Frequency, Histologic, and Prognostic Significance of CD30 Expression in AIDS-associated Diffuse Large B-Cell Lymphoma

Abstract Introduction: AIDS-related Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, with a variable response to chemotherapy depending on, and not limited to, cell of origin, double/triple hit, or MYC/BCL-2 co-expression status. Similar to DLBCL, AIDS-related DLBCL (ARL) with non-germinal center histology or MYC expression reports poorer response to treatment. In the immunocompetent population CD30+ DLBCL defines a histology with improved survival, however, the characteristics and outcomes of ARL expressing CD30 are not well studied. Methods: We assessed 3 cohorts of ARL. The first cohort, consisted of of an immunohistochemistry tissue microarray (TMA) of 30 ARL patients, followed by two validation cohorts. The first validation was a TMA of 80 ARL, from the AIDS Cancer Specimen Resource. Both TMAs were stained for CD10, BCL6, MUM1, CD20, Ki67, EBER, MYC (by IHC) cut off at 40%, BCL2 (by IHC) cut off 50%, and CD30 (considered positive if any CD30 was expressed on the malignant cells). The third validation cohort was from the County Hospital AIDS Malignancy Project (CHAMP), a prospective database of patients with hematological malignancies and HIV. Of the 100 cases with ARL, only 25 cases were found to have CD30 staining performed, thus only those cases were included. In total, 135 patients diagnosed with ARL were assessed. Cell of origin and germinal (GCB) vs. non-germinal center (NGC) was determined by the Hans algorithm. Statistical differences between groups were analyzed by the fisher exact test. Survival data, when available, was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 135 ARL, 30% (n=41) were CD30+. Ninety-one% of the cohort was male. EBER was 23% positive in the entire cohort (n=29/126). EBER was positive in the CD30+ vs. CD30- population, 59% (N=17) vs 26% (p<0.01). Despite 59% of the CD30+ population being EBER positive, 92% of the population had a NGC phenotype, 2% was germinal, and 5% had a null phenotype (p<0.01). Of the 86 patients that were CD30-, 88% were GC vs. 12% NGC (P<0.01). The CD4+ T-cell count at presentation was higher in the CD30- cohort with a mean CD4+ T-cell count of 234 vs.164 cells/ul (p<0.05), similar to historical studies demonstrating a similar effect in germinal vs. non-germinal center ARL. Ki67 > 80% was also higher in the CD30- vs the CD30+ cohort 75 vs.60%, (p=0.052). Myc, BCL2, and double expressor lymphomas were identified 59 vs. 57%, 59 vs. 57%, and 31 vs. 28%, respectively, in the CD30+ ARL vs. the CD30- population, none were statistically significant. Survival data was only obtained for 56 of the patients. In the patients treated in the combined anti-retroviral era (ART), there was no difference in survival in the CD30+ vs. CD30- population, 74% (n=18) vs. 84% (n=12) at 5 years (p=0.8). In the 15 patients treated in the early ART era, the OS at 5 years was 48% for the CD30+ vs. 52% (p=0.4), the rest were treated in the pre-ART era. Conclusion: CD30+ ARL in this cohort represents 30% of all ARL evaluated, and presents almost exclusively as a non-germinal center phenotype and has a strong correlation with EBV. While no differences in survival were identified in this study, possible due to the small numbers of patients assessed with survival data, historically, NGC ARL have been shown to have poorer outcomes, by 20-30% in studies with da-EPOCH. As such, the need for better therapies, potentially to overcome these poor prognostic factors, should be studied further. Figure 1 Figure 1. Disclosures Reid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator.

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Outcome of R-CHOP or CHOP Regimen for Germinal Center and Nongerminal Center Subtypes of Diffuse Large B-Cell Lymphoma of Chinese Patients

The Scientific World JOURNAL ◽

10.1100/2012/897178 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Ying Huang ◽

Sheng Ye ◽

Yabing Cao ◽

Zhiming Li ◽

Jiajia Huang ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Survival Data ◽

Prognostic Value ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Chinese Patients ◽

First Line ◽

Large B Cell Lymphoma ◽

Large B Cell

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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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 ◽

10.1182/blood.v128.22.3054.3054 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3054-3054

Author(s):

Zohra