRNA expression of components of the IL-4 signaling pathway (IL-4Rα, IRS, p110 subunit of PI-3 kinase, and PKC delta) in the GCB-like DLBCL (Alizadeh et al Nature. 2000;403:503). Identification of IL-4 inducible genes in normal B-lymphocytes revealed additional IL-4 target genes that are expressed at higher levels in GCB-like DLBCL compared to ABC-like DLBCL. Together, these observations support the distinct activity of the IL-4 signaling pathway in DLBCL subtypes. Accordingly, IL-4 stimulation of GCB-like (SUDHL6, SUDHL4 and OCILY19) and ABC-like (OCILY10 and OCILY3) DLBCL cell lines increased expression of its known target genes only in GCB-like, but not in ABC-like DLBCL. Further, IL-4 stimulation led to AKT phosphorylation in the ABC-like but not in the GCB-like cells. Conversely, IL-4 induced STAT6 phosphorylation (pSTAT6) in all the tested GCB-like and in the OCILY10 cell lines but not in the OCILY3 ABC-like cell-line. IL-4 induced progressive accumulation of large quantities of pSTAT6 in both the cytoplasm and in the nucleus in the GCB-like DLBCL. In contrast, in IL-4 treated ABC-like OCILY10 cells, pSTAT6 did not accumulate in either cytoplasm or nucleus, and much smaller amounts of pSTAT6 were detected in the nuclear extracts from stimulated cells. The latter observation was at least partially attributed to different extent of pSTAT6 nuclear deposphorylation and proteasomal degradation in the GCB-like and ABC-like DLBCL, as determined by exposure of these cell lines to STAT6 nuclear export inhibitor (leptomycin B) and phosphatase and proteasome inhibitors. Nuclear protein tyrosine phosphatase assays revealed significantly higher phosphatase activity in the ABC-like compared to the GCB-like DLBCL cell-lines. Evaluation of mRNA expression of 51 known tyrosine phosphatases in the GCB-like and ABC-like DLBCL tumors based on array data revealed that mRNA expression of 13 protein tyrosine phosphatases was significantly higher (p<0.001) in the ABC-like compared to GCB-like DLBCL. In vitro pSTAT6 dephosphorylation studies suggested that PTPN2, expressed in ABC-like but not in the GCB-like cell-lines, is a putative STAT6 phosphatase. Taken together with the independent prognostic significance of IL-4 target genes (e.g., BCL-6 and HGAL) and distinct effects of IL-4 on proliferation and immuno-chemosensitivity of GCB-like and ABC-like cells (Abstract by Nechushtan et al), the observed differences in the intracellular IL-4 signaling might contribute to different clinical outcome of patients with DLBCL.
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Costa, Luciano J., Andrew L. Feldman, Ivana N. Micallef, David J. Inward, Patrick B. Johnston, Luis F. Porrata, Mark R. Litzow, and Stephen M. Ansell. "Germinal Center B Cell and Non-Germinal Center B Cell-Like DLBCL Have Similar Clinical Features at the Time of Progression and Comparable Outcome Following Autologous HSC Transplantation." Blood 110, no. 11 (November 16, 2007): 1901. http://dx.doi.org/10.1182/blood.v110.11.1901.1901.
Abstract:
Abstract Background: Germinal center B cell-like (GCB) DLBCL, as determined by gene expression profiling or immunohistochemistry, is more likely to be cured by initial conventional chemoimmunotherapy than non-germinal center B cell-like (non-GCB) DLBCL. For patients with relapsed or refractory chemosensitive DLBCL, high-dose chemotherapy and autologous hematopoietic stem cell (HSC) transplant is considered standard-of-care treatment, but it is unknown whether the outcome of these patients is similarly influenced by the subtype of DLBCL. We therefore explored the differences between patients with GCB and non-GCB DLBCL as regards their clinical features at relapse after first line therapy and their outcome following salvage autologous HSC transplant. Methods: Patients undergoing BEAM conditioning and autologous HSC transplantation for relapsed or refractory chemosensitive DLBCL at Mayo Clinic, Rochester, MN between 2001 and 2006 were included. Immunohistochemical analysis was performed for CD10, BCL-6 and MUM1 allowing classification in GCB and non-GCB-like DLBCL, as well as for BCL-2. GCB and non-GCB groups were compared in terms of known prognostic factors at time of progression and outcome after HSC transplant Results: Fifty-nine patients were included and had retrievable tumor samples to allow immunohistochemical analysis. Median follow-up of survivors was 25 months; median age at the time of transplant was 60 years (range 17–77); All patients had failed at least one previous anthracycline-based regimen (15 had refractory disease). Overall, 25/59 cases (42%) were positive for CD10, 32/58 (55%) for BCL-6, and 19/58 (32%) for MUM1. Thirty-two patients (54%) were classified as having GCB and 27 (46%) non-GCB-like DLBCL. Patients in the GCB and non-GCB group had similar time to progression (TTP) (median 12.5 months vs. 11 months, Wilcoxon P=0.81) after first line therapy and similar IPI-R scores (Chi-square, P=0.38). In univariate analysis, GCB and non-GCB did not differ in time to relapse after HSC transplant (log rank test P=0.77) or survival (log rank test P=0.48; figure). The lack of demonstrable difference in survival persisted even after correction for IPI-R and TTP, factors know to affect transplant outcome (Cox regression, RR=0.80 for GCB; P=0.28). BCL-2 was highly expressed in both GCB (81%) and non-GCB (96%) and did not correlate with outcome in the entire population nor in any of the two groups. Conclusion: Patients with chemosensitive relapsed or refractory GCB and non-GCB-like DLBCL derive similar benefit from autologous HSC transplant. Figure Figure
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Julianty, Patricia Fransisca, Maria Francisca Ham, Kusmardi Kusmardi, and Agnes Stephanie Harahap. "CD30 Expression in Germinal Center B-cell-like and non-Germinal Center B-cell-like Subtypes of Diffuse Large B-cell Lymphoma." Open Access Macedonian Journal of Medical Sciences 8, B (April 17, 2020): 375–80. http://dx.doi.org/10.3889/oamjms.2020.4645.
Abstract:
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common and most heterogeneous type of non-Hodgkin lymphoma. With current therapeutic modalities, 30%–40% of DLBCL cases still experience recurrence. The discovery of CD30 expression in DLBCL in several studies has opened up alternative opportunities for new target therapies.
AIM: This cross-sectional study aimed to determine CD30 expression in DLBCL and its difference in expression in germinal center B-cell such as (GCB) and non-GCB subtypes.
METHODS: The sample consisted of 25 GCB and 25 non-GCB cases based on immunohistochemical examination performed at Cipto Mangunkusumo Hospital from 2014 to 2017. CD30 staining was carried out and assessed using tumor cells percentage with positive cutoff values of >0%, >10%, and >20%.
RESULTS: Positive CD30 expression was obtained in 8 (16%), 4 (8%), and 3 (6%), out of 50 DLBCL cases with positive cutoff values of >0%, >10%, and >20%, respectively. We performed Fisher’s exact test to determine CD30 expression in the GCB and non-GCB subtypes and found no significant difference with p > 0.05.
CONCLUSION: Our study found no significant difference between CD30 expression in the GCB and non-GCB subtypes of DLBCL.
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Lenz, Georg, George Wright, Sandeep Dave, Alexander Kohlmann, Wenming Xiao, John Powell, Hong Zhao, et al. "Gene Expression Signatures Predict Overall Survial in Diffuse Large B Cell Lymphoma Treated with Rituximab and Chop-Like Chemotherapy." Blood 110, no. 11 (November 16, 2007): 348. http://dx.doi.org/10.1182/blood.v110.11.348.348.
Abstract:
Abstract Gene expression profiling has been used to distinguish two major subtypes of diffuse large B cell lymphoma (DLBCL), termed germinal center B cell-like (GCB) DLBCL and activated B cell-like (ABC) DLBCL. Following CHOP-like chemotherapy, GCB and ABC DLBCLs had distinct 5-year survival rates of ∼60% and ∼30%, respectively. Prognostic gene expression signatures in CHOP-treated DLBCL include the lymph node signature, which reflects a non-malignant host response, the MHC class II signature, both favorable when expressed and the proliferation signature which is adverse when expressed. The addition of rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the outcome for DLBCL patients. We therefore investigated, if gene expression signatures that predicted survival among DLBCL patients treated with CHOP remained predictive for DLBCL patients treated with R-CHOP. Gene expression profiling was performed on 156 samples from previously untreated patients with DLBCL using Affymetrix U133 plus arrays. All patients received rituximab and CHOP-like chemotherapy. Samples were classified as GCB DLBCL, ABC DLBCL, or unclassified, and were assessed for expression of the lymph node and proliferation signatures. A Cox-proportional hazards model was used to determine the association of these gene expression features with overall survival (OS). 71 DLBCL samples were classified as GCB DLBCL, 63 as ABC DLBCL, and 22 were unclassified. The addition of rituximab improved OS for both GCB and ABC DLBCL compared to historical controls treated with CHOP-like chemotherapy alone. After a median follow-up of 2.3 years, GCB DLBCL had a more favorable OS than ABC DLBCL, with 3-year OS rates of 86% vs. 68% (p = 0.014). The 3-year OS rate of unclassified DLBCLs was 69%. The lymph node signature was associated with favorable OS (p = 0.023) and the proliferation signature with inferior OS (p = 0.009), whereas the MHC class II signature was not associated with OS (p = 0.44). In summary, addition of rituximab to CHOP-like chemotherapy improved OS for both GCB and ABC DLBCL but ABC DLBCL remained inferior to GCB DLBCL. The prognostic value of the lymph node and proliferation signatures were maintained in the context of R-CHOP therapy. An understanding of the biological attributes of DLBCL tumors that are reflected in these gene expression signatures remains critical to our ability to improve survival of these patients.
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Nechushtan, Hovav, Joseph D. Rosenblatt, and Izidore S. Lossos. "IL-4 Affects Proliferation, Chemosensitivity-and Rituximab Sensitivity of Germinal Center B-Cell like (GCB) and Activated B-Cell like (ABC) Diffuse Large B-Cell Lymphoma Differently." Blood 104, no. 11 (November 16, 2004): 242. http://dx.doi.org/10.1182/blood.v104.11.242.242.
Abstract:
Abstract Diffuse Large B-cell Lymphoma (DLBCL) represent a diverse group of lymphoid neoplasms with heterogeneous clinical, histological, immunophenotypic, cytogenetic and molecular genetic features. Approximately 50% of DLBCL patients are not cured by the standard combination chemotherapy regimens. DLBCL can be subclassified into GCB-like DLBCL which are characterized by expression of genes normally expressed in germinal center B cells, and having a significantly better overall survival (OS) than the ABC-like DLBCL, which are characterized by expression of genes induced during in vitro activation of normal B cells. At least two markers of the GCB-phenotype - BCL6 and HGAL - are IL-4 target genes, increased expression of which independently predicts better OS. These observations suggest that endogenous or exogenously administered IL-4 may influence behavior of DLBCL. IL-4 mRNA was detected at low levels in 5 of 7 GCB-like and in all 4 ABC-like DLBCL tumor specimens. Two of 7 GCB-like tumors showed high expression levels of IL-4 as determined by real-time RT-PCR. Examination of the effects of IL-4 on proliferation of GCB-like (SUDHL6, SUDHL4 and OCILY19) and ABC-like (OCILY10 and OCILY3) DLBCL cell lines showed that IL-4 mildly increased DNA synthesis, as assessed by thymidine incorporation, in all the GCB-like DLBCL. Conversely, IL-4 markedly decreased proliferation in the ABC-like DLBCL cell lines by inducing G1 arrest. IL-4 also differently affected the sensitivity of GCB-like and ABC-like DLBCL to doxorubicin. IL-4 reduced doxorubicin-induced cell death of ABC-like cell lines (20–50% reduction) while it markedly increased the killing of the GCB-like cells (40–80% induction). IL-4 also prevented serum starvation-induced cell death of the ABC-like DLBCL, but it increased cell death of the GCB-like DLBCL cell lines. Recently, Rituximab was shown to improve survival of DLBCL patients when added to the CHOP regimen. The precise mechanisms of its action are unknown; however present data suggest that it may affect lymphoma cells either by activation of complement lysis or by mediating ADCC. IL-4 reduced the complement mediated Rituximab cell lysis of the ABC-like cell lines, while it increased the complement mediated Rituximab cell lysis of the GCB-like DLBCL cell lines. Expression levels of surface markers that modulate complement cell lysis (CD46, CD55 and CD59) were not affected by IL-4 exposure. In contrast, IL-4 did not affect killing of GCB-like and ABC-like cells by ADCC. These observations suggest that DLBCL subtypes may respond differently to the in vivo cytokine milieu of the tumor. Different responsiveness to IL-4 may modulate tumor sensitivity to the current therapeutic modalities and can potentially be explored to augment response to chemotherapy and Rituximab.
