scholarly journals Distinctive Genomic Alterations in Testicular Diffuse Large B Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3655-3655
Author(s):  
Connie Batlevi ◽  
Franck Rapaport ◽  
Lu Wang ◽  
Andrew M. Intlekofer ◽  
Amanda R. Copeland ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Snp Array ◽  
B Cell Lymphoma ◽  
Immune Recognition ◽  
Variant Allele Frequency ◽  
Large B Cell Lymphoma ◽  
Myd88 L265p

Abstract Background: Primary testicular diffuse large B cell lymphoma (DLBCL) is an uncommon malignancy portending a poor prognosis with increased risk of central nervous system disease. Phenotypically, most primary testicular lymphomas have a non-germinal center B-cell like (non-GCB) origin. To identify the genetic characteristics of testicular DLBCL, we evaluated DNA copy number and mutational profiling using SNP array and a next generation targeted sequencing platform. Methods: Twelve cases of testicular DLBCL with patient consent for tissue specimens and sufficient tumor tissue were retrospectively identified. Cell of origin was determined by Hans immunohistochemistry (IHC) model. We performed a custom, targeted deep-sequencing assay of 585 cancer genes (HemePACT) on matched tumor and normal pairs. Barcoded pools were sequenced on Illumina HiSeq 2500 to 500-1000x coverage per sample Sequencing was compared to a matched normal tissue control (N=10) if available or alternatively a pooled normal tissue control. We excluded all mutations either present at a high variant allele frequency in the matching germline samples, present in two databases of inherited variants (DBSNP and 1000 genomes) or present in one databases of inherited variants and absent from COSMIC. We evaluated copy number and allelic imbalance with an Affymetrix OncoScan SNP-array. IHC was performed for select genes. Results were compared to a panel of non-testicular DLBCL previously described (N=78). Results: The median age of the patients was 55.1 years (range 21.9-77.9). Patients had clinical stage IE (50%) and IV (50%) disease. All samples were sequenced from pre-treatment biopsies. Eleven of 12 patients were initially treated with R-CHOP chemotherapy, intrathecal methotrexate and radiation. Treatment history for one patient was unknown. We identified 124 mutations in 12 cases of testicular DLBCL. The most common mutation was MYD88 occurring in 10/12 patients (83%) with 6 mutations in non-GCB and 2 mutations in GCB (Fig 1A). The MYD88 L265P allele was most frequent and occurred in 9/12 patients (75%). The median MYD88 L265P variant allele frequency was 0.36 (range 0.07-0.51) with normal copy number status at that loci. In contrast, MYD88 mutations were less frequent in DLBCL without testicular involvement, 12/37 (32%) non-GCB and 3/41 (7%) GCB DLBCL, p<0.05 by Fisher's t-test (Fig 1B). Furthermore, mutations in CD79B were significantly more common in testicular DLBCL (5/12, 42%) versus non-testicular DLBCL (7/78, 9%). Concurrent mutations affecting the BCR receptor pathway was noted in 10/12 patients (83%): CD79B (5/12, 42%), TNFAIP3 (1/12, 8%), CARD11 (1/12, 8%) (Fig 1A). Frequency of TNFAIP3, CARD11 was not statistically significant between testicular versus non-testicular DLBCL. Other commonly mutated pathways include epigenetics (10/12, 83%) and immune recognition (6/12, 50%). Deregulation of immune recognition was noted by HLA-A (3/12, 25%) and beta-2-microglobulin (2/12, 17%) mutations as well as loss of HLA locus in 8/10 samples (80%) (Fig 1C). IHC revealed 6/10 (60%) cases with no MHC Class I expression of the tumor cells. MHC Class I negative cases also lacked B2M expression (3/6) or displayed mislocalization of B2M to the cytosol (3/6). PD-L1 was expressed by lymphoma cells as assayed by IHC in 1/10 (10%) cases but no amplification or mutation was identified. No copy gains of the 9p24.1, PD-1, PD-L1, PD-L2 locus were identified via HemePACT or SNP array. Although mutations in CDKN2A/B were not identified in HemePACT, SNP array confirmed loss of CDKN2A/B at the 9p21 loci in 3/10 cases (30%). Conclusion: Targeted genomic sequencing and SNP array analysis have identified a distinctive genetic pattern with alterations of MYD88, BCR pathway mutations, and immune recognition deficiency in testicular DLBCL compared to non-testicular DLBCL. These findings may have implications in guiding the design of future treatment strategies for testicular DLBCL. Disclosures Younes: Novartis: Research Funding; Janssen: Honoraria; Johnson and Johnson: Research Funding; Takeda Millenium: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Bayer: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Celgene: Honoraria; Incyte: Honoraria.

