STAT3 Expression and Clinical Implications In De Novo Diffuse Large B-Cell Lymphoma: A Report From The International DLBCL Rituximab-CHOP Consortium Program

Abstract Introduction Expression of signal transducer and activator of transcription 3 (STAT3) in de novo diffuse large B-cell lymphoma (DLBCL) has not been studied broadly and the prognostic value of STAT3 expression in DLBCL is controversial. Methods The study group included 876 de novo DLBCL patients. All patients were treated with rituximab, cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone (R-CHOP). Cases excluded from the study group included large cell transformation from low-grade B-cell lymphoma, primary cutaneous large B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary DLBCL of the central nervous system and cases associated with Epstein-Barr virus or human immunodeficiency virus. Immunohistochemical (IHC) studies for several biomarkers were performed using fixed, paraffin embedded sections of tissue microarrays. Fluorescence in situ hybridization (FISH) for BCL2, BCL6, MYC, and TP53 were performed andTP53 was also sequenced Gene expression profiling (GEP) was performed on 500 cases and the cell of origin (COO) classification was determined by GEP (gold standard) and immunohistochemistry. Results STAT3 was positive in 240 (32.9%) patients, including 133 men and 107 women. The median age of STAT3+ DLBCL patients was 65 years (range, 21-93) and was similar to STAT3- DLBCL patients (63, range 12-95). B symptoms (44.4% vs. 35.2%, P=0.021) and advanced stage (60.5% vs. 52.1%, P=0.035) were more commonly present in STAT3+ DLBCL compared with STAT3- DLBCL patients. Other clinical characteristics were similar between the groups. STAT3+ DBLCLs were more often activated B-cell (ABC) type than STAT3- DLBCLs (61.8% vs. 41.1%, P<0.001). STAT3+ DLBCLs more often expressed MYC (76.7% vs. 56.5%, P<0.001), p50 (43.3% vs. 34.1%, P=0.018), and p65 (33.9% vs. 25.3%, P=0.017) than STAT3- DLBCLs. c-Rel, however, was less commonly expressed in STAT3+ DLBCL (18.9% vs. 27.2%, P=0.018). Expression of BCL2 was similar between the two groups. Genetic aberrations involving BCL2 (10.9%), MYC (7.6%) and TP53 deletion (8.1%) by FISH were uncommon. Aberrations of BCL6 were present in 24.6% of STAT3+ DLBCL. TP53 mutation was found in 27 patients (20.1%). The frequency of genetic aberrations by FISH was similar in the STAT3+ and STAT3- DLBCL groups. Patients with STAT3+ versus STAT3- DLBCL had similar OS (P=0.494) and PFS (P=0.224). When looking at all DLBCL cases divided into GCB versus ABC type, STAT3 expression did not predict survival in the GCB (OS, P=0.945 and PFS, P=0.604) or ABC types (OS, P=0.211 and PFS, P=0.079, respectively). In multivariate analysis, STAT3 expression did not show an increased hazard ratio (HR 0.806, 95% CI 0.578-1.125, P=0.205). Conclusion STAT3 is expressed in approximately 1/3 of de novo DLBCLs. STAT3 expression is associated with B symptoms, advanced stage of disease, ABC type, and expression of MYC. Expression of p50 and p65 are more frequently expressed in STAT3+ DLBCL, illustrating activated NF-κB through canonical pathway. C-Rel is less commonly expressed in STAT3+ DLBCL, suggesting p65 is the principal partner for p50. Genetic aberrations are rare. Although STAT3 expression is associated with several adverse prognostic parameters, it does not confer inferior OS and PFS in DLBCL overall, suggestive of the presence of yet unidentified putative tumor suppressive functions in STAT3+ DLBCL patients. Disclosures: Winter: Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents & Royalties.

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A Retrospective Analysis of Gastric Diffuse Large B-Cell Lymphoma with or without MALT Component

Blood ◽

10.1182/blood.v120.21.4856.4856 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4856-4856

Author(s):

Xiaowu Li ◽

Bing Xia ◽

Shanqi Guo ◽

Eduardo M. Sotomayor ◽

Yong Yu ◽

...