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Locatelli, Silvia L., Roberto Papait, Giuseppa Careddu, Ada Koschorke, Giuliano G. Stirparo, Monica Balzarotti, Luca Castagna, Armando Santoro, and Carmelo Carlo-Stella. "Upregulation of Cereblon Expression By the DNA Methyltransferase Inhibitor Azacytidine Strongly Enhances Lenalidomide Cytotoxicity in Germinal Center B-Cell-like (GCB) and Activated B-Cell-like (ABC) Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 124, no. 21 (December 6, 2014): 2253. http://dx.doi.org/10.1182/blood.v124.21.2253.2253.
Abstract:
Abstract INTRODUCTION: Lenalidomide monotherapy exerts clinical activity in relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) with better response rate and progression-free survival being recorded in activated B-cell-like (ABC) rather than germinal center B-cell-like (GCB)-DLBCL. Reasons for such a difference are likely due to different expression of key molecules involved in mediating activity of Lenalidomide, such as Interferon regulatory factor 4(IRF4) and cereblon (CRBN). Evidences supporting the key role of DNA methylation and histone modifications in regulating genome stability and gene expression in DLBCL prompted us to investigate the capacity of Azacytidine in modulating Lenalidomide activity, thereby sensitizing GCB-DLBCL to Lenalidomide and enhancing Lenalidomide efficacy in ABC-DLBCL. METHODS: DLBCL cell lines with ABC (U-2932, RIVA) or GCB (SU-DHL4, SU-DHL6) genotype were used to investigate the effects of Lenalidomide and Azacytidine on cell growth and cell death. Western blotting (WB) and immunofluorescence analysis were used to assess modulating effects of the two-drug combination on molecular determinants of Lenalidomide activity. Additionally, we studied CRBN, IRF4 and CRBN binding proteins expression, such as Ikaros and Aiolos (IKZF1 and IKZF3) by real time polymerase chain reaction (RT-PCR) in response to drug treatment. RESULTS: Graded concentrations of Lenalidomide (0.1-100 µM) inhibited cell proliferation by 20% to 40% and increased cell death up to 30% to 40% in ABC-DLBCL cell lines, whereas had minimal effects on GCB-DLBCL cell lines. Untreated ABC-DLBCL but not GCB-DLBCL consistently showed a high expression of CRBN and IRF4. Upon Lenalidomide treatment (3 days) CRBN was significantly upregulated and IRF4 downregulated in ABC-DLBCL, but not GCB-DLBCL cells. Since DNA methylation regulates gene expression in DLBCL cell lines, we next examined whether Azacytdine could modulate CRBN and IRF4 expression and in turn enhance responsiveness to Lenalidomide. Exposure of both ABC- and GCB-DLBCL cell lines to Azacytidine (up to 72 hours) induced a marked increase of CRBN and IRF4 transcripts; addition of Lenalidomide strongly increased Azacytidine-induced increase of CRBN and significantly downregulated IRF4 expression; the combined treatment induced a marked downregulation of Ikaros and Aiolos protein levels. At the cellular level, the concomitant Azacytidine (10 μM)/Lenalidomide (10 μM) treatment inhibited in a synergistic manner the mean (±SEM) cell growth of both ABC-DLBCL (Lena: -16 ± 4%; AZA: -22 ± 2%; AZA/Lena: -70 ± 1%, P<0.001) and GCB-DLBCL (Lena: -17 ± 3%; AZA: -40 ± 4%; AZA/Lena: -82 ± 2%, P<0.001). Additionally, the two drug exposure was associated with a 3-fold decrease of S phase cells(Lena: 28 ± 2%; AZA: 22 ± 0.8%; AZA/Lena: 9 ± 1%, P<0.001); a marked p21 overexpression, and a 3- to 4-fold cell death increase (P<0.001) in both ABC- and GCB-DLBCL. CONCLUSIONS: Our results indicate that Azacytidine sensitizes GCB-DLBCL to the cytotoxic effects of Lenalidomide and enhances Lenalidomide efficacy against ABC-DLBCL resulting in synergistic anti-proliferative and pro-apoptotic effects in both ABC- and GCB-DLBCL cell lines. Cytotoxicity of the two drug combination is mediated by signaling events involving CRBN upregulation and IRF4 downregulation leading to CRBN-binding proteins downregulation. Azacytidine-dependent activation of CRBN and IRF4 expression allow to hypothesize a methylation-driven regulation of these genes. These results might provide a rationale for clinical studies using Azacytidine and Lenalidomide combination in ABC- and GCB-DLBCL. Disclosures No relevant conflicts of interest to declare.
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Kleinstern, Geffen, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, et al. "Abstract 741: Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin." Cancer Research 82, no. 12_Supplement (June 15, 2022): 741. http://dx.doi.org/10.1158/1538-7445.am2022-741.
Abstract:
Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 741.
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Fu, Kai, Dennis D. Weisenburger, William W. L. Choi, Kyle D. Perry, Lynette M. Smith, Xinlan Shi, Christine P. Hans, et al. "Addition of Rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell–Like and Non–Germinal Center B-Cell–Like Subtypes of Diffuse Large B-Cell Lymphoma." Journal of Clinical Oncology 26, no. 28 (October 1, 2008): 4587–94. http://dx.doi.org/10.1200/jco.2007.15.9277.
Abstract:
Purpose Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subtypes (ie, germinal center B-cell–like [GCB] and activated B-cell–like [ABC] DLBCL), which initially were characterized by gene expression profiling and subsequently were confirmed by immunostaining. However, with the addition of rituximab to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear. Patients and Methods We studied 243 patient cases of de novo DLBCL, which included 131 patient cases treated with rituximab plus standard chemotherapy (rituximab group) and 112 patient cases treated with only standard chemotherapy (control group). The cases were assigned to GCB or non-GCB subgroups (the latter of which included both ABC DLBCL and unclassifiable DLBCL) on the basis of immunophenotype by using the Hans method. Clinical characteristics and survival outcomes of the two patient groups were compared. Results The clinical characteristics of the patients in the rituximab and the control groups were similar. Compared with the control group, addition of rituximab improved the 3-year overall survival (OS; 42% v 77%; P < .001) of patients with DLBCL. Rituximab-treated patients in either the GCB or the non-GCB subgroups also had a significantly improved 3-year OS compared with their respective subgroups in the control group (P < .001). In the rituximab group, the GCB subgroup had a significantly better 3-year OS than the non-GCB subgroup (85% v 69%; P = .032). Multivariate analyses confirmed that rituximab treatment was predictive for survival in both the GCB and the non-GCB subgroups. Conclusion In this retrospective study, we have shown that the subclassification of DLBCL on the basis of the cell of origin continues to have prognostic importance in the rituximab era.
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Cao, Yabing, Ying Huang, Sheng Ye, and Tongyu Lin. "Prognostic impact of immunohistochemically defined germinal center B-cell and nongerminal center B-cell subtypes of diffuse large B-cell lymphoma in rituximab era." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e18517-e18517. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e18517.
Abstract:
e18517 Background: Diffuse large B-cell lymphoma (DLBCL) can be molecularly subtyped as either germinal center B-cell (GCB) or non-GCB. The role of rituximab(R) in these two groups remains unclear. Methods: We studied 204 patients with de novo DLBCL (107 treated with CHOP; 97 treated with R-CHOP); patients being stratified into GCB and non-GCB on the basis of BCL-6, CD10 and MUM1 protein expression. The relationships between clinical characteristics, survival data and immunophenotype were studied. Results: The median follow-up was 51months for CHOP group and 56 months for R-CHOP group. The 5-year overall survival (OS) in the CHOP and R-CHOP group was 50.4% and 66.6% (p=0.031), respectively. GCB patients had a better 5-year OS than non-GCB patients whether treated with CHOP (65.0% vs. 40.9%; p=0.011). In contrast, there’s no difference in the 5-year OS for the GCB and non-GCB with R-CHOP (76.5% vs. 61.3%; p=0.141). In non-GCB subtype, additional rituximab improved survival than CHOP (61.3% vs. 40.9%; p=0.0303). Conclusions: These results indicated that addition of rituximab to standard chemotherapy eliminate the prognostic value of immunohistochemically defined GCB and non-GCB phenotypes in DLBCL by improving the prognostic value of non-GCB subtype of DLBCL
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Huang, Ying, Sheng Ye, Yabing Cao, Zhiming Li, Jiajia Huang, He Huang, Muyan Cai, Rongzhen Luo, and Tongyu Lin. "Outcome of R-CHOP or CHOP Regimen for Germinal Center and Nongerminal Center Subtypes of Diffuse Large B-Cell Lymphoma of Chinese Patients." Scientific World Journal 2012 (2012): 1–7. http://dx.doi.org/10.1100/2012/897178.
Abstract:
Diffuse large B-cell lymphoma (DLBCL) can be molecularly subtyped as either germinal center B-cell (GCB) or non-GCB. The role of rituximab(R) in these two groups remains unclear. We studied 204 patients with de novo DLBCL (107 treated with first-line CHOP; 97 treated with first-line R-CHOP), patients being stratified into GCB and non-GCB on the basis of BCL-6, CD10, and MUM1 protein expression. The relationships between clinical characteristics, survival data, and immunophenotype (IHC) were studied. The 5-year overall survival (OS) in the CHOP and R-CHOP groups was 50.4% and 66.6% (P=0.031), respectively. GCB patients had a better 5-year OS than non-GCB patients whether treated with CHOP or not (65.0% versus 40.9%;P=0.011). In contrast, there is no difference in the 5-year OS for the GCB and non-GCB with R-CHOP (76.5% versus 61.3%;P=0.141). In non-GCB subtype, additional rituximab improved survival better than CHOP (61.3% versus 40.9%;P=0.0303). These results indicated that addition of rituximab to standard chemotherapy eliminates the prognostic value of IHC-defined GCB and non-GCB phenotypes in DLBCL by improving the prognostic value of non-GCB subtype of DLBCL.
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Dunleavy, Kieron, Stefania Pittaluga, Myron S. Czuczman, Sandeep S. Dave, George Wright, Nicole Grant, Margaret Shovlin, et al. "Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma." Blood 113, no. 24 (June 11, 2009): 6069–76. http://dx.doi.org/10.1182/blood-2009-01-199679.
Abstract:
Abstract Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell–like (GCB) and activated B cell–like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor–kappa B (NF-κB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-κB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-κB through blocking IκBα degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (10.8 vs 3.4 months; P = .003) in ABC compared with GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.ClinicalTrials.gov under identifier NCT00057902.
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Wenzl, Kerstin, Bryce Manso, Yan W. Asmann, Matthew J. Maurer, Michelle Manske, Zhi-Zhang Yang, Susan L. Slager, et al. "Whole-Exome Analysis Reveals Novel Somatic Genomic Alterations Associated with Cell of Origin in Diffuse Large B-Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 2935. http://dx.doi.org/10.1182/blood.v128.22.2935.2935.