scholarly journals The Copy Number Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Christopher Rushton ◽  
Miguel Alcaide ◽  
Matthew Cheung ◽  
Neil R Michaud ◽  
Scott Daigle ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Treatment Resistance ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Liquid Biopsies ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) are treated with standard frontline immunochemotherapy (R-CHOP). However, for cases where R-CHOP fails (relapsed-refractory DLBCL, rrDLBCL), prognosis is extremely poor, with 2-year overall survival of 20-40%. The successful development of new therapies may be hampered by our limited understanding of the genetic and molecular mechanisms underpinning treatment resistance. For example, recent data from our group has highlighted novel mutations that emerge following treatment with R-CHOP. The contribution of copy-number variations (CNVs) towards treatment resistance has not yet been thoroughly explored. A more complete characterization of these genetic alterations may lead to new prognostic biomarkers or treatment strategies. Methods We analyzed exome sequencing data from 59 rrDLBCL cases derived from either tissue biopsies or liquid biopsies collected after relapse, including both unpublished and previously published cases (Schmitz et al. (2018) NEJM 378:1396-1407 and Morin et al. (2016) Clin Can Res 22(9)). We separately performed low-pass whole-genome sequencing (lpWGS, 0.1-1x coverage) on 45 rrDLBCL liquid biopsies with ctDNA levels insufficient for exome-based analysis, for a total of 104 cases with copy-number information. We identified CNVs from exome and lpWGS data using Sequenza and ichorCNA, respectively. Next, we identified significant peaks of recurrent gains and losses using GISTIC2. Comparison of these peaks to CNVs in a previously published diagnostic DLBCL cohort (Schmitz et al. (2018) NEJM 378:1396-1407) enabled the identification of events that were significantly more prevalent in rrDLBCL. Results Overall, the landscape of CNVs in rrDLBCL is reminiscent of diagnostic DLBCL, with recurrent amplifications of chromosome 7 (43/104, 41.3%) and 18q (42/104, 40.4%) and recurrent deletions of 6q (25/104, 24.0%) and 17p13 (39/104, 37.5%). We identified nine regions enriched for recurrent amplifications or deletions among rrDLBCLs. These include deletions of 17p13.1 (20.4% in diagnostic biopsies vs 41.3% of rrDLBCLs, q=8.53x10-5) and recurrent amplifications of 8q24 (18.5% vs 42.3%, q=5.72x10-7) and 7p22 (27.2% vs 57.9%, q=6.29x10-8). Many of these peaks represent focal events that are exceedingly rare in diagnostic DLBCL and do not contain established lymphoma-associated genes, including amplifications affecting 700kb of 6p11.2 (2.03% vs 7.69%, q=0.0178) and 500kb of 19p13.3 (6.7% vs 31.7%, q=9.99x10-10). Notably, the 6p11.2 amplifications were associated with inferior progression-free survival following R-CHOP (p=0.02), with most tumors harboring this alteration relapsing within 12 months. We also identified a novel, recurrent deletion affecting a 20mb region of 5q (2.78% vs 10.6%, q=0.00604) which was significantly deleted in rrDLBCL. For tumors with additional samples collected prior to R-CHOP and following salvage therapy, deletions of 5q appeared to emerge following frontline therapy and persisted after subsequent treatments, suggesting they may contribute to treatment resistance. Discussion The 17p13.1 deletion enriched in rrDLBCL encompasses TP53, which is a common target of somatic point mutations in rrDLBCL and associated with inferior treatment outcomes. The amplification of 8q24 and 7p22 include MYC and GNA12/CARD11, respectively, although these large events encompass numerous additional genes which may be the target of such events. Curiously, the focal 6p11.2 amplification only overlaps a handful of genes including miR_598, which has been predicted to target CD27 and CD38 and whose expression is upregulated in B-cell cell lines (Lawrie et al. (2008) Leukemia 22:1440-2446). Further investigation and validation of these events and their corresponding targets will provide insight into the biology of rrDLBCL and may reveal novel therapeutic targets. Disclosures Michaud: Epizyme: Current Employment. Daigle:Epizyme: Current Employment. Jain:Kite/Gilead: Consultancy; Novartis: Consultancy. Kuruvilla:Merck: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Honoraria; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Antengene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; TG Therapeutics: Honoraria. Crump:Servier: Consultancy; Roche: Consultancy; Kite/Gilead: Consultancy. Assouline:BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Bayer: Consultancy; Curis Inc: Consultancy. Johnson:AbbVie: Research Funding; Roche/Genentech, Merck: Honoraria; Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie: Consultancy. Scott:NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Janssen: Consultancy, Research Funding; Roche/Genentech: Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Morin:Celgene: Consultancy.