Keyword(s):

Surgical Treatment ◽

B Cell ◽

Clinical Characteristics ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advanced Stage ◽

Large B Cell Lymphoma ◽

H Pylori ◽

Large B Cell

Abstract Abstract 4856 Background: The aim of this study was to evaluate the clinical characteristics, prognostic factors and survival outcomes of patients with gastric diffuse large B-cell lymphoma (DLBCL). Patients and methods: 162 patients with gastric DLBCL were evaluated retrospectively. Comparisons were made between patients of gastric DLBCL with component of mucosa-associated lymphoid tissue lymphoma (DLBCL/MALT) and patients of gastric DLBCL without detectable MALT component (de novo DLBCL). Results: Results according to the distribution of sex, age, stage, performance status, and other clinical characteristics were similar between de novo DLBCL group and DLBCL/MALT group (p>0.05). The ratio of patients with the germinal center B-cell-like (GCB) subtype to non-GCB subtype did not differ significantly between the two groups (1:1.1 versus 1:1.6, p=0.319). However, the proportion of patients with the stage-modified international prognostic index (m-IPI) ≥2 was higher in DLBCL/MALT groups (18%) than taht in de novo DLBCL groups (34%) (p=0.026). In addition, the H. pylori infection rate was 75% in DLBCL/MALT versus 38% in de novo DLBCL (p<0.001). Patients with de novo DLBCL have better 5-year PFS and OS estimates than those DLBCL/MALT patients (p=0.037 and 0.019 for the 5-year PFS and OS estimates, respectively). Surgical treatment did not offer survival benefit when compared with chemotherapy (p=0.405 and 0.065 for the 5-year PFS and OS estimates, respectively). Multivariate analysis revealed that non-GCB classification and m-IPI≥2 were independently associated with shorter OS and advanced stage was independently associated with shorter PFS. Conclusion: Gastric DLBCL is a heterogeneous disease that included de novo DLBCL and DLBCL/MALT lymphoma. Compared with the former, the latter has a higher H. pylori infection rate. And what's more, the proportion of patients with m-IPI≥2 is higher in DLBCL/MALT groups. De novo DLBCL was associated with higher 5-year PFS and OS estimates. Non-surgical treatment should be a primary consideration for gastric DLBCL. Immunophenotype classification and m-IPI were the most reliable factors for OS, and advanced stage was for PFS. Disclosures: No relevant conflicts of interest to declare.

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Genomic Characterization of Diffuse Large B-Cell Lymphoma Transformation from Nodular Lymphocyte Predominant Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-125095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1486-1486

Author(s):

Joo Y. Song ◽

Caoimhe Egan ◽

Alyssa Bouska ◽

Weiwei Zhang ◽

Qiang Gong ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

Immune Surveillance ◽

B Cell Lymphoma ◽

Pi3k Pathway ◽

Large B Cell Lymphoma ◽

Frequent Mutations ◽

Large B Cell

Introduction: Transformed nodular lymphocyte predominant Hodgkin lymphoma (tNLPHL) with a typical diffuse large B-cell lymphoma (DLBCL) pattern is rare and not well studied by genomic analysis. We employed next generation sequencing and copy number analysis (CNA) to examine the pathogenesis of these tumors. Methods: We identified 19 cases of tNLPHL with DLBCL morphology and sheet-like growth from three institutions. NLPHL preceded transformation in 5 patients and was concurrent with transformation in 11. All cases of tNLPHL were sequenced using a targeted sequencing panel of 356 genes that included commonly mutated genes associated with lymphoma. We had 8 cases with matched germline DNA. We also performed CNA using Oncoscan on 18 cases of tNLPHL. Library preparation with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Fisher's exact test was used to compare the role of mutations in tNLPHL to three large series of de novo DLBCL. Results: The CNA showed frequent gains in REL and loss of CDKN2A. Mutation analysis showed frequent mutations of genes associated with the PI3K pathway such as SGK1 (26%), ZFP36L1 (16%), PIK3R1 (11%), and IL7R (11%), the NF-kB pathway such as CARD11 (21%), JUNB (21%), BCL10 (11%), NFKBIA (11%), TNFAIP3 (11%), histone/DNA modification such as KMT2D (26%), EP300 (21%), TET2 (11%), TET3 (11%), and the NOTCH pathway such as NOTCH2 (16%), NOTCH1 (1 case), CTBP2 (11%). Mutations in genes involved in immune surveillance and TP53 abnormalities were infrequent. Compared to de novo DLBCL, mutations in IL7R (10.5% vs 0.6%, p=0.03), JUNB (21% vs 4.2%, p=0.01), and SMARCAL1 (11% vs 0%, p=0.01) were significantly higher in tNLPHL than in germinal center B-cell (GCB) subtype of DLBCL. Conclusion: The mutational spectrum of tNLPHL resembles the DLBCL Cluster 4 of Chapuy et al (Nat Med, 2018), which were primarily GCB-DLBCL with frequent mutations in the PI3K pathway (SGK1), NF-kB pathway (CARD11, JUNB), and histone modification. The mutational spectrum is also distinctive in having frequent mutations that are not often seen together in DLBCL, such as TET2, JUNB and NOTCH2. Distinct from transformed follicular lymphoma, TP53 abnormalities and mutations affecting immune surveillance are uncommonly observed. This study provides new insights into the biology of tNLPHL and may highlight potential targets for therapy in the future. Disclosures Herrera: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding.