Abstract:
Abstract Gene expression profiling has shown that diffuse large B-cell lymphoma (DLBCL) clusters into three major subtypes based on similarity in expression patterns to their cell of origin (COO): germinal center B-cell-like (GCB-DLBCL), activated B-cell-like DLBCL (ABC-DBLCL) and primary mediastinal B-cell lymphoma (PMBCL). These subtypes of DLBCLs are associated with distinctly different overall survival rates after standard immunochemotherapy. However, clinical and prognostic heterogeneity remains within COO subsets and strategies are needed to further stratify patients to identify and target high-risk subsets. A comprehensive genomic analysis of COO on a clinically defined set of DLBCL cases has not been performed and the aim of this study was to use whole-exome sequencing (WES) data from 58 paired tumor-normal DLBCL samples to assess association of known DLBCL genomic alterations with cell COO as well as for identification of novel and relevant genetic biomarkers. To investigate genomic alterations associated with DLBCL subsets, we analyzed WES and genome wide copy number data from 58 paired tumor-normal DLBCL tumors. Gene expression profiling or Hans classification was performed to determine DLBCL COO subtype; 31 patients were classified as GCB and 27 as non-GCB. The WES data were used to 1) assess the association of known DLBCL genomic alterations with COO, and 2) identify novel alternations associated with COO. Statistical analysis was performed and the data were ranked by significance (p≤ 0.05) within each DLBCL subtype. In total, 45 genomic abnormalities were analyzed for their association with either GCB, non-GCB or both. Mutations in CREBBP, EZH2, MEF2B, FOXO1 and REL have also been reported as GCB driver mutations and we observed GCB patients with these mutations, but the mutation clustering was not wholly associated with GCB. MYC double-hits were exclusively found in the GCB-subtype group. For the non-GCB cases we found that mutations in MAP2K3 and MYD88 were significantly associated with this subtype(p< 0.05). In addition to mutational patterns, we identified several copy number alterations (CNA) across both groups. Chromosomal losses in GCB patients were found at chromosomes 10q11.21-10q24.23, 4q12-4q35.2, 3q12.1-3q29, 4p12-4p16.3, 10p11.21-10p15.3, and 14q11.2-14q24.3 whereas gains were localized to 7q11.1-7q36.3, 7p11.2-7p22.3, and 1q21-1q32.1 (p < 0.05). No CNA was observed to directly associate with non-GCB patients, however, a loss at 9p21 and gains at 9q24.1 and 18q21.33 trended with the non-GCB subtype, supporting previous reports. Loss at 10q23.31 or a gain in 2p13-2p12 have been reported as being specific for GCB and our data confirmed the association of 10q23.31 with GCB while a gain at 2p13-2p12 (REL)was found in both subtypes. To further understand genomic differences between DLBCL subtypes, we evaluated the relative percentage of each genomic feature. 18/45 (40%) were only observed in GCB patients whereas 2/45 (5%) were specific to the non-GCB subtype. The majority (25/45, 55%) overlapped between the two subtypes. Throughout our analysis we noted that 7 non-GCB cases lacked any of the driver mutations analyzed in the study. While all cases carried mutations, they consisted of low frequency mutations that were not specifically associated with COO. 2/7 cases had a gain at 9p24.1 that included CD274 and JAK2. Because 9p24.1 gains have not been fully defined in DLBCL, we reviewed all cases and identified 4 (7%) with a 9p24.1 gain, 3 of which were non-GCB and 1 GCB. One non-GCB case was EBV+ and none of the cases showed evidence of PMBCL. Of the 9p24.1 cases, three had RNAseq data available and we found that PDL1 and JAK2 expression was elevated (12 fold p< 0.01 and 7 fold p< 0.01, respectively) when compared to the 9p24.1 normal cases (n=32). While outcome was not the focus of the study, we did note that 6/7 cases that lacked driver mutations achieved event free survival at 24 months (EFS24). Taken together, this analysis has further characterized the genetic profile of each COO subtype and has identified novel GCB CNAs which require independent replication. Additionally, we identify a subgroup of non-GCB DLBCL patients that do not harbor known driver mutations and require further genomic study to better resolve the biology of these tumors. Together, these data provide insight on the genetic heterogeneity of DLBCL and identify genetic variants that may inform subtype specific therapy. Disclosures Nowakowski: Morphosys: Research Funding; Celgene: Research Funding; Bayer: Consultancy, Research Funding. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL..
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De Paepe, Pascale, Ruth Achten, Gregor Verhoef, Iwona Wlodarska, Michel Stul, Vera Vanhentenrijk, Marleen Praet, and Chris De Wolf-Peeters. "Large Cleaved and Immunoblastic Lymphoma May Represent Two Distinct Clinicopathologic Entities Within the Group of Diffuse Large B-Cell Lymphomas." Journal of Clinical Oncology 23, no. 28 (October 1, 2005): 7060–68. http://dx.doi.org/10.1200/jco.2005.15.503.
Abstract:
Purpose The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. Patients and Methods All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. Results Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. Conclusion Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.
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Dekker, Joseph D., Daechan Park, Arthur L. Shaffer, Holger Kohlhammer, Wei Deng, Bum-Kyu Lee, Gregory C. Ippolito, et al. "Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1." Proceedings of the National Academy of Sciences 113, no. 5 (January 19, 2016): E577—E586. http://dx.doi.org/10.1073/pnas.1524677113.
Abstract:
High expression of the forkhead box P1 (FOXP1) transcription factor distinguishes the aggressive activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) subtype from the better prognosis germinal center B-cell (GCB)-DLBCL subtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways. FOXP1 promoted gene expression underlying transition of the GCB cell to the plasmablast—the transient B-cell stage targeted in ABC-DLBCL transformation—by antagonizing pathways distinctive of GCB-DLBCL, including that of the GCB “master regulator,” BCL6 (B-cell lymphoma 6). Cell-line derived FOXP1 target genes that were highly correlated with FOXP1 expression in primary DLBCL accurately segregated the corresponding clinical subtypes of a large cohort of primary DLBCL isolates and identified conserved pathways associated with ABC-DLBCL pathology.
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Waller, Rosalie Griffin, Dennis P. Robinson, Anne J. Novak, Lisa M. Rimsza, Kerstin Wenzl, Rebecca L. King, Andrew L. Feldman, et al. "Abstract 1181: Etiologic heterogeneity of genetic risk for DLBCL cell-of origin molecular subtypes." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1181. http://dx.doi.org/10.1158/1538-7445.am2023-1181.
Abstract:
Abstract Diffuse large B-cell lymphoma (DLBCL) is clinically and biologically heterogenous. Based on gene expression profiling of the tumor, DLBCL is classified into two major molecular subtypes linked to cell-of-origin (COO): germinal center (GCB) and activated B-Cell (ABC). The GCB subtype is characterized by a high prevalence of somatic mutations, particularly in apoptosis genes (e.g., BCL2) which is characteristic of follicular lymphoma (FL, another GCB lymphoma). The development of the validated NanoString gene expression test as well as immunohistochemistry markers that work in formalin-fixed, paraffin-embedded tissue allows for the classification of DLBCL by COO in epidemiological studies. We hypothesized that integration of COO with germline genetics could provide insight into the underlying biology driving this heterogeneity, as well as insight into putative function of germline risk variants. Prior genome wide association studies (GWAS) have identified 7 SNPs in 6 susceptibility loci for DLBCL, including: 2p23.3 (rs79480871 NCOA1), 3q13.33 (rs9831894 CD86), 3p24.1 (rs6773363 EOMES), 6p21.33 (rs2523607 HLA-B), 6p25.3 (rs116446171 EXOC2), and 8q24.21 (rs13255292 and rs4733601 PVT1 and MYC). Two of these loci were also identified in FL GWAS (different lead SNPs): 6p21.33 (rs3130437) and 8q24.21 (rs13254990 PVT1). Additional published FL susceptibility loci include: 3q28 (rs6444305 LPP), 6p21.32 (rs9268839), 11q23.3 (rs4938573 CXCR5), 11q24.3 (rs4937362 ETS1), and 18q21.33 (rs17749561 BCL2). Here we evaluated whether the published DLBCL/FL loci differ by COO molecular subtypes. We evaluated each of the 14 DLBCL/FL SNPs by case-case (GCB vs. nonGCB DLBCL) and polytomous case-control (GCB, nonGCB, and FL vs. controls) analyses. DLBCL cases were classified into GCB vs. nonGCB based on best available data from NanoString, RNAseq, followed by the Hans algorithm. A total of 778 DLBCL cases (470 GCB and 308 nonGCB), 1,050 FL cases, and 1,383 controls were analyzed. Odds ratios (OR) based on ordinal encoding of each SNP and 95% CI were calculated for each of the comparison groups. The ORs for four GWAS SNPs were significantly elevated in GCB vs. nonGCB DLBCL as well as in FL; two were FL GWAS SNPs from the HLA region (6p21.32 and 6p21.33) and the other two (BCL2 and ETS1) are important in the germinal center program. In contrast, one SNP (EXOC2) was significantly elevated in nonGCB-DLBCL and was not associated with GCB-DLBCL or FL; this SNP is also near IRF4 (MUM1), a gene important in the ABC program. For the remaining SNPs, there were suggestive associations for GCB-DLBCL and FL versus nonGCB DLBCL (CD86, CXCR5); nonGCB-DLBCL vs. GCB-DLBCL and FL (NCOA1, PVT1); and associations that showed no pattern with COO (EOMES, LPP, HLA-B and MYC). These findings provide insight into the shared pathogenesis of FL and GCB-DLBCL to inform etiologic mechanisms and risk assessment. Citation Format: Rosalie Griffin Waller, Dennis P. Robinson, Anne J. Novak, Lisa M. Rimsza, Kerstin Wenzl, Rebecca L. King, Andrew L. Feldman, Matthew J. Maurer, Grzegorz S. Nowakowski, Brian K. Link, Thomas M. Habermann, Susan L. Slager, James R. Cerhan. Etiologic heterogeneity of genetic risk for DLBCL cell-of origin molecular subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1181.
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Kim, Yu Ri, Soo-Jeong Kim, June-Won Cheong, Yundeok Kim, Ji Eun Jang, Jung Yeon Lee, Deok-Hwan Yang, et al. "Upfront Autologous Stem Cell Transplantation Overcome the poor Prognosis of Non-Germinal Center Subtype of diffuse Large B-Cell Lymphoma in Patients with Advanced Stage and Elevated Serum Lactate Dehydrogenase." Blood 124, no. 21 (December 6, 2014): 3998. http://dx.doi.org/10.1182/blood.v124.21.3998.3998.
Abstract:
Abstract Introduction: The role of frontline autologous hematopoietic stem cell transplantation (ASCT) high-risk diffuse large B-cell lymphoma (DLBCL) is still controversial. We investigated the role of upfront ASCT as consolidation for high-risk DLBCL treated with rituximab containing chemotherapy according to molecular classification. Methods: A total of 195 newly diagnosed DLBCL patients with advanced stage and elevated serum lactate dehydrogenase from three centers were retrospectively analyzed. All patients achieved more than partial response (PR) after completing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) with rituximab (R-CHOP). Molecular classification was performed according to Han's algorithm. Results: One hundred fifty (76.9%) patients achieved complete response (CR) and 45 (23.1%) patients PR after frontline R-CHOP chemotherapy. Among these patients, sixty six (33.8%) patients were received ASCT. The 2-year overall survival (OS) was 82.9% and the 2-year progression-free survival (PFS) was 72.1%. Seven (10.6%) patients were relapsed after ASCT while 29 (22.5%) patients were relapsed in non-transplant patients. Patients who treated with ASCT showed superior OS and PFS (P=0.036, P=0.005). According to final response, ASCT showed superior OS and PFS in PR patients (P = 0.024, P = 0.009) while it did not in CR patients. Among the 128 patients that underwent immunohistochemistry for molecular classification, 36 patients (28.1%) were classified to GCB type, 92 (72.9%) patients were non-GCB type. Twenty five (27.1%) non-GCB patients received ASCT showed significant survival benefit for OS and PFS (P=0.032, P=0.011) while GCB patients did not show the survival difference according to ASCT (Figure 1). In non-GCB DLBCL, ASCT was related with superior PFS both interim and final PR status (P = 0.006, P=0.028). There was no difference for OS and PFS between GCB and non-GCB type in ASCT patients while GCB patients showed superior OS and PFS in non-transplant patients (P = 0.048, P=0.009). Conclusions: ASCT as consolidation improved OS and PFS in high risk DLBCL patients following R-CHOP chemotherapy. Especially, it could overcome the poor prognosis of non-GCB type DLBCL. Upfront ASCT could be considered effective treatment options for non-GCB type high risk DLBCL. Figure 1. Overall survival and progression free survival according to autologous hematopoietic stem cell transplantation in non-GCB type DLBCL. Figure 1. Overall survival and progression free survival according to autologous hematopoietic stem cell transplantation in non-GCB type DLBCL. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
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Soo, Joanne, David Matthew Kurtz, Florian Scherer, Alexander F. M. Craig, Michael C. Jin, Jason R. Westin, Davide Rossi, et al. "Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 7538. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.7538.
Abstract:
7538 Background: Patients with diffuse large B cell lymphoma (DLBCL) exhibit significant differences in clinical outcome based on cell-of-origin (COO). Patients are categorized as having germinal-center-like (GCB) or activated-B-cell-like (ABC) disease based on RNA microarray and histopathological analyses of tumor biopsies. We recently described an accurate sequencing-based method for determination of COO in DLBCL utilizing stereotyped differences in mutations (Scherer et al., 2016). Here, we further explore the mutational patterns in patients with differing molecular subtypes of DLBCL based on sequencing of circulating tumor DNA. Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) to pretreatment plasma samples and matched germline from a cohort of 115 patients with DLBCL. We then identified somatic alterations, which were used to determine COO molecular subtypes as previously described. Finally, we compared mutational patterns in patients with GCB and non-GCB DLBCL. Results: We detected a significantly greater number of total mutations (GCB: 1766 ± 160 mutations per Mb of targeted sequencing; non-GCB: 1364 ± 150 mutations per Mb of targeted sequencing; p < 0.05) and coding mutations (GCB: 145 ± 21 mutations per Mb of targeted sequencing; non-GCB: 28 ± 8.5 mutations per Mb of targeted sequencing; p < 0.001), particularly in immunoglobulin (Ig) regions (p < 0.05). In addition, GCB and non-GCB samples exhibited distinct mutational patterns within Ig regions. GCB samples were enriched for mutations in regions of switch mu (Sμ) (p < 0.01) and IGHV2-70 (p < 0.01), while non-GCB samples were enriched for mutations in regions of IGHG3 (p < 0.03), IGHV4-34 (p < 0.03), and IGLL5 (p < 0.05). GCB samples were also significantly enriched for coding mutations in SOCS1 (p < 0.01), a gene not included in our original COO classifier. Conclusions: Patients with GCB and non-GCB DLBCL exhibit distinct mutational patterns across both Ig and non-Ig loci of the genome. These differences in mutational patterns can be used to classify molecular subtypes noninvasively, potentially providing further utility to noninvasive genotyping and liquid biopsies.