MYD88, CD79B, and CD79A Gene Mutations in CD5-Positive Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1861-1861
Author(s):  
Toshifumi Takeuchi ◽  
Motoko Yamaguchi ◽  
Kyoko Kobayashi ◽  
Kana Miyazaki ◽  
Hiroshi Imai ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Direct Sequencing ◽  
B Cell Lymphoma ◽  
The Other ◽  
Large B Cell Lymphoma ◽  
Brain Involvement ◽  
Myd88 L265p ◽  
Large B Cell

Abstract INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) is regarded as a clinicopathologically heterogeneous group of lymphomas and is classified as activated B-cell-like (ABC) DLBCL or germinal center B-cell-like (GCB) DLBCL based on the cell-of-origin (COO). Nuclear factor-kappa B (NF-kB) activation is indispensable for ABC DLBCL cell survival. Genes in the NF-kB signaling pathway, such as myeloid differentiation factor 88 (MYD88) and CD79B, are mutated in 20-40% of ABC DLBCLs. CD5 is expressed in approximately 10% of DLBCLs. CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is characterized by frequent central nervous system (CNS) relapse and a predominant activated B-cell-like nature. Primary DLBCL in sanctuary sites (DLBCL-SS) also shows these features, and more than 70% of the patients exhibit MYD88 (L265P) and CD79B mutations. This study aimed to ascertain the frequencies of MYD88 (L265P), CD79B, and CD79A mutations in CD5+ DLBCL and to determine whether CD5+DLBCL shows the same features as DLBCL-SS in terms of gene mutations. PATIENTS AND METHODS This study included 40 patients with CD5+DLBCL. All the patients were diagnosed with DLBCL, not otherwise specified, according to the 2008 WHO classification between 1993 and 2014 at Mie University Hospital. CD5 expression in tumor cells was analyzed by immunohistochemistry using frozen sections or by flow cytometry. Mutation analysis was performed by direct sequencing. RESULTS Direct sequencing was successful with samples from all 40 patients with CD5+ DLBCL. The median age was 64 years (range: 15 to 91 years). The COO classification was determined by gene expression profiling (GEP) in 29 patients. In the other 11 patients, the COO was identified by immunohistochemistry according to Hans' criteria. Thirty-six (90%) cases were confirmed as ABC/non-germinal center DLBCL. Two patients fulfilled the criteria for primary testicular DLBCL. One patient had systemic CD5+ DLBCL with bone and brain involvement. None of the other patients had CNS involvement at diagnosis. The MYD88 L265P mutation was identified in 13 (33%) of the cases, and no other MYD88 mutations were found. CD79B mutations were detected in 15 (38%) cases, and 10 of these cases overlapped with the MYD88-mutated group. One of the two patients with testicular involvement had double mutations. The other had MYD88 mutation alone. One patient with brain involvement had double mutations. Only one case (3%) had a CD79A mutation as well as CD79B and MYD88 mutations. The incidence of MYD88 L265P, CD79B, and CD79A mutations in ABC/non-GCB DLBCLs was 13/36 (36%), 14/36 (39%), and 1/36 (3%), respectively. Of the 15 cases with a CD79B mutation, 14 had missense mutations in an immunoreceptor tyrosine-based activation motif (ITAM) domain; all of these mutations occurred in the first tyrosine of the ITAM (Y196H [7/14], Y196S [4/14], Y196N [2/14], and Y196C [1/14]), and two cases showed double mutations (Y196H/H225Y and Y196S/K219R). One case had a 13-base deletion in exon 5 before the first tyrosine of the ITAM. MYD88 and CD79B mutations were associated with localized disease (P = 0.038 and P = 0.003, respectively). Clinical information on first-line treatment was available for 38 patients. Before 2002, anthracycline-containing chemotherapies without rituximab were selected as first-line treatment. Since 2002, CHOP chemotherapy with rituximab (R-CHOP) has predominated. For this reason, 18 patients who were treated with R-CHOP were included in the survival analysis in this study. The COO of these 18 patients was confirmed as ABC/non-GCB DLBCL. Two patients with primary testicular lymphoma and one with CD5+ DLBCL with brain involvement were not included in this cohort of 18 patients. With a median follow-up of 7.1 years, there was no significant difference in overall survival based on MYD88 mutation status (P = 0.98) or CD79B mutation status (P= 0.69). CONCLUSIONS To the best of our knowledge, this is the first study toreport the frequency of MYD88, CD79B, and CD79A mutations in the largest cohort of CD5+ DLBCLpatients. The incidence of MYD88 and CD79B mutations in CD5+ DLBCL is lower than that in DLBCL-SS, suggesting that CD5+DLBCL is not the same disease as DLBCL-SS. Disclosures Takeuchi: Chugai: Honoraria. Yamaguchi:Chugai: Honoraria; Eisai: Honoraria; Takeda: Honoraria; Kyowa-Hakko Kirin: Honoraria; Zenyaku: Honoraria. Miyazaki:Eisai: Honoraria; Kyowa Kirin: Honoraria; Chugai: Honoraria. Tawara:Astellas: Honoraria. Katayama:Bristol-Myers Squibb Japan: Honoraria; Alexion Pharmaceuticals: Honoraria; Eisai: Honoraria; Taisho Toyama Pharma: Honoraria; Nippon Shinyaku: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria; Chugai: Honoraria, Research Funding; Takeda: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Shionogi: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