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Lymphocyte-to-Monocyte Ratio at Diagnosis and Survival in De Novo Double/Triple Hit Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3885.3885 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3885-3885

Author(s):

Luis Porrata ◽

Kay Ristow ◽

Ellen D. McPhail ◽

William Macon ◽

Matthew J Maurer ◽

...

Keyword(s):

Prognostic Factor ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocyte To Monocyte Ratio ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

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Clinical Significance of Co-Expression of MYC and BCL2 Protein in Advanced Diffuse Large B-Cell Lymphoma Treated with a Dose-Intensified Immunochemotherapy

Blood ◽

10.1182/blood.v126.23.3940.3940 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3940-3940

Author(s):

Hiromichi Takahashi ◽

Sumiko Kobayashi ◽

Katsuhiro Miura ◽

Daisuke Kurita ◽

Yoshihiro Hatta ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Intermediate Risk ◽

Chugai Pharmaceutical ◽

Large B Cell Lymphoma ◽

Bcl2 Protein ◽

Large B Cell

Abstract Background Recent studies have shown that the concurrent expression of MYC and BCL2 protein evaluated by immunohistochemistry (IHC) in patients with de novo diffuse large B-cell lymphoma (DLBCL) is associated with worse survival when treated with standard R-CHOP, but the effect of intensive chemotherapies for such patients is unknown. Thus, we evaluated the impact of the co-expression of MYC and BCL2 protein among patients with advanced DLBCL, who were treated with a dose-intensive immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). Patients and Methods This is a retrospective analysis of patients with de novo DLBCL, who were categorized into high/high-intermediate risk by the age-adjusted International Prognostic Index (aaIPI). They were consecutively treated with the R-Double-CHOP regimen, consisting of rituximab (375 mg/m2, day -2), cyclophosphamide (750 mg/m2, day 1, 2), doxorubicin (50 mg/m2, day 1, 2), vincristine (1.4 mg/m2 [maximum 2.0 mg/body], day 1) and prednisolone (50 mg/m2, day 1-5) followed by consolidative high-dose chemotherapies at our institution from 2001 to 2013. MYC and BCL2 protein were measured by IHC assay using formalin-fixed paraffin-embedded tissue specimens for all available cases. Cut-off values of positivity for MYC and BCL2 protein were set as 40% and 50% of stained tumor cell, respectively. Lymphomas showing concurrent positivity for MYC and BCL2 protein were defined as "Double expressor lymphoma (DEL)". Results A total of 40 patients with a median 53-years (range 19-68) of age were analyzed. Twenty-one patients were at high risk and the other 19 patients were at high-intermediate risk by aaIPI. Cell of origin (COO) subtypes classified by Hans algorithm consisted of 14 germinal center B-cell (GCB) type and 26 non-GCB type. Totally, 10 (25%) patients were categorized into DEL. The overall response (OR) and the complete response (CR) rates to R-Double-CHOP for all patients were 93% and 83%, respectively. The OR and the CR rates were not significantly different between the DEL group and the non-DEL group (100% vs 90%, and 80% vs 83%, respectively). The proportion of patients proceeding to ASCT was not significantly different among these groups (50% vs 60%). With a median 52 months (range 3-155) of follow-up, the 3-year progression-free survival (PFS) and the overall survival (OS) rates for all patients were 55% and 72%, respectively (Figure a, b). Both the PFS and the OS were significantly worse in the DEL group than in the non-DEL group (Figure c, d). As for aaIPI and COO subtyping, either high/high-intermediate risk or GCB/non-GCB subtype were not significantly associated with the outcome of PFS or OS. Conclusion The concurrent expression of MYC/BCL2 protein in advanced DLBCL was associated with shorter remission duration and worse survival despite similar susceptibility to the treatment when a dose-intensive immunochemotherapy was applied. Our findings suggest that patients with advanced DEL may not benefit from dose-intensified therapies, and therefore need highly discrete strategies. Disclosures Miura: Astellas Pharma Inc.: Honoraria; Celgene K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; Meiji Seika Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Hatta:Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Celgene K.K.: Honoraria. Iriyama:Brystol-Myers K.K.: Honoraria. Takei:Kyowa Hakko Kirin CO., Ltd, Japan: Research Funding; Bristol-Myers K.K.: Research Funding; Nippon Kayaku Co.: Research Funding; Shionogi & Co.: Research Funding; Meiji Seika Pharma: Research Funding; Astellas Pharma Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; TEIJIN PHARMA LIMITED: Research Funding; CSL Behring K.K: Research Funding; Japan Blood Products Organization: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; TORII, PHAMACEUTICAL CO: Research Funding; Alexion Pharmaceuticals: Research Funding; YAKULT HONSHA CO., Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO. LTD: Research Funding.