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Xu-Monette, Zijun Y., Ling Li, John C. Byrd, Kausar J. Jabbar, Ganiraju C. Manyam, Charlotte Maria de Winde, Michiel van den Brand, et al. "Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma." Blood 128, no. 26 (December 29, 2016): 3083–100. http://dx.doi.org/10.1182/blood-2016-05-715094.
Abstract:
Key Points CD37 positivity predicts significantly better survival for DLBCL, and is superior to other prognostic factors in GCB-DLBCL. CD37 loss is an important risk factor for R-CHOP resistance in both GCB- and ABC-DLBCL.
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Foureau, David, Lawrence J. Druhan, Nury M. Steuerwald, Sarah A. Baxter, Omotayo O. Fasan, Belinda R. Avalos, and Nilanjan Ghosh. "Cytokine Profiling of ABC-Subtype and GCB-Subtype Diffuse Large B Cell Lymphoma: Systemic Nfkb Activation and Impact on Myeloid-Derived Suppressor Cells Distribution." Blood 126, no. 23 (December 3, 2015): 2666. http://dx.doi.org/10.1182/blood.v126.23.2666.2666.
Abstract:
Abstract Background. Among patients with newly diagnosed diffuse large B cell lymphoma (DLBCL), undergoing standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), overall survival is significantly worse for those with activated B cell-like (ABC) subtype compared with germinal center B cell-like (GCB) subtype. Among the key differences between DLBCL subtypes, constitutive activation of nuclear factor kappa B (NFκB) in the ABC-subtype has been associated with a rise of circulating myeloid-derived suppressor cells (MDSC). Patients and Methods. In this pilot study, blood samples were collected from 6 ABC-subtype and 5 GCB-subtype newly diagnosed DLBCL patients prior to and after R-CHOP therapy. To assess the systemic impact of constitutive NFκB activation in ABC-subtype compared with GCB-subtype DLBCL, serum concentrations of 27 immune analytes (15 NF-κB-dependent chemokines, cytokines and growth factors, 12 NFκB-independent chemokines and cytokines) were measured retrospectively using a BioPlex platform. ABC-subtype and GCB-subtype DLBCL immune profiles were further investigated using a 6-color flow cytometry panel (BD FACS Aria II), in which peripheral blood samples were prospectively analyzed for expression of CD11b, HLA-DR, CD33 and IL-4R to define MDSC (CD11b+, HLA-DR-/low, CD33+, IL-4R+), either monocytic (IL-14+) or granulocytic (CD15+). Results. Among the 11 patients enrolled in the study, 7 (5 ABC and 2 GCB) have completed R-CHOP therapy and are in complete remission. Twenty out of 27 immune analytes surveyed to establish DLBCL immune profiles were either not detected or constitutively expressed among ABC and GCB patients (pre or post therapy). At baseline, the predominant difference between DLBCL subtypes was centered around 3 NFκB-independent immune analytes. The IRF4-dependent chemokine CXCL10 was highly expressed in ABC-subtype DLBCL while elevated IL-12p70 and IL-13, (T-bet and Gata3-dependent cytokines, respectively) were mainly found in GCB-subtype DLBCL. Post R-CHOP therapy, serum concentrations of NFκB-dependent innate immune mediators, the cytokine IL-6 and the chemokine CXCL8, decreased by »50% regardless of DLBCL subtypes. While no systemic difference in NFκB-dependent immune analytes could distinguish the ABC-subtype from GCB-subtype DLBCL, circulating gMDSC and mMDSC were 8 and 3 times more prevalent among ABC patients. Following R-CHOP, their levels decreased to those observed in patients with the GCB subtype. Conclusions. Although constitutive NFκB activation is the hallmark of ABC-subtype DLBCL, no systemic NFκB-dependent immune analyte could distinguish ABC from GCB-subtype DLBCL in this pilot study. Despite the lack of a "NFκB immune signature", MDCSs (especially mMDSC) were predominantly found in ABC-subtype DLBCL. Significant differences were also observed among NFκB-independent immune analytes, predominantly adaptive cytokines, indicating GCB-subtype DLBCL have a more profound effect on T cell polarization, specifically TH2, than ABC-subtype. Disclosures Ghosh: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Havranek, Ondrej, Jingda Xu, Stefan Koehrer, Zhiqiang Wang, Justin M. Comer, Lisa Becker, Allen F. Yi, et al. "Molecular Aspects of Tonic B-Cell Receptor Signaling in Diffuse Large B-Cell Lymphoma Provide Biomarkers and Targets for Specific Inhibition." Blood 128, no. 22 (December 2, 2016): 779. http://dx.doi.org/10.1182/blood.v128.22.779.779.
Abstract:
Abstract Introduction. Targeting antigen-driven B-cell receptor (BCR) signaling with the BTK inhibitor ibrutinib is clinically effective against most B-cell lymphomas, including activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), but not germinal center B-cell (GCB) DLBCL. We have formally confirmed that GCB-DLBCL cell lines utilize tonic BCR signaling, by showing: 1) sensitivity (variable) to knockout (KO) of the BCR, SYK, and CD19; 2) dependence on CD79A ITAM phosphorylation; and 3) independence from BCR antigen specificity. However, uncertainty remains about molecular events in upstream parts of tonic BCR signaling, why dependence of GCB-DLBCL cells on tonic BCR signaling is variable, and their clinical relevance. Methods. We used CRISPR/Cas9 methods to modify selected genes by KO and/or knock-in (KI) of the cDNA of a fluorescent protein (FP; e.g., GFP), with the FP serving as a marker of cells with gene KO or modification, or as a gene-fused tag for localization or quantitation. Cells expressing a membrane-targeted Forster resonance energy transfer (FRET) based AKT activity reporter (Lyn-AktAR2) were used to measure AKT activity directly by flow cytometry (FCM). Results. The effect of KI of CD79A Y188F mutation alone was similar to complete BCR KO, implying that CD79A Y188 phosphorylation is essential for tonic BCR signal transduction. Western blot analysis of GCB-DLBCL cell lines after BCR KO showed variable decreases of AKT S473 phosphorylation (frequently used as surrogate measure of AKT activity), but these did not correlate well with the variable decreases in proliferation of GCB-DLBCL cell lines caused by BCR KO. Measuring AKT activity directly (Fig. 1), or by another indirect approach (surface expression of CXCR4, a target gene of FOXO1 inhibited by AKT activity), showed high correlation between decreases in AKT activity and proliferation after BCR KO. In contrast to the variable effect of BCR KO on growth, pan-AKT KO was uniformly growth-slowing in GCB-DLBCL lines (Fig. 2). Interestingly, baseline surface density of BCR units in GCB lines, quantified by FCM using CD79A-GFP KI cells or anti-CD79B staining, correlated highly with reduction in growth or AKT activity caused by BCR KO (Fig. 3). These findings lead us to conclude that the BCR contributes to AKT activation in GCB-DLBCL cell lines, to a variable degree determined by BCR surface density. We also conclude that BCR surface density is determined by cell line-specific factors, as well as immunoglobulin heavy (IgH) and light (IgL) hypervariable region (HVR) sequences, based on measurements of BCR surface levels after exchanging endogenous HVR sequences in OCI-Ly19 and OCI-Ly7 cell lines for HVRs derived from other GCB and ABC-DLBCL cell lines. Reduction of AKT activity after BCR KO (measured by FRET reporter) and baseline BCR surface density in GCB-DLBCL cell lines also correlated well with the sensitivity of GCB-DLBCL lines to the clinically-tested SYK inhibitor (P505-15, PRT062607) or FDA-approved PI3K p110d isoform specific inhibitor (idelalisib). Interestingly, isogenic GCB-DLBCL cell lines with KO of PTEN, a negative regulator of AKT activation, were substantially more resistant to both inhibitors. A crucial role of PTEN deletion in overcoming dependence on tonic BCR signaling in GCB-DLBCL is supported by evidence from two naturally PTEN-deficient cell lines: SUDHL10, which adjusts to BCR KO and resumes normal growth, and HT, which lacks BCR expression, due to a frameshifting deletion in its IgH HVR. Re-expression of the BCR in HT, by KI to correct the IgH sequence, does not affect HT cell line growth. Conclusion. Our findings suggest a biomarker-guided therapeutic strategy in GCB-DLBCL: targeting tonic BCR signaling in BCR-high patients, by inhibiting CD79A phosphorylation, SYK, or PI3K, and downstream targeting of AKT in BCR-low and/or PTEN-deficient patients. Figure 1. Correlation of relative proliferation after BCR KO with decrease of AKT activity (as measured by FRET efficiency of AKT activity reporter) in GCB-DLBCL cell lines. Figure 1. Correlation of relative proliferation after BCR KO with decrease of AKT activity (as measured by FRET efficiency of AKT activity reporter) in GCB-DLBCL cell lines. Figure 2. Effect of BCR KO or pan-AKT KO in GCB-DLBCL cell lines. Figure 2. Effect of BCR KO or pan-AKT KO in GCB-DLBCL cell lines. Figure 3. Correlation of relative proliferation after BCR KO with baseline BCR surface density (as measured by flow cytometry of cells with CD79A-GFP fusion) in GCB-DLBCL cell lines. Figure 3. Correlation of relative proliferation after BCR KO with baseline BCR surface density (as measured by flow cytometry of cells with CD79A-GFP fusion) in GCB-DLBCL cell lines. Disclosures Burger: Pharmacyclics: Research Funding. Westin:Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees.
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Takizawa, Jun, Sadao Aoki, Akihito Momoi, Toshiki Kitajima, Masutaka Higashimura, Naoya Nakamura, and Yoshifusa Aizawa. "BCL6 Rearrangement Detected by FISH Analysis Is a Poor Prognostic Factor in the “Non-Germinal Center Phenotype” of Diffuse Large B-Cell Lymphoma." Blood 108, no. 11 (November 16, 2006): 4620. http://dx.doi.org/10.1182/blood.v108.11.4620.4620.
Abstract:
Abstract Background: Diffuse large B-cell lymphoma (DLBCL), which is the most common type of adult non-Hodgkin lymphoma, is considered to be heterogeneous in cytogenetics, immunophenotype and clinical feature. As the results of gene expression profiling, DLBCL can be divided into prognostically significant 3 subgroups of germinal center B-like (GCB), activated B-like and type 3. Chromosomal translocations affecting the BCL6 locus at the 3q27 locus are common in DLBCL, however, the prognostic significance of BCL6 rearrangement is still controversial. Methods: Twenty-six cases of DLBCL were examined with interphase fluorescence in situ hybridization (FISH) on touch preparations of lymph nodes using LSI BCL6 dual color probes (Vysis) for the incidence of BCL6 rearrangement and immunohistochemistry on paraffin section using CD10, BCL6 and MUM1 for subclassfying “GCB phenotype” and “non-GCB phenotype”. The correlation of BCL6 rearrangement with survival was investigated in two subgroups of DLBCL. Results: Of the 26 DLBCL cases, 6 cases (23%) were considered GCB phenotype and 20 cases (77%) non-GCB phenotype. BCL6 rearrangements were detected in 2 of 6 cases (33%) with GCB phenotype and 9 of 20 (45%) with non-GCB phenotype (total 11/26, 42%). ALL 6 cases with the GCB phenotype achieved sustained complete remission after chemotherapy and are alive. On the other hand, complete remission rate was 22% for the cases with BCL6 rearrangement but 73% for the cases without BCL6 rearrangement in the non-GCB phenotype (p=0.069). BCL6 rearrangement had a significant adverse effect on progression free survival within the non-GCB phenotype (P=0.016), but there was no significant correlation between BCL6 rearrangement and overall survival. Conclusion: FISH-based technique of the BCL6 rearrangements using touch preparations of lymph nodes could be developed for the retrospective analysis on survival. BCL6 rearrangement showed a poor prognostic effect particular in the non-GCB subgroup of DLBCL. Overall survival Overall survival Progression free survival Progression free survival
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Gupta, Mamta, Guangzhen Hu, Steven Offer, Matthew J. Maurer, Linda Wellik, Jing Jing Han, Ahmet Dogan, Robert B. Diasio, and Thomas E. Witzig. "Expression but Not Promoter Hypermethylation of the Tyrosine Phosphatase PTPN6 Is Associated with Activated STAT3 and Inferior Prognosis in Diffuse Large B Cell Lymphoma Molecular Subtypes." Blood 120, no. 21 (November 16, 2012): 2655. http://dx.doi.org/10.1182/blood.v120.21.2655.2655.