scholarly journals Open-Labeled, Multicenter Phase II Study of Bortezomib for Maintenance Therapy in Patients with High Risk Diffuse Large B Cell Lymphoma (DLBCL): Borma Trial from Consortium for Improving Survival of Lymphoma (CISL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2884-2884
Author(s):  
Jae-Cheol Jo ◽  
Ho Sup Lee ◽  
Cheolwon Suh ◽  
Hye Jin Kang ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Risk Patients ◽  
Large B Cell Lymphoma ◽  
Risk Patients

Background: High-intermediate or high risk in international prognostic index (IPI) has a long-term chance of cure in the range about 50% in patients with diffuse large B cell lymphoma (DLBCL) treated by R-CHOP. These high risk patients should be considered for additional new treatment to standard R-CHOP or investigational approaches in the context of clinical trials that are designed to ensure that potentially curative therapy. Bortezomib inhibits NF-κB activation through proteasome inhibition, providing rationale for its use in cells that constitutively express NF-κB. Non-germinal center B cell (GCB) DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic NF-κB pathway, which can inhibit chemotherapy. There is no study of bortezomib as maintenance therapy after treated with R-CHOP in high risk patients with DLBCL. So we applied additional bortezomib as maintenance therapy in order to assess improving efficacy and survival rates in high risk patients with non-GCB DLBCL who had been confirmed complete response (CR) after treated with R-CHOP. Methods: Patients with newly diagnosed stage II(bulky)-IV DLBCL with high or high intermediate IPI score of 3 to 5, and patients achieving a CR at the end of 6 or 8 cycles of R-CHOP21 were eligible for enrollment. Non-GCB DLBCL according to Hans criteria confirmed by central review was need before enrollment. Bortezomib maintenance treatment was consisted of bortezomib 1.3mg/m2 subcutaneously administration day 1 and day 15 per 28-day cycle with a total of 12 cycles. The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoints were 3-year overall survival (OS), and toxicites. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results: Fifty-nine patients were enrolled between May 2014 and Oct 2018. The type of Non-GCB DLBCL in all patients was confirmed by the central pathology review. The median age was 65 years (range: 27-86 years), and 60% were > 61 years. The baseline clinical features were as follows: female sex, 45.8%; ECOG >1, 10.2%; stage II bulky (>10cm), 6.8%; stage III/IV, 93.2%. At the time of analysis, 29 patients completed 12-cycles of bortezomib maintenance, and 3 patients is ongoing. Seven patients did not finished maintenance therapy due to toxicities (fatigue, atrial flutter, neuropathy, pleural effusion, thrombocytopenia), and withdrawal of informed consent (n=4). Sixteen patients experienced disease progression during bortezomib maintenance treatment. With a median follow-up of 25.1 months, 3-year PFS rate was 56.9% and 3-year OS rate was 86.4% (Figure 1). Toxicity was assessed in 489 cycles of bortezomib maintenance in all 59 patients. There was no treatment-related death and febrile neutropenia. Conclusion: Bortezomib maintenance showed 3-year PFS rate of 56.9% with acceptable toxicities in patients with high risk DLBCL achieving a CR at the end of 6 or 8 cycles of R-CHOP21. Figure 1 Disclosures Kim: Celltrion: Research Funding; Novartis: Research Funding; J + J: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