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Upregulation of CD47 Expression in De Novo Diffuse Large B-Cell Lymphoma Is More Frequent in Activated B-Cell Type

Blood ◽

10.1182/blood-2021-152071 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3507-3507

Author(s):

Winston Y Lee ◽

Anamarija M. Perry ◽

Vero Azcutia ◽

Alex F. Herrera ◽

Pamela Skrabek ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Surface Receptor ◽

Large B Cell Lymphoma ◽

Frequent Mutations ◽

Large B Cell

Abstract CD47 is a marker of self that provides a "don't-eat-me-signal" through activation of signal-regulatory protein alpha (SIRPa), a cell surface receptor expressed on monocytes/macrophages and granulocytes. This interaction negatively regulates effector functions such as, phagocytosis, migration, and superoxide production. Upregulation of CD47 expression in cancer, including diffuse large B-cell lymphoma (DLBCL), has emerged as a mechanism to escape innate immune surveillance. Using conventional immunohistochemical detection, we assessed CD47 expression in DLBCL and interrogated its association with clinicopathologic features. Patients with de novo DLBCL were identified from two large institutions and were uniformly treated with R-CHOP and had sufficient material for study. Immunohistochemical stains (IHC) were performed on FFPE tissue (Hans algorithm, BCL2, MYC, and CD47) and scored semi-quantitatively from no reactivity (0) to strong (2 and 3; Figure 1). Mutational analysis using a 334 gene target sequencing panel, gene expression profiling using Lymph2Cx to determine the cell of origin (COO), and FISH analysis for MYC, BCL2, and BCL6 translocations, were performed. The Lymphgen tool (Wright et al, 2020) was also used to determine the DLBCL group. Fisher's exact test and Kaplan-Meier survival analysis for overall survival (OS) were performed and P <0.05 was considered significant. CD47 expression was assessed by IHC in a cohort of 152 cases of de novo DLBCL, including 107 cases of germinal center B-cell (GCB) type (70%), 37 cases of activated B-cell (ABC) type (24%), and 8 cases of intermediate type (5%). A total of 17 cases (11%) showed strong and diffuse CD47 expression with IHC scores of 2 or above (CD47hi). CD47hi cases were significantly more frequent in ABC DLBCL (24%, 9/37) than GCB DLBCL (6%, 6/107; P=0.003). The remaining 2 CD47hi cases were in the intermediate DLBCL group (25%, 2/8). ABC DLBCL with CD47hi showed more frequent mutations with TET2 (33% vs 7%; P=0.08) and ZFP36L1 (22% vs 0%; P=0.05) compared to cases with low expression of CD47 with IHC scores of less than 2 (CD47low). ABC DLBCL with CD47low showed more frequent mutations of NOTCH2 (18% vs 0%; P=0.31) and MYD88 (29% vs 11%; P=0.4) compared to CD47hi. GCB DLBCL with CD47hi showed frequent mutations of TP53 (67% vs 21%; P=0.026) and CCND1 (33% vs 0%; P=0.003) compared to CD47low. None of the 13 cases with double- or triple-hit for MYC, BCL2 and/or BCL6 showed CD47 expression. The Lymphgen tool showed that cases of DLBCL with CD47hi were mostly in the 'other' group (50%), with other groups represented such as ST2 (21%), EZB (14%), MCD and BN2 (1 case each). There was no difference in overall survival (OS) between CD47hi and CD47low DLBCL (5-year OS, 75% vs 72%; P=0.57), or with the GCB or ABC subtypes. Strong expression with CD47 is more frequent in ABC DLBCL and is seen in a subset of GCB DLBCL with mutations in TP53 and/or CCND1. The level of CD47 expression does not appear to predict OS in patients with DLBCL treated with R-CHOP. This study demonstrates that conventional immunohistochemical methods can readily identify DLBCL with high CD47 expression, and these patients may benefit from the use of anti-CD47 therapy. Figure 1 Figure 1. Disclosures Herrera: Gilead Sciences: Research Funding; Takeda: Consultancy; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding.