Abstract:
Abstract Abstract 2655 Diffuse large B cell lymphoma (DLBCL) has been classified into two distinct molecular subtypes: germinal center B cell–like (GCB), non-germinal centre-like (non-GCB). To improve outcomes for DLBCL patients, it is necessary to identify additional novel targets within GCB and non-GCB classifications to further stratify patients for prognosis and assist in choosing therapy for the individual patient. We have recently demonstrated that STAT3 activation is frequent in the DLBCL tumors, however the exact molecular mechanism(s) of STAT3 activation in DLBCL tumors are not known. Molecular mechanisms such as epigenetic silencing of negative regulators of the STAT3 pathway such as protein tyrosine phosphatase 6 (PTPN6) may contribute to STAT3 activation. We aimed to learn whether PTPN6 was expressed in GCB and non-GCB DLBCL, and if so, how that expression correlated with STAT3 activation and prognosis. We first performed epigenetic studies of PTPN6 in 38 DLBCL tumors and 6 DLBCL cell lines by methylation specific (MSP) PCR and high resolution melting array (HRM) methods. Surprisingly, PTPN6 promoter hypermethylation (0/38) was not detected in patient sample and cell lines by both the methods. Since the MSP PCR technique yields qualitative rather than quantitative data, we next performed pyrosequencing on the 38 DLBCL samples, and found results consistent with the MSP PCR analysis. Our data conclusively demonstrate that PTPN6 hypermethylation is absent in DLBCL tumors. We next sequenced the 600 bp upstream of the transcription initiation site of PTPN6 promoter 2 and 1 in 10 DLBCL tumors. We did not detect any point mutations in the promoter 2 and 1 core regions. Since PTPN6 promoter hypermethylation and mutations were absent in DLBCL tumors, we determined the expression level of the PTPN6 protein in 40 DLBCL tumors by molecular subtype. Formalin fixed paraffin-embedded DLBCL tumor samples were stained by immunohistochemistry (IHC) for the determination of molecular subtype using the Hans algorithm and the detection of PTPN6 expression. Using a threshold of ≥30%, 75% (30/40) of cases were PTPN6 positive with various levels of expression: 11 cases had 30–80% of tumor cells staining positive and 19 had >80% of cells PTPN6 positive. PTPN6 expression by IHC was only correlated with higher IPI scores and a trend towards a shorter event free survival (EFS) (p=0.07). Within the 29 GCB tumors 69% (20/29) were PTPN6 positive; 100% (10/10) of non-GCB cases were PTPN6 positive. These data clearly suggest that PTPN6 expression is found in both GCB and non-GCB with the latter being uniformly positive (p=0.03) and PTPN6 negative cases being uniformly GCB. PTPN6 mRNA and protein was detected in all three ABC lines (LY3, Ly10, DHL2). Within the GCB lines (DHL6, Ly1 and Ly19) DHL6 was weakly positive and Ly1 and Ly19 were negative for PTPN6 mRNA and protein. Furthermore, within the GCB group PTPN6 positive cases had inferior EFS as compared to PTPN6 negative cases. In the non-GCB group all cases were PTPN6 positive with an EFS similar to PTPN6 positive GCB cases. The role of PTPN6 in the persistent activation of the STAT3 pathway in DLBCL patients has not been investigated. We hypothesized that tumors with activated STAT3 would have loss of PTPN6. Interestingly, this hypothesis was disproven. Within the 15-pSTAT3 positive cases 12 (80%) were PTPN6 positive. Conversely, 26% (6/23) of the pSTAT3 negative cases were PTPN6 negative. The distribution of pSTAT3 and PTPN6 by IHC in samples was evaluated in both GCB and non-GCB groups. Within the PTPN6+/pSTAT3+ group out of the 12 cases most were non-GCB (8/12; 66%). However, within the PTPN6-/pSTAT3- group all the 5 cases were GCB (5/5; 100%). Survival analysis revealed that the groups with the best EFS were those with PTPN6-/pSTAT3- tumors (n=5); those with PTPN6+/pSTAT3+ group (n=12) had the shortest EFS; and those with PTPN6+/pSTAT3- tumors (n=17) being intermediate between the other groups. In summary, we have demonstrated for the first time that PTPN6 is highly expressed in DLBCL tumors, and a common abnormality in non-GCB subtypes, which is positively correlated with activated STAT3. PTPN6 expression in the DLBCLs is not regulated through SHP1 promoter hypermethylation or point mutations. The finding that SHP1 loss was found only in GCB cases and was especially favorable should be explored further and may provide an important new stratification factor for future DLBCL studies. Disclosures: No relevant conflicts of interest to declare.
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Zhao, Fengyi, Lei Zhang, Yan Qin, Ming-Zhe Han, Xiaohong Han, Shiyu Jiang, and Yuankai Shi. "Characterization of Methylation Patterns in Diffuse Large B Cell Lymphoma By Genome-Wide Methylation Analysis." Blood 134, Supplement_1 (November 13, 2019): 1243. http://dx.doi.org/10.1182/blood-2019-131656.
Abstract:
Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide. Although the reference standard for identifying of the cell types is considered of gene expression profiling (GEP). But immunohistochemistry (IHC) is the most common method commercially available. The purpose of this study was to characterize the circulating cell-free DNA (cfDNA) methylation profile in DLBCL and to compare this profile with methylation observed in formalin fixed paraffin-embedded (FFPE) tissues. Additional efforts were made to correlate the observed methylation patterns with prognostic analysis and selected clinical features. Methods: The cfDNA and DNA of FFPE were extracted from 72 patients and 39 patients respectively. We assessed DNA methylation from plasma samples obtained from 29 individuals with GCB DLBCL at the time before treatment along with 43 samples of non-GCB DLBCL as controls. DNA from FFPE tissues were extracted from 11 individuals of GCB DLBCL and 28 individuals with non-GCB DLBCL. DNA methylation was analyzed with the Infinium MethylationEPIC BeadChip that quantitatively measures the methylation levels of more than 850,000 CpG sites across the genome. M values were used for visualization and intuitive interpretation of the results. Moreover, pathway enrichment analysis was performed with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. Results: We found a total of 207 significant differentional differentially methylated positions (DMPs) of cfDNA between the GCB and non-GCB groups, identified with a p value of 0.001 (Fig. 1A). Of these, 65 presented at least 10% (|Δbeta| > 0.1) difference in the methylation level between GCB and non-GCB. 29 (44.6%) were found hypermethylated in GCB DLBCL, while 36 (55.4%) appeared hypomethylated (Fig. 1B). The distribution of the DMPs identified according to their location relative to CpG islands (CGI) were represented in Fig. 1C. Unsupervised clustering performed on DNA methylation values for the 207 DMPs identified is presented in Fig. 1D. These results highlight the differences between GCB and non-GCB samples. There are 1549 significant DMPs of DNA from FFPE between the GCB and non-GCB groups, identified with a p value of 0.001 (Fig. 1E). Of these, 1512 presented at least 10% (|Δbeta| > 0.1) difference in the methylation level between GCB and non-GCB . 1370 (90.6%) were found hypermethylated in GCB DLBCL, while 142 (9.4%) appeared hypomethylated (Fig. 1F). The distribution of the DMPs identified according to their location relative to CpG islands (CGI) were represented in Fig. 1G. Unsupervised clustering performed on DNA methylation values for the 1549 DMPs identified is presented in Fig. 1H. These results highlight the differences between GCB and non-GCB in FFPE samples which according with that in serum. The KEGG pathway enrichment analysis of DNA from FFPE tissue methylation revealed that the process "PI3K/Akt, Ras, MAPK signaling pathway" and "Human papillomavirus infection" are likely major contributors to Hans pathological type. In addition, the enrichment analysis of cfDNA methylation revealed that the process "MAPK signaling pathway" is likely the most important factor. Furthermore, we also have analyzed the methylation level between refractory or relapsed (R/R) DLBCL patients and individuals with a good prognosis. The differential methylation patterns were also found both in serums and FFPE tissues. Conclusions: The DNA methylation differs in GCB and non-GCB DLBCL patients. MAPK signaling pathway plays an important role in it. The mechanism needs to be further explored. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Alcoceba, Miguel, Elena Sebastián, Ana Balanzategui, Luis Marín, Santiago Montes-Moreno, Teresa Flores, Noemí Puig, et al. "Preferential Acquision of N-Glycosylation Sites in the VDJ Region in Germinal Center B-Cell-Like Difusse Large B-Cell Lymphoma." Blood 120, no. 21 (November 16, 2012): 1589. http://dx.doi.org/10.1182/blood.v120.21.1589.1589.
Abstract:
Abstract Abstract 1589 Introduction: Acquired potentially N-glycosylation sites are produced by somatic hypermutation (SHM) in the immunoglobulin (Ig) variable region. This phenomenon is produced in ∼9% of normal B-cells and seems to be related to certain B-cell lymphoproliferative disorders (B-LPDs) such as follicular lymphoma (FL, 79%), endemic Burkitt lymphoma (BL, 82%) and diffuse large B-cell lymphoma (DLBCL, 41%). These data suggest that new potential N-glycosylation sites could be related to germinal center B (GCB)-LPDs. By contrast, in other B-LPDs, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), MALT lymphoma, Waldenström macroglobulinemia (WM) or multiple myeloma (MM), these modifications have not been analyzed in deep. Aims: To evaluate the acquisition of potential N-glycosylation sites in B-LPDs, including immunohystochemical DLBCL subtypes (GCB and non-GCB) and specific non-GCB-LPDs, such as hairy cell leukemia (HCL), splenic marginal-zone lymphoma (SMZL), CLL, MCL, ocular extranodal marginal zone lymphoma (OAEMZL), MM and WM. Patients: A total of 953 sequences (203 from our group and 750 previously published sequences) of B-LPDs were included. Diagnosis distribution was as follows: DLBCL (n=235), MCL (n=235), CLL (n=166), MM (n=96), OAEMZL (n=82), SMZL (n=68), WM (n=38) and HCL (n=33). Methods: Acquired N-glycosylation sites were counted according to the sequence Asn-X-Ser/Thr, where X could be any amino acid except Pro. Natural motifs in germline sequences of IGHV1–08, IGHV4–34 e IGHV-5a were not considered. Fisher test was used to perform comparisons between groups. To distinguish DLBCL biological subtypes (GCB and non-GCB DLBCL), Hans' algorithm was used. Results: A total of 83 out of the 235 DLBCL cases acquired at least a new N-glycosylation site, a higher value than in normal B-cells (35% vs. 9%, p<0.0001). Higher incidence of these motifs in the group of GCB as compared to non-GCB DLBCL were observed (52% vs. 20%, p<0.0001). Those cases diagnosed of HCL, CLL, MCL, MM, WM, OAEMZL and SMZL presented a reduced number of new N-glycosylation sites, showing similar values than normal B-cells (range 3–18%, p=ns). Conclusions: We described for the first time the pattern of N-glycosylation in HCL, SMZL, OAEMZL and in the immunohystochemical DLBCL subtypes, where the GCB-DLBCL showed a higher number of new N-glycosylation sites with respect to non-GCB DLBCL and other non-GCB-LPDs. The presence of novel N-glycosylation sites in FL, BL and in GCB-DLBCL strongly suggests that these motifs are characteristic of the germinal center B-LPDs. Disclosures: No relevant conflicts of interest to declare.
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Nowakowski, Grzegorz S., Betsy LaPlant, William R. Macon, Craig B. Reeder, James M. Foran, Garth D. Nelson, Carrie A. Thompson, et al. "Lenalidomide Combined With R-CHOP Overcomes Negative Prognostic Impact of Non–Germinal Center B-Cell Phenotype in Newly Diagnosed Diffuse Large B-Cell Lymphoma: A Phase II Study." Journal of Clinical Oncology 33, no. 3 (January 20, 2015): 251–57. http://dx.doi.org/10.1200/jco.2014.55.5714.
Abstract:
Purpose Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL. Patients and Methods Eligible patients were adults with newly diagnosed untreated stages II to IV CD20+ DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP. Results In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively). Conclusion R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.