scholarly journals Genome-wide characterization of copy number variations in diffuse large B-cell lymphoma with implications in targeted therapy

2019 ◽  
Vol 2 (4) ◽  
pp. 246-258
Author(s):  
Prashanthi Dharanipragada ◽  
Nita Parekh
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Copy Number Variations ◽  
Model Systems ◽  
Significant Heterogeneity ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the aggressive form of haematological malignancies with relapse/refractory in ~ 40% of cases. It mostly develops due to accumulation of various genetic and epigenetic variations that contribute to its aggressiveness. Though large-scale structural alterations have been reported in DLBCL, their functional role in pathogenesis and as potential targets for therapy is not yet well understood. In this study we performed detection and analysis of copy number variations (CNVs) in 11 human DLBCL cell lines (4 activated B-cell–like [ABC] and 7 germinal-centre B-cell–like [GCB]), that serve as model systems for DLBCL cancer cell biology. Significant heterogeneity observed in CNV profiles of these cell lines and poor prognosis associated with ABC subtype indicates the importance of individualized screening for diagnostic and prognostic targets. Functional analysis of key cancer genes exhibiting copy alterations across the cell lines revealed activation/disruption of ten potentially targetable immuno-oncogenic pathways. Genome guided in silico therapy that putatively target these pathways is elucidated. Based on our analysis, five CNV-genes associated with worst survival prognosis are proposed as potential prognostic markers of DLBCL.

scholarly journals The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma

2020 ◽  
Vol 143 (6) ◽  
pp. 520-528
Author(s):  
Yang Xia ◽  
Xinlian Zhang
Keyword(s):  
B Cell ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Novel Therapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

MYC, as a powerful transcription factor, plays a vital role in various cancers. The clinical significance of MYC alterations in diffuse large B-cell lymphoma (DLBCL) has been investigated for a long time. In this study, we comprehensively summarize the different alterations of MYC in DLBCL, including MYC overexpression, <i>MYC</i> translocations, <i>MYC</i> mutations, and increased gene copy number of <i>MYC</i>. Noteworthy, lone MYC overexpression or <i>MYC</i> translocation is not significantly associated with poor clinical outcomes, and their detrimental effects depend on the genetic alterations of BCL2 or BCL6. Both double-expressor DLBCL (DE-DLBCL), defined as overexpression of MYC and BCL2 proteins, and double-hit lymphoma (DHL), defined as a dual translocation of <i>MYC</i> together with <i>BCL2</i> or <i>BCL6</i>, represent the distinct subgroups of DLBCL with inferior clinical outcomes. The mechanism may be that MYC activation induces cell proliferation, without the threat of the apoptotic brake in the presence of BCL2 overexpression. In addition, most of <i>MYC</i> mutations are present with favorable prognosis, and the nonsignificant effect of MYC copy number amplification has been observed. It has been proved that cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab show limited effects for DHL or DE-DLBCL, and the rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seem to be efficacious for DHL. The novel therapy is urgently needed for clinical improvement in DHL and DE-DLBCL.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma: Analysis of Incidence and Prognostic Factors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1666-1666
Author(s):  
Masahiro Uni ◽  
Yuki Kagoya ◽  
Yasuhito Nannya ◽  
Fumihiko Nakamura ◽  
Mineo Kurokawa
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Initial Diagnosis ◽  
High Dose ◽  
Cns Involvement ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Large B Cell