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A Phase I Trial of Brentuximab Vedotin in Combination with Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3988.3988 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3988-3988 ◽

Cited By ~ 2

Author(s):

Jeffrey P. Ward ◽

Jessica Thein ◽

Jingqin Luo ◽

Nina D. Wagner-Johnston ◽

Amanda F. Cashen ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The addition of rituximab to CHOP has improved the overall survival of patients with diffuse large B-cell lymphoma (DLBCL); however, approximately 30% of patients will relapse. Stem cell transplantation (SCT) provides a second chance at cure, but the prognosis for patients who are not candidates for SCT or who have refractory disease is poor, and new treatments with novel agents are needed. Brentuximab vedotin (BV), an antibody-drug conjugate that combines an anti-CD30 monoclonal antibody and the microtubule disrupting agent MMAE, has a single agent response rate (RR) of 44% (CR 17%) in CD30 (+) (Jacobsen, Blood 2015) and 27% (CR 3.7%) in CD30 (-) relapsed/refractory (rel/ref) DLBCL (Bartlett, ASH 2014). Lenalidomide (Len), an immunomodulator with multiple described mechanisms of action, has a single agent RR of 28% (CR 7%) in rel/ref DLBCL (Witzig, Ann Oncol 2011). Notably, the Len RR was 52.9% in the subset of patients with non-germinal center-like (non-GCB) DLBCL, compared to 8.7% in GCB DLBCL (Hernandez-Ilizaliturri, Cancer 2011). Given that both compounds have single agent activity in DLBCL and favorable, non-overlapping toxicity profiles, we hypothesized that the combination of BV and Len would be an effective and tolerable regimen in rel/ref DLBCL. Methods: This investigator initiated, phase I/dose expansion trial is ongoing to identify the safety and maximum tolerated dose (MTD) of the combination of BV and Len (Clinical Trials.gov NCT02086604). Eligible patients have rel/ref de novo or transformed DLBCL after at least one prior systemic therapy and have previously received or are ineligible for SCT. Response assessments are performed after cycles 2, 4, 6, 9 and then every six months for two years by PET/CT scan and response determined per the Revised International Working Group Response Criteria for Malignant Lymphoma 2007. The study is in two parts, a dose-escalation portion using a 3+3 design to determine the MTD, followed by a dose-expansion cohort enrolling patients with either CD30 (+) or CD30 (-) DLBCL assessed by visual assessment using routine IHC per local laboratory. BV is administered every 21 days and Len is dosed continuously for a maximum of 16 cycles until disease progression or unacceptable toxicity. Results: Eighteen patients have been enrolled to date. The median age is 61 years (range 51-79), with 83% having an ECOG performance status of 0-1. Median number of prior therapies is 2 (range 1-6), with 39% undergoing a previous autoSCT, and one patient a previous alloSCT. 72% of patients were refractory to their last regimen. 13 patients have CD30 (-) and 5 CD30 (+) DLBCL. Treatment-related adverse events (AEs) occurring in >20% of patients include anemia (50%), elevated ALT (28%), hypocalcemia (22%), peripheral neuropathy (22%), neutropenia (28%), thrombocytopenia (33%), and hypokalemia (28%). Anemia, febrile neutropenia, thrombocytopenia, and hypokalemia were the only grade 3/4 related AEs observed in >10% of patients. Growth factors were not given during cycle 1 but were administered in 11 patients with subsequent cycles. One patient came off study for thrombocytopenia after completing 8 cycles, while in a CR. 47% have required at least one dose reduction. The DLTs per dose cohort are summarized in the table. The MTD of the combination is 1.2 mg/kg of BV Q21d with 20 mg Len given continuously. At the time of this analysis, 17 patients (1 too early) have had restaging evaluations; 7 CR (41%), 2 PR, 3 SD, and 5 PD, for an overall RR of 53%. Five CRs occurred after C2, 1 after C6 and 1 after C8. All responses are ongoing with a range of 5 to 35 wks. Among the 7 CRs, 2 patients have CD30 (+) and 5 patients CD30 (-) DLBCL, 4 pts were GCB and 3 non-GCB. Of the four patients with CD30 (-) disease categorized as GCB, two achieved a CR. Conclusions: This Phase I study of BV plus Len identified the MTD of the combination at BV 1.2 mg/kg Q21d with Len 20 mg/d continuously. Dose expansion cohorts of 15 patients each for CD30 (-) and CD30(+) DLBCL are currently accruing. The predominant toxicity of the study regimen is related to cytopenias, consistent with prior experience. Although patient numbers are small, the high CR rate is intriguing. Updated results will be presented at the meeting. Table 1. # Patients Assigned BV Dose Assigned Len Dose # of DLT DLT Toxicity 9 1.2mg/kg 20mg 1 Neutropenia 6 1.2mg/kg 25mg 2 Neutropenia, DVT 3 1.8mg/kg 25mg 2 Fatigue, Neutropenia Disclosures Ward: Boehringer Ingelheim: Consultancy. Wagner-Johnston:Celgene: Research Funding; Gilead: Consultancy. Fehniger:Celgene: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