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Gozgit, Joseph M., Youngchul Song, Scott Wardwell, Sara Nadworny, Yaoyu Ning, and Victor M. Rivera. "Potent Preclinical Activity of Ponatinib in Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma (GCB-DLBCL) Models." Blood 126, no. 23 (December 3, 2015): 4000. http://dx.doi.org/10.1182/blood.v126.23.4000.4000.
Abstract:
Abstract Introduction Diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin lymphoma (NHL), comprises 2 major molecular subtypes: germinal center B-cell-like (GCB) and activated B cell-like (ABC). Although standard therapy (rituximab+ chemotherapy [R-CHOP]) is effective in most patients (pts), a significant proportion do not achieve durable remissions. Treatment of relapsed and refractory DLBCL pts with targeted therapy, such as the BTK inhibitor ibrutinib, has shown some promise; however, responses are mostly restricted to the ABC subtype. Treatment options for pts with relapsed/refractory GCB, outside of stem cell transplantation, are especially limited. Ponatinib is a potent pan-BCR-ABL inhibitor approved for pts with refractory or T315I+ chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. Initial characterization of the in vitro kinase activity of ponatinib demonstrated substantial activity against a number of additional oncogenic kinases, including KIT, RET, FLT3, and members of the FGFR, PDGFR, and SRC families. To obtain a broad, unbiased, assessment of the anti-proliferative effects of ponatinib, we screened a panel of 246 human tumor cell lines. Based on the novel finding that a GCB-DLBCL cell line was amongst those inhibited most potently by ponatinib, we conducted studies to further characterize the activity of ponatinib in NHL, and GCB-DLBCL in particular. Results A broad cell-based screen identified a small subset of cell lines (18/246; 7%) whose growth was potently inhibited by ponatinib (GI50<42 nM). A majority of these lines express activated variants of previously validated targets of ponatinib: ABL (N=5, GI50 <0.3 nM), FLT3 (N=1, GI50 1 nM), FGFR2 (N=2, GI50s 5-29 nM), and PDGFRα (N=1, 14 nM). In addition, ponatinib potently inhibited growth of the GCB-DLBCL cell line DoHH2 (GI50 8 nM). The cellular activity of ponatinib was next examined in a larger set of NHL cell lines enriched for the GCB subtype (Table 1). Ponatinib only exhibited modest activity (GI50 46-119 nM) against 2 mantle cell lymphoma (MCL) lines, but potently inhibited growth (GI50≤10 nM) of the one Burkitt's lymphoma (BL) line tested (Daudi). Most notably, ponatinib also potently inhibited growth of 5/9 GCB cell lines. In contrast, none of the GCB lines showed sensitivity to ibrutinib (GI50s >100 nM). Finally, we evaluated the in vivo potency of ponatinib in mice implanted with the GCB cell lines exhibiting the greatest (SU-DHL-4) and weakest (SU-DHL-10) in vitro sensitivity to ponatinib, using dosing regimens previously shown to be active in BCR-ABL models predictive of efficacy in patients. Once-daily oral administration of ponatinib resulted in a dose-dependent inhibition of SU-DHL-4 tumor growth, with 10 mg/kg inducing 78% tumor regression, and 30 mg/kg rapidly inducing complete regression that was maintained in all mice for an additional 2 weeks after ponatinib dosing was stopped. In contrast, ponatinib had much more modest effects on SU-DHL-10 tumors with 30 mg/kg only inhibiting tumor growth by 39%. Conclusion Ponatinib has promising in vitro and in vivo activity against a substantial subset of GCB-DLBCL models tested, with potency similar to that observed in BCR-ABL models. These results provide support for evaluating ponatinib in GCB-DLBCL pts who have failed prior therapy. Studies to further characterize the molecular basis for the activity of ponatinib in NHL are ongoing. Table 1. In vitro drug activity in 12 NHL cell lines Cell line Type Ponatinib GI50 (nM) Ibrutinib GI50 (nM) SU-DHL-4 GCB DLBCL 1.3 313 DoHH2 GCB DLBCL 2.5 114 Pfeiffer GCB DLBCL 6 2,074 SU-DHL-6 GCB DLBCL 9.8 1,041 WSU-NHL GCB DLBCL 10 1,672 Farage GCB DLBCL 51 1,409 U-2932 GCB DLBCL 79 >10,000 RL GCB DLBCL 212 6,939 SU-DHL-10 GCB DLBCL 238 2,827 Daudi BL 2.9 4,319 Mino MCL 46 >10,000 Jeko-1 MCL 119 4,781 GI50: the concentration that causes 50% growth inhibition. Disclosures Gozgit: ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Song:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Wardwell:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Nadworny:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Ning:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Rivera:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed).
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Zettl, Andreas, Silvia Bea, George Wright, Itziar Salaverria, Philipp Jehn, German Ott, Wing-Chung Chan, et al. "Chromosomal Imbalances in Germinal Center B-Cell-Like and Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Influence Gene Expression Signatures and Improve Gene Expression-Based Survival Prediction(the First Two Authors Contributed Equally to This Work)." Blood 104, no. 11 (November 16, 2004): 415. http://dx.doi.org/10.1182/blood.v104.11.415.415.
Abstract:
Abstract Introduction: Germinal center B-cell (GCB)-like and activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL) are characterized by different recurrent chromosomal imbalances. In a series of 177 untreated de novo DLBCL analyzed by comparative genomic hybridization (CGH), GCB-like DLBCL had shown more frequent gains of chromosome 12p/12cen-q14 (22% vs 5%, p=.0025), whereas ABC-like DLBCL had shown more frequent gains of 3/3q27-qter (34% vs 6%; p<0.0001), 18q21 (36% vs 11%;p=0.0002) and losses of 6q21-q23 (36% vs 20%; p=0.0269). We investigated the impact of chromosomal imbalances on the transcription of genes localized in the corresponding chromosomal regions, and on gene expression signatures, as previously defined (Rosenwald et al, N Engl J Med2002;346:1937–1947), as well as on survival. Results: Gains/amplifications of chromosomes 2p, 3q, 12q and 18q resulted in different gene expression patterns depending on the array-defined DLBCL subtype. For example, 18q gains/amplifications correlated with overexpression of P15RS, MADH2, MADH4, LOC51320 and PMAIP1 in GCB-like DLBCL, whereas P15RS, MIZ1, MADH2, ME2, MADH4, LOC51320, MALT1, PMAIP1, BCL2, FVT1 and NFATC1 were overexpressed in ABC-like DLBCL with 18q gains/amplifications (p<0.05). Chromosomal imbalances also were strongly associated with certain alterations of gene expression signatures. Gains of chromosome 7 in GCB-like DLBCL, losses of chromosome 17p13 in ABC-like DLBCL, and gains of chromosome 12 both in GCB- and ABC-like DLBCL resulted in a loss of the T-cell signature (p<0.001). Similarily, ABC-like DLBCL with gains of chromosome 3q but not Xp, or gains of 8q showed a loss of the lymph node signature, whereas ABC-like DLBCL with gains of Xp but not 3q showed a strong lymph node signature (p<0.001). Importantly, chromosomal imbalances were identified (gains of Xp, 3p, and losses of 6q13) that significantly improved the previously-defined gene expression-based outcome predictor for DLBCL patients (Rosenwald et al., NEJM, 2002). Conclusion: In GCB-like and ABC-like DLBCL, chromosomal imbalances lead to subgroup-specific overexpression of genes located within the gained/amplified regions. Chromosomal imbalances furthermore are associated with profound changes in the gene expression signatures in both GCB- and ABC-like DLBCL. Importantly, consideration of chromosomal imbalances significantly improves on the previously-defined gene expression based outcome predictors for DLBCL patients.
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Cao, Y., T. Lin, S. Wang, X. Fu, J. Xiao, J. Yi, H. Lin, and Z. Guan. "A phase II study of R-CHOP in treatment of diffuse large B-cell lymphoma (DLBCL) subgroups." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 17540. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17540.
Abstract:
17540 Background: Recent studies with genes expression profiling and tissue microarray have divided the diffuse large B cell lymphoma (DLBCL) into prognostically important subgroups with germinal center B cell like (GCB) and non-GCB. However, these results are based on the samples of patients who were received standard CHOP regimen. Combination with CHOP and Rituximab (R-CHOP) has been proved to improve the survival of patients with DLBCL. To evaluate the efficacy of R-CHOP in different subgroups of DLBCL, this phase II study has been conducted. Methods: Previously untreated patients with DLBCL were enrolled in this study. No upper age limit was specified. Patients received six cycles of R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 40 mg/m2 for 5 days) every 3 weeks. Immunohistochemical stains on paraffin-embedded tissues from diagnostic biopsies from these patients with antibodies against GCB cell (CD10 and Bcl-6) and activation (MUM1). These patients are divided into GCB and non-GCB groups according to the expression of antibodies against CD10, BCL-6 and MUM1. Results: A total of 64 patients were evaluated, 19 in GCB group and 45 in non-GCB group. Complete Remission (CR) rate was achieved 57.9% and 53.3%, in GCB group and in non-GCB group, respectively. (p = 0.737). A median follow-up of 2.2 years, the two-year failure free survival was no different between two groups (p = 0.566). Conclusions: In patients with GCB group or non-GCB group of DLBCL, addition of Rituximab in CHOP regimen, preliminary result was showed in similar response and survival. No significant financial relationships to disclose.
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Zhao, Peiqi, Huilai Zhang, Kai Fu, Xianhuo Wang, Lanfang Li, Zhengzi Qian, Lihua Qiu, and Shiyong Zhou. "CD5 Expression Correlates with Inferior Survival and Enhances the Negative Effect of p53 Overexpression in Diffuse Large B Cell Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 4117. http://dx.doi.org/10.1182/blood-2019-127666.
Abstract:
Purpose De novo CD5+ DLBCL is increasingly recognized as a distinct pathologic phenomenon with a specific clinical picture. However, De novo CD5+ DLBCL has not been studied on a large scale in China. In this study, we evaluated the frequency, clinicopathological characteristics of de novo CD5+ DLBCL and prognostic impact of CD5 expression, and patient survival in our center. Methods In this study, we retrospectively investigated 745 DLBCL cases treated at Tianjin medical university cancer institute and hospital between 2000 and 2017, sub-classifying them as germinal center B cell-like (GCB) and non-GCB type by immunohistochemical staining with CD10, BCL6 and MUM-1, and then comparing the prognosis. We used a cutof ≥50% tumor cells for CD5 to be considered positive. Results In the enrolled DLBCL patients, 64 (9.2%) were CD5+ and 631 (90.8%) were CD5-. There was no significant difference in age, sex, extranodal involvement, serum LDH, C-myc overexpression and CNS relapse between these two groups. In the CD5+group, the cell of origin was non-GCB type in 46 cases (71.9%); the ratio of non-GCB type in the CD5+ group was higher than that in the CD5-group (P=0.033). Comparison of the clinical characteristics of CD5+ vs CD5-DLBCL patients showed that CD5+ DLBCL patients were more frequently elderly (>60 years), and had B-symptoms, high performance status, stage III-IV, an IPI score >2, and BM involvement. 46.9% of the CD5+ patients, compared to 9.4% CD5-DLBCL patients, showed BM involvement at diagnosis. Almost 84.4% of CD5+DLBCL patients had concurrent overexpression (≥50% of the tumor cells) of antiapoptotic Bcl-2, an unfavorable biomarker. This frequency was significantly higher than that in CD5-DLBCL patients (67.2%, P=0.032). Similarly, the P53 positive rate (≥50% of the tumor cells) of CD5+DLBCL (46.9%) is significantly higher than that of CD5-DLBCL (17.6%, P=0.011). Univariate Cox analysis identified the following prognostic factors: CD5 positive, age >60 years, IPI≥3, BM/PB involvement, performance status and stage (III or IV). Intensive chemotherapy was not identified as significantly prognostic by univariate analysis. The CD5+GCB group showed no significant differences compared to CD5-GCB group for both PFS and OS, whereas the CD5+ non-GCB DLBCL and CD5- non-GCB DLBCL showed significantly worse prognosis compared to other groups. (P < 0.001, PFS and OS, respectively) (Fig.1A; 1B; 1C; 1D) In CD5+ DLBCL, PFS and OS in patients treated with rituximab were significantly better than those without rituximab. Three-year PFS was 41.1% for the former and 15.4% for the latter (P=0.036, Fig. 1E), and three-year OS were 60.7 and 46.2% (P=0.047, Fig. 1F). Next, we evaluated the therapeutic responses of different chemotherapy regiments. A total of 20 patients received treatment with R-CHOP and 24 patients received DA-EPOCH-R. Patients treated with R-CHOP showed similar PFS and OS compared with intensive treatment group (Fig. 1G,1H). Of the 631 cases of CD5- DLBCL, only 111 cases (17.6%) showed p53 overexpression. In contrast, p53 was overexpressed in 30 (46.9%) of 64 CD5+ DLBCL. As shown in Fig. 1, PFS and OS in patients with overexpression of either p53 or CD5 alone were significantly different from those in patients with p53- /CD5- DLBCL. However, patients with p53 and CD5 co-overexpression had the worst PFS and OS (P < 0.001, PFS and OS, respectively) (Fig. 1I, 1J). These data suggest that the negative prognostic impact of p53 and CD5 overexpression was augmented when both variables existed. In fact, all 30 patients with p53 and CD5 co-overexpression died within 40 months of diagnosis. Conclusion In summary, in this study we show that de novo CD5+ DLBCL, which occurs at a frequency (9.2%), was associated with unfavorable clinicopathologic variables and with inferior survival following R-CHOP and DA-EPOCH-R treatment. CD5+ DLBCL has a high frequency of p53 overexpression and CD5 augments the negative effect of p53 overexpression in DLBCL. Fig. 1 PFS (A) and OS (B) of patients with DLBCL according to the presence or absence of CD5. PFS (C) and OS (D) for the four DLBCL groups: CD5+ GCB DLBCL, CD5+ non-GCB DLBCL, CD5- GCB DLBCL and CD5- non-GCB DLBCL. PFS (E) and OS (F) of CD5+ DLBCL in the chemotherapy group and in the R-chemotherapy group. PFS (G) and OS (H) in CD5+ DLBCL treated with RCHOP and DA-EPOCH-R regimens. PFS (I) and OS (J) in patients with de novo DLBCL stratified according to p53 and CD5 immunostaining status. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Wang, Y. Lynn, Jiao Ma, Wei Xing, Pin Lu, Karen Dresser, Ailin Guo, Anjali Pandey, Pamela B. Conley, Hongbo Yu, and Greg Coffey. "SYK and STAT3 Are Active in Diffuse Large B-Cell Lymphoma: Activity of Cerdulatinib, a Dual SYK/JAK Inhibitor." Blood 124, no. 21 (December 6, 2014): 926. http://dx.doi.org/10.1182/blood.v124.21.926.926.