Abstract The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone) has significantly improved the outcome of diffuse large B-cell lymphoma (DLBCL). However, its secondary involvement in the central nervous system (CNS) is still a fatal event, and optimal therapeutic strategies have remained to be established. Combined immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine is currently in use for patients with CNS relapse, though treatment outcome has not been evaluated enough. In the present study, we aimed to analyze the incidence and prognosis of CNS relapse of aggressive B-cell lymphoma in comparison with those of systemic relapse in the era of rituximab-containing regimens. We also estimated the risk factors and prognostic factors for CNS relapse. We retrospectively analyzed 278 consecutive adult patients (≥16 years old) who were diagnosed as DLBCL or primary mediastinal large B-cell lymphoma (PMLBL) at The University of Tokyo Hospital, Tokyo, Japan, from August 2003 through August 2013. We excluded patients who had CNS or intraocular involvement at diagnosis since those patients had received high-dose methotrexate-based therapy instead of R-CHOP. Four to six courses of intrathecal administration of methotrexate were performed in patients with adrenal gland, testis or breast involvement as prophylaxis for CNS relapse. The median follow-up period was 42 months, and the median age was 66 years (range, 23-91). Overall, 67 patients (24.1%) had relapse at any site, of which 24 patients (35.8%) had CNS involvement. The median interval between initial diagnosis and the occurrence of secondary CNS involvement was 212 days, and 15 of the 24 patients (62.5%) had CNS relapse within 1 year from the initial diagnosis. Multivariate analysis revealed that multiple or diffuse extranodal involvement at initial diagnosis (hazard ratio [HR] 3.74, 95% confidence interval [CI] 1.28-10.91; P<0.01) was associated with the development of CNS relapse against non-CNS relapse. Chromosomal abnormality was investigated in 112 patients, of which 38 had abnormal karyotypes as identified by G-banding analysis for lymph nodes. Patients with CNS relapse more frequently harbored chromosomal abnormalities compared with those without relapse in univariate analysis (P=0.01). We also analyzed the survival of patients with primary CNS lymphoma (PCNSL) as a control. Only two (7%) of 27 patients with PCNSL died during the follow-up period. Five-year OS from initial diagnosis was 92.3% (95% CI: 82.5-100.0%), and was significantly better than that for patients with CNS relapse (33.9%, 95% CI: 17.3-66.3%, P<0.01). Among 24 patients with CNS relapse, eight (33%) had systemic lesions other than CNS when diagnosed as CNS relapse, and four (17%) patients newly developed systemic lesions while treated for CNS relapse. Patients without concurrent systemic lesions attained a rather good prognosis by chemo-radiotherapy, while those harboring concurrent systemic lesions had dismal outcome (one-year OS after the diagnosis of relapse: 74.0% versus 12.4%, P<0.01, Figure 1, systemic relapse was treated as a time-dependent covariate). These results indicate that controlling systemic lesions as well as CNS ones is essential for treating patients with secondary CNS involvement of DLBCL. CNS lesions would be well controlled with R-MPV implementation as salvage therapy, nevertheless we should be careful for concurrent systemic lesions which might require different therapeutic strategies. Disclosures Nannya: Chugai Pharmaceutical　CO., LTD: Speakers Bureau; Pfizer: Research Funding. Kurokawa:Chugai Pharmaceutical　CO., LTD: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding.

Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: Subgroup Analysis from the UK NCRI R-CHOP 14 Vs 21 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1516-1516
Author(s):  
Andrea Kühnl ◽  
David Cunningham ◽  
Nicholas Counsell ◽  
Eliza A Hawkes ◽  
Wendi Qian ◽  
...  
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Bulky Disease ◽  
Large B Cell Lymphoma ◽  
The Uk ◽  
Large B Cell ◽  
Grade Iii