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Pro-Angiogenic Mir-296 Is Frequently Overexpressed and Is Associated with Advanced Stage Disease in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1570.1570 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1570-1570

Author(s):

Natália Morais Borges ◽

Marina Lourenço de Conti ◽

Tathiana Azevedo de Andrade ◽

Marina Petaccia Macedo ◽

Maria Dirlei Ferreira de Souza Begnami ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Advanced Stage ◽

Large B Cell Lymphoma ◽

Stage Disease ◽

Significant Difference ◽

Large B Cell

Abstract Abstract 1570 Introduction: MicroRNAs (miRNAs) are a class of endogenous short non-coding RNAs that control gene expression by acting on target mRNAs for promoting either their degradation or translational repression. Some of them have involvement in regulating various aspects of angiogenesis, including proliferation, migration and morphogenesis of endothelial cells, which are important in regulating cardiovascular development and cancer. The term “angiomiR” is used to define the miRNAs that control angiogenesis. They are classified into pro-angiomiRs, those that promote angiogenesis, and anti-angiomiRs, those that inhibit angiogenesis. The identification of angiomiRs as the key to regulating angiogenesis has opened new paths in the treatment of vascular and oncology diseases. Aims: This study aims to analyze the expression angiomiRs in diffuse large B-cell lymphoma (DLBCL) and to correlate them with clinical and histological features to identify possible biomarkers and prognostic factors. Patients and Methods: We studied 93 samples of de novo DLBCL diagnosed between 2000 and 2010. All the cases were HIV-negative. MicroRNAs were obtained from paraffin embedded tumor samples using RecoverAll™ Total Nucleic Acid Isolation Kit for FFPE Tissues (Applied Biosystems). Four angiomiRs (miR-378, miR-296, miR-210 and miR-126) were analyzed. RNU44 and U18 were used as endogenous controls for quantitative PCR (TaqMan®Small RNA Assays). We set a threshold of a 1.5-fold difference in angiomiRs expression compared to controls (palatine tonsil). Results: miR-378, miR-296, miR-210 and miR-126 overexpression were observed in 43%, 47%, 22% and 5%, respectively. Considering that miR-378 and miR-296 were frequently overexpressed in DLBCL, we further analyzed the following variables: age (<=60 versus >60 years), Ann Arbor Staging System (I-II versus III-IV), International Prognostic Index (0–2 versus 3–5), DLBCL classification (NOS versus subtypes), tumor origin according to Hans (2004) algorithm (GCB versus non-GCB). We observed higher median miR-296 expression in DLBCL classified as stage III-IV (p = 0.0415, Mann-Whitney). For the other variables, were did not find any statistically significant difference between groups. Conclusions: miR-296, that directly decreased the levels of hepatocyte-growth factor regulated tyrosine kinase substrate (HGS) and indirectly upregulate VEGFR2 and PDGFRβ, was overexpressed in almost 50% of de novo DLBCL and was associated with advanced stage disease. Our study brings new information about the role of microRNA importance in DLBCL development and can be explored as prognostic and therapeutic target for patients suffering from this prevalent malignancy (Supported by FAPESP 2010/17668-6). Disclosures: No relevant conflicts of interest to declare.

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