Abstract:
Abstract Non-Hodgkin Lymphoma (NHL) represents about 5 percent of all cancers diagnosed in the United States. While incidence of NHL has increased slightly over the past decade, death rates have been declining steadily. These declines in mortality can be attributed to improvements in treatment that are based on an increased understanding of the biology of the disease. Diffuse large B-cell lymphoma (DLBCL) accounts for ~30% of NHLs and greater than 80% of aggressive NHLs. Recent studies including large-scale genetic analyses have demonstrated the critical roles of the B-cell receptor’s (BCR) and JAK/STAT pathways in DLBCL. Herein, we investigated the anti-lymphoma activity of cerdulatinib (aka PRT062070), a novel compound that dually targets both SYK and JAK/STAT signaling pathways. To determine whether targeting both SYK and JAK/STAT is relevant in DLBCL, we examined the expression of p-SYK (pY525/526) and p-STAT3 (pY705) on a tissue microarray of 62 DLBCL primary tumors, including 41 GCB and 21 non-GCB cases. p-SYK expression was detected in 29 (47%) cases with a characteristic peri-membrane staining pattern. Of those 29 p-SYK positive cases, 17 were GCB type (17/41, 41%) and 12 were non-GCB type (12/21, 57%). p-STAT3 exhibits a characteristic nuclear staining pattern in DLBCL cases. A total of 26 (42%) stained positive for p-STAT3; 16 were GCB type (16/41, 39%) and 10 were non-GCB type (10/21, 48%). Interestingly, there are 19 cases (31%) with reactivity for both p-SYK and p-STAT3, among which, 11 were GCB type (27%) and 8 were non-GCB type (38%). SYK and STAT3 are also phosphorylated in a panel of nine DLBCL cell lines. Immunoblotting analyses showed that ABC and GCB subtypes of DLBCL cells appear to exhibit different JAK/STAT and BCR signaling profiles. For instance, p-AKT was highly expressed in GCB cells, whereas p-STAT3 was more strongly expressed in ABC cells. Overall, the DLBCL cells are more sensitive to the dual inhibitor than to the SYK-specific inhibitor alone. In both GCB and ABC cell lines, cerdulatinib induced apoptosis via down-regulation of MCL1 protein and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest through inhibition of RB phosphorylation and down-regulation of cyclin E. Further analyses of the cell signaling activities showed that STAT3 phosphorylation was sensitive to inhibition by cerdulatinib in ABC cell lines while phosphorylation of SYK, PLCg2, AKT and ERK was sensitive to inhibition by cerdulatinib in GCB cell lines. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in GCB and non-GCB primary human DLBCL cells, which led to cell death of these cells. Our work provided mechanistic insights into the actions of SYK/JAK dual inhibitor cerdulatinib, suggesting that the drug may be a potent treatment of DLBCL with a broader anti-tumor activity in both ABC and GCB subtypes of the lymphoma. Disclosures Pandey: Portola Pharmaceuticals: Employment. Conley:Portola Pharmaceuticals: Employment. Coffey:Portola Pharmaceuticals: Employment.
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Feng, Ru, Xiaolei Wei, Meng Xu, Fen Huang, Yongqiang Wei, Tong Zhao, and B. Hilda Ye. "STAT3 Predicts Poor Outcome In Patients With Advanced Diffuse Large B Cell Lymphoma." Blood 122, no. 21 (November 15, 2013): 5069. http://dx.doi.org/10.1182/blood.v122.21.5069.5069.
Abstract:
Abstract Objective To explore the expression and prognosis of STAT3 in Chinese patients with diffuse large B-cell lymphoma (DLBCL). Methods The expression of STAT3 was examined by the immunohistochemistry (IHC) method.120 patients with de novo DLBCL were reviewed retrospectively. Results Among the 120 patients, the ratio of male to female was 1.26:1, 47.5% of them were Non-GCB and 52.5% were GCB-DLBCL. The expression of STAT3 was observed in 50 of 120 cases (41.7%) and more frequent in the non-germinal center B cell-like (Non-GCB) DLBCL than that in the GCB subtype. The prognosis analysis showed that age, B symptom, bone marrow involvement, number of extranodal involvement, LDH, cell of origin and IPI related with prognosis, but not the expression of STAT3. However, in patients with advanced diffuse large B cell lymphoma, the expression of STAT3 was a poor prognostic factor. Conclusion STAT3 is expressed predominantly in Non-GCB DLBCL. The expression of STAT3 correlates poor outcome in patients with advanced diffuse large B cell lymphoma. Disclosures: No relevant conflicts of interest to declare.
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Qu, Jie, Matthew J. Maurer, James R. Cerhan, Anne J. Novak, Thomas M. Habermann, William R. Macon, Andrew L. Feldman, et al. "Similar Phenotypes Demonstrated upon Initial Diagnosis and at Time of Recurrence in Relapsed DLBCL." Blood 128, no. 22 (December 2, 2016): 5299. http://dx.doi.org/10.1182/blood.v128.22.5299.5299.
Abstract:
Abstract BACKGROUND: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL), though defined as one disease entity, consists of two main cell-of-origin (COO) subtypes, germinal center B-cell like (GCB) and activated B-cell like (ABC), with the latter predicting a significantly worse prognosis using conventional chemotherapy. Up to 40% of all patients diagnosed with DLBCL will experience relapse, and outcomes are generally poor in this setting. In this study, we examine the proportion of GCB vs. non-GCB subtypes at initial diagnosis and at time of relapse, and assess the incidence of reclassification from one subtype to another. METHODS: Patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. All relapse events were validated by review of the medical record. This analysis includes patients diagnosed with DLBCL who underwent initial treatment and subsequently experienced relapse as confirmed by biopsy. Immunohistochemical staining data including CD10, Bcl-6, and Mum-1, were collected from available pathology reports and classified to either GCB or non-GCB subtypes as predicted by the Hans algorithm. We compared subtype classification and individual immunohistochemical data both at the time of diagnosis and relapse. The overall subtype agreement between the two diagnostic time points was assessed. RESULTS: 1023 patients with newly diagnosed DLBCL were enrolled in the MER from 2002 - 2012. Of those, 249 had documented disease relapse. Of those analyzed, a total of 43 patients had COO classification based on the Hans algorithm from tissue biopsy at both diagnosis and relapse. Thirty patients were characterized as GCB DLBCL on initial presentation, and upon relapse 28 were noted to be GCB, while 2 were noted to be the non-GCB subtype. Of the 13 that were characterized as non-GCB on initial presentation, 10 remained non-GCB while 3 were reclassified as GCB. The overall agreement of DLBCL COO phenotypes between initial diagnosis and relapse was 88%. Seven percent of those initially diagnosed as GCB were reclassified as non-GCB subtype; in contrast, 23% of those initially diagnosed as non-GCB had changed to GCB upon relapse. Similar analysis was performed on individual immunohistochemical staining factors including CD10, Bcl-6, and Mum-1, and we observed overall agreement of 88%, 87%, and 91%, respectively. CONCLUSIONS: A majority of patients with relapsed DLBCL exhibit similar COO phenotypes at initial presentation and at relapse, and the incidence of reclassification from one subtype to another is uncommon. This suggests that the initial treatment regimen for DLBCL rarely alters the basic cancer phenotype when immunohistochemistry laboratory technical factors and pathologist interpretive discrepancies are excluded as causes for this change. However, reclassification from GCB to non-GCB subtypes is observed in a minority of cases, which may affect the overall outcome and response to treatment. Further studies are needed using gene expression to categorize COO and to examine the factors surrounding the time of relapse for possible harbingers of relapse as well as the behavior and outcome of reclassified DLBCL. Table Table. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.
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Ennishi, Daisuke, Ali Bashashati, Saeed Saberi, Anja Mottok, Barbara Meissner, Merrill Boyle, Susana Ben-Neriah, et al. "Frequent Genetic Alterations of PI3K-AKT Pathway and Their Clinical Significance in Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 607. http://dx.doi.org/10.1182/blood.v128.22.607.607.
Abstract:
Abstract Diffuse large B cell lymphoma (DLBCL) comprises two distinct molecular subtypes: germinal center B cell (GCB) subtype and activated B cell (ABC) subtype. The pathogenesis of ABC-DLBCL is characterized by two processes - the activation of NF-KB and a block in terminal B-cell differentiation. However, in GCB-DLBCL only a few biologically relevant pathways have been identified, which has hampered the development of targeted therapies with specific efficacy in this subtype. Recurrent genetic alterations involved in PI3K-AKT signaling pathway have been identified in the patients with solid cancers, and dramatic responses have been observed to PI3K inhibitors in clinical trials. The prevalence and clinical significances of genetic alterations in PI3K-AKT pathway have not been well studied in DLBCL. Previous studies have reported that loss of PTEN expression was observed in almost half of GCB-DLBCL cases but were largely absent in the ABC-DLBCL. In addition, functional studies have recently shown that the inactivation of Gα13 signaling pathway genes may also activate AKT in germinal center driven lymphoma, raising the possibility that additional genes within these pathways are affected in GCB-DLBCL. Herein, we identified genetic alterations involved in the PI3K-AKT pathway and evaluated their clinical impact. We analyzed biopsies from 347 patients newly diagnosed with de novo DLBCL uniformly treated with R-CHOP at the BC Cancer Agency. High-resolution copy number analyses were performed using Affymetrix SNP 6.0 arrays. Mutation status was determined using deep targeted re-sequencing of the coding exons of 61 genes with a Truseq Custom Amplicon assay (Illumina) and/or Fluidigm Access Array chips, and RNAseq. Immunohistochemical staining of phospho-AKT (pAKT) was performed on tissue microarrays (n=332). Cell-of-origin (COO) was assigned by gene expression (Lymph2Cx assay) in 323 cases - 183 GCB, 104 ABC and 36 unclassifiable. GISTIC analysis revealed several COO-specific peaks with copy number changes. Among them, focal 10q23.3 deletion including PTEN was detected in GCB-DLBCL (q-value=1.7e-7), but not in ABC-DLBCL. We also identified two focal amplification peaks in GCB-DLBCL containing microRNAs MIR17HG (13q31.1;q=1.01e-24) and MIR21 (17q23.3; q=1.45e-6), which are known to down-regulate PTEN and result in activation of PI3K-AKT signaling. Furthermore, we detected recurrent INPP4B deletion (4q21.23) in GCB-DLBCL (q= 0.004) only. Of note, the lipid phosphatase INPP4B has been shown to play a role as a tumor suppressor that controls the levels of PI3K lipid products leading to AKT activation and metastasis of some solid cancers. This is consistent with the observation that PTEN and INPP4B deletions were individually associated with increased pAKT protein expression in our cohort (p=0.015 and p<0.0001, respectively). With respect to mutations, GNA13, P2RY8 and ARHGEF1 were more frequently mutated in the GCB than ABC subtype (26% vs 0.6%; p<.0001, 25% vs 7%; p=.0002, and 8% vs 0.5%; p=0.008, respectively). Previously known mutations of PI3KCA and PI3KCB were not recurrently observed in GCB-DLBCL. Based on these genetic data, we found that the PI3K-AKT signaling pathway was more commonly altered in GCB-DLBCL (64% (114/177)) than in ABC-DLBCL (23% (23/98) p<0.0001; Fig1). Consistent with this, pAKT protein expression was significantly higher in GCB-DLBCL than ABC-DLBCL (p<0.0001). The cases with higher pAKT protein expression (defined as the 25% highest pAKT protein expressors) were associated with significantly inferior outcome in GCB-DLBCL (5y-PFS 75% vs 59 %, p= 0.007 and 5y-OS 81% vs 64%, p=0.004; Fig2). At the genetic level PTEN and INPP4B deletions were individually associated with poor outcome in GCB-DLBCL (p=0.01 and p=0.045, respectively), and further, patients whose tumors harbored both genetic alterations had even worse prognosis (p= 0.004, Fig 3). In conclusion, genetic alterations in the PI3K-AKT pathway were frequently observed in GCB-DLBCL and were associated with activation of the pathway and inferior outcomes. These results suggested that AKT and mTOR inhibitors might be beneficial in a greater proportion of GCB-DLBCL than expected. Fig 1. The distribution of genetic alterations of PI3K-AKT pathway and pAKT protein expression. Fig 1. The distribution of genetic alterations of PI3K-AKT pathway and pAKT protein expression. KM curves according to pAKT protein expression (Fig 2) and PTEN and INPP4B deletions (Fig 3). KM curves according to pAKT protein expression (Fig 2) and PTEN and INPP4B deletions (Fig 3). Disclosures Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Connors:F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.