Abstract Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis compared to younger patients. Dose intense administration of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP14) is superior to 3-weekly CHOP in elderly DLBCL patients (Pfreundschuh, Blood 2004), but this benefit has not been demonstrated with addition of rituximab (Delarue, Lancet Oncol 2013). We have previously shown that R-CHOP14 did not improve outcome compared to standard R-CHOP21 in newly diagnosed DLBCL patients aged 19-88 years across all subgroups (Cunningham, Lancet 2013). Here, we provide a detailed subgroup analysis of elderly patients (over 60 years) from the UK NCRI R-CHOP14 vs 21 randomised phase 3 trial. Methods: Between 2005 and 2008, 1080 patients were randomly assigned to receive 8 cycles R-CHOP21 or 6 cycles R-CHOP14 (+ G-CSF) with two additional rituximab applications. Of these, 604 patients were over 60 years and included in the current analysis (301 in the R-CHOP21 arm, 303 in the R-CHOP14 arm), with a median follow-up of 45 months. Results: Baseline characteristics were well balanced between treatment arms. 36% of patients were over 70 years, 15% had a WHO performance status (PS) of 2, 65% stage III/IV disease, 44% bulky disease and 42% B symptoms. There was a trend towards a higher rate of BCL6 rearrangements (26% vs. 16%; P=0.10) and concurrent MYC - and BCL2 rearrangements (double hit lymphoma as determined by FISH, 8% vs. 2%; P=0.06) in the R-CHOP14 arm compared to the R-CHOP21 arm. 85% (257/303) of patients received 8 cycles of R-CHOP14, whereas only 76% (230/301) completed all 8 cycles R-CHOP21. However, percentage of patients receiving at least 6 cycles of therapy was similar (88% and 89%, respectively). Dose delays of myelosuppressive drugs occurred more frequently in patients receiving R-CHOP21 vs. R-CHOP14 (51% vs. 39%; P=0.03) due to a higher incidence of haematological toxicities likely related to the reduced use of G-CSF. G-CSF was mandatory for patients on R-CHOP14 and was given to 57% of patients on R-CHOP21 as secondary prophylaxis. The frequency of dose reductions was similar in the R-CHOP21 and R-CHOP14 arms (15% vs. 16%; P=0.73). Toxicities of grade III+ were seen in 72% and 60% of patients in the R-CHOP14 and R-CHOP21 arms, respectively. There was evidence of a higher incidence of grade III+ neutropenia (62% vs. 36%) and a lower rate of thrombocytopenia (7% vs. 12%) in the R-CHOP21 arm compared to R-CHOP14. The incidence of fever and infections was similar in both arms. There was no evidence of a difference in response rates between the R-CHOP14 and R-CHOP21 arms [complete response (CR)/unconfirmed CR (CRu) rates: 62% vs. 67%, respectively; overall response rate both 91%]. CR/CRu rates after 4 cycles of therapy were 33% and 39% respectively (P=0.15). There was no difference regarding progression-free survival (PFS) and overall survival (OS) between arms, neither in the total cohort of elderly patients, nor in the subgroup of patients over 70 years [OS (all elderly): hazard ratio (HR) 0.91 (95% CI: 0.67-1.24); P=0.55; PFS (all elderly): HR 0.98 (95% CI: 0.74-1.29); P=0.86]. 3-year PFS was 71% (95% CI: 67-74) in all patients over 60 years and 64% (95% CI: 58-71) in patients over 70 years. 3-year OS was 75% (95% CI: 72-79) and 67% (95% CI: 61-74) in patients over 60 years and over 70 years, respectively. In multivariate analysis including individual factors of the International Prognostic Index (IPI), as well as age as continuous variable, gender, presence of B symptoms, bulky disease, b2-microglobulin higher than 3mg/l and albumin higher than 35 g/l, only age was of independent prognostic significance for OS (P=0.01). Besides the standard IPI and the NCCN-IPI, an elderly IPI (E-IPI; Advani, BJH 2010) and the ABE4 score (Prochazka, PLoS One 2014) have been proposed for better prognostication of elderly DLBCL patients. A detailed comparison of these different prognostic models in our dataset will be presented at the meeting. Conclusion: Outcome and toxicities in DLBCL patients over 60 years treated within the NCRI R-CHOP14 vs 21 trial are comparable to results from other randomised studies investigating R-CHOP14 or R-CHOP21 in elderly DLBCL patients. Our data further support the similar efficacy and tolerability of both R-CHOP variants for first-line treatment of this patient group. Disclosures Cunningham: Amgen: Research Funding; Medimmune: Research Funding; Astra Zeneca: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; Merrimack: Research Funding; Merck Serono: Research Funding; Celgene: Research Funding; Sanofi: Research Funding. Pocock:Janssen: Honoraria. Ardeshna:Roche: Honoraria.

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