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Prakash, Gaurav, Atul Sharma, Vinod Raina, Lalit Kumar, and Mehar C. Sharma. "Outcome in different molecular subtypes of diffuse large B-cell lymphoma: Indian experience." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e18518-e18518. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e18518.
Abstract:
e18518 Background: DLBCL has emerged as a heterogeneous disease and gene expression profiling has divided it into distinct molecular subtypes of Germinal center B-Cell (GCB) and Non-GCB- cell origin. These subtypes are reported to vary in the treatment responses and outcome. Methods: We analysed 97 consecutive patients of DLBCL who had satisfactory paraffin block of baseline biopsy. After reviewing diagnosis of DLBCL, sequential immunohistochemical staining with CD10, bcl6 and MUM1 was performed in all the cases. Using these markers the cases were sub-classified into GCB and non-GCB types as per Hans’ algorithm. Baseline presentation, stage, international prognostic score and treatment outcome were recorded. Survival was assessed by Kaplan-Meier survival curves and results were compared using log-rank test. Results: Thirty-three (34%) patients were classified in GCB group while 64(66%) patients in non-GCB group. Median age in both the groups was 50 years. High IPI score2-5 (GCB-34%, non GCB-72%;p 0.005) and stage 3,4 (GCB-39%,nonGCB-61%;p 0.04) were higher in non-GCB group. All the patients were treated with 6-8 cycles of CHOP based regimen and involved field radiotherapy wherever required. Complete remission rate (GCB-52%, nonGCB-27%; p0.02) was higher in GCB group. Three year overall survival, 75% and 63 %( p0.04), and event free survival was 63% and 43 %( p0.02) in GCB and non GCB subtypes, respectively. There was no difference in between two groups for performance status, LDH level and age. Conclusions: In our study, GCB-DLBCL patients had better response rate, EFS and OS in comparison to non GCB subtype. There were higher number of patients with advanced stage and high IPI score in non-GCB subtype which might have contributed to the poorer outcome.
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Yunalda, Indah, Krisna Murt, Aida Farida, Ika Kartika, and Erial Bahar. "Density of CD8 in Tumor Microenvironment of Diffuse Large B Cell Lymphoma Subtypes." Majalah Patologi Indonesia 30, no. 2 (May 1, 2021): 227–33. http://dx.doi.org/10.55816/mpi.v30i2.466.
Abstract:
BackgroundDiffuse Large B Cell Lymphomas (DLBCL) is divided into two subtypes, GCB and non-GCB, which are determined based on Hans'salgorithm. The GCB subtype has a better prognosis than non-GCB. Some studies indicate that the tumor progression wasinfluenced by tumor microenvironment, including CD8+ TILs located both surrounding tumor cells and peripheral. This study aims todetermine the density of CD8+ TILs in the tumor microenvironment of DLBCL subtypes.MethodsA Cross sectional study of 40 samples of DLBCL registered to Department of Anatomical Pathology Faculty of Medicine UniversitasSriwijaya/Dr. Mohammad Hoesin Palembang Hospital from 1st October 2017 to 31st December 2018. All samples were stained usinganti-CD8 antibody, afterward, lymphocytes express CD8 were assessed both in surrounding tumor cells and peripheral. The densityof CD8 in each DLBCL subtype was analyzed statistically using Mann Whitney U Test.ResultsIn this study, non-GCB subtype was found higher in comparison to GCB subtype (72.5%) and the samples was dominated by youngages (75%). Significantly, peripheral CD8 density was higher than that of surrounding tumor cells, both in the GCB (p=0.003) andnon-GCB subtypes (p=0.000).ConclusionIn both subtypes, CD8 density is higher in peripheral than surrounding tumor cells and a high density in surrounding tumor cells willbe followed by an increase in peripheral CD8 density.
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Tatterton, Dylan J., Benjamin Sale, Joel Allen, Maddy L. Newby, Giorgia Chiodin, Patrick J. Duriez, John Butler, et al. "Oligomannose-Type Glycans in the Antigen Binding Site Identify Origin and Prognosis of Diffuse Large B Cell Lymphoma." Blood 142, Supplement 1 (November 28, 2023): 428. http://dx.doi.org/10.1182/blood-2023-188721.
Abstract:
The acquisition of N-glycosylation sites (AGS) in the complementarity-determining region (CDR) of the tumor immunoglobulin (Ig) is an early clonal requirement of classic follicular lymphoma (FL). In FL, the AGS are occupied by oligomannose-type glycans, which mediate lymphoma Ig interaction with the microenvironmental lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). This interaction induces a persistent low-level signal, favouring adhesion and ultimately survival and growth of the lymphoma cells in their protected environment . Oligomannose-type glycans can also occupy the CDR-located AGS of a subset of germinal-centre B cell-like (GCB) diffuse large B-cell lymphomas (DLBCL) but the consequences of AGS in DLBCL are less known. We determined the frequency, distribution, and composition of the glycan structures occupying the AGS in DLBCL using a discovery-validation approach with two large independent international public cohorts (BCC, dataset ID: EGAD00001003783; NCI accession phs001444.v1.p1), following our RNAseq Ig assembly pipeline (Ig-Seq-R) and high-resolution mass-spectrometry. Glycan types were compared to our FL cohort (12 samples) and correlated with DLBCL cell of origin (COO), genetic, clinical characteristics and outcome. The full IGHV-IGHD-IGHJ-IGHC transcript sequences were obtained from 251 DLBCL of the BCC, and 339 of the NCI cohort. Sample distribution by COO, clinical or molecular features, LymphGen subtype, progression-free survival (PFS) and overall survival (OS) were not different from the extended public cohorts. AGS were observed in 48-55% GCB-DLBCL, with 84-85% of them located in the CDR. Overall, frequency of CDR-located AGS contrasted dramatically between GCB-DLBCL (41-46%) and activated B-cell like (ABC)-DLBCL (7-10%). Also, within GCB-DLBCL, CDR-located AGS associated mostly with the EZB subtype (68-73%). However, only 66-61% EZB were AGS+ve, all of which were CDR+ve, while the remaining 34-39% had no AGS (AGS-ve EZB). The glycan structures of the synthetic F(ab)s from 35 AGS+ve DLBCL and 12 FL were analyzed by site-specific mass spectrometry. The DLBCL comprised 12 AGS+ve EZB and 23 AGS+ve non-EZB (14 CDR+ve, 9 located in the framework region). Glycan analysis revealed that all AGS+ve EZB and FL were invariably occupied by oligomannose-type glycans (Ig-Mann+ve DLBCL). In contrast, the other AGS+ve DLBCL were not occupied by oligomannose type glycans. They were either occupied by complex glycans (the remaining non-EZB GCB-DLBCL) or not occupied (preferentially the ABC-DLBCL), irrespective of AGS location. These data indicated that CDR+ve EZB Ig were universally and exclusively Ig-Mann+ve DLBCL, share the COO of FL, and have likely been influenced by an environmental driver distinct from the other GCB-DLBCL and ABC-DLBCL. We compared the clinical behavior of Ig-Mann+ve DLBCL versus other DLBCL subtypes including AGS-ve EZB and the other non-EZB GCB-DLBCL and ABC-DLBCL. In both the BCC and NCI cohorts, Ig-Mann+ve DLBCL status identified the subset with the worst PFS and OS of all GCB-DLBCL, not different from ABC-DLBCL (Figure 1A). This contrasted with the other GCB-DLBCL (AGS-ve/EZB and AGS+ve/non-EZB), which all shared an extremely good PFS and OS (Figure 1A). Univariate and multivariate analyses revealed that Ig-Mann+ve status was an independent prognostic factor for PFS and OS (Figure 1B). Gene expression profile analysis revealed that Ig-Mann+ve status associated with an enrichment of MYC, PI3K-Akt-mTORC1, pro-survival, and cell cycle pathways, while proinflammatory and apoptotic pathways were decreased in the Ig-Mann+ve DLBCL compared to AGS-ve/EZB and AGS+ve/non-EZB, independently of MYC translocations and double-hit signature. These data indicate identical COO of a EZB subset with FL cells, and point to a highly selective chronic environmental pressure on Ig-Mann+ve DLBCL negatively affecting patients survival. The combination of Ig gene analysis with the lymphGen classification can predict Ig glycan structure and provide a new fundamental approach to identifying the most aggressive GCB-DLBCL subtype, and the precise environmental tumour interaction (DC-SIGN:Ig-Mann) to intercept therapeutically early in the natural history of Ig-Mann+ve DLBCL.
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Fu, K., K. D. Perry, L. M. Smith, C. P. Hans, T. C. Greiner, W. C. Chan, D. D. Weisenburger, et al. "Effect of addition of rituximab to CHOP on survival of patients in both the GCB and non-GCB subgroups of diffuse large B-cell lymphoma." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 8040. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8040.
Abstract:
8040 Background: Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subgroups, i.e. germinal center B-cell (GCB) and activated B-cell (ABC) DLBCL, which were initially characterized by gene expression profiling and subsequently validated by immunostaining. Bcl-2 has also been identified as a prognostic indicator in the ABC subgroup. However, with the addition of rituximab (R) to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear. Methods: We studied 119 cases of de novo DLBCL including 70 cases treated with R-CHOP and 49 cases treated with CHOP. The cases were assigned to either the GCB or non-GCB subgroups using the methodology described by Hans et al (Blood 2004; 103:275). Characteristics of the patients were compared using the Chi-square test. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan Meier method and compared with the log-rank test. Results: The median age of the 119 patients was 67 years, ranging from 20 to 90 years, and there were 62 males and 57 females. The clinical characteristics of patients treated with CHOP versus R-CHOP, including the IPI, were comparable. R-CHOP was more effective than CHOP with improved 5-year EFS (63% vs 41%, p=0.013) and OS (78% vs 47%, p<0.001). In both patient groups treated with R-CHOP or CHOP, the GCB subgroup had a significantly better 5-year EFS and OS compared to the non-GCB subgroup (OS: 91% vs 64% for R-CHOP, p=0.0073; 67% vs 31% for CHOP, p=0.034, respectively). Additionally, both the GCB and non-GCB subgroups treated with R-CHOP had a significantly improved OS compared to their respective subgroups receiving CHOP alone (GCB, p=0.015; non-GCB, p=0.019). Bcl-2 expression was not a significant predictor in either the GCB or non-GCB subgroups treated with R-CHOP (OS, GCB: p=0.32; non-GCB: p=0.43). Conclusions: In this retrospective study, we demonstrate that subclassification based on the cell of origin continues to have prognostic significance in patients with DLBCL treated with R-CHOP. Addition of rituximab to CHOP improves the overall survival of patients with DLBCL in both the GCB and non-GCB subgroups. No significant financial relationships to disclose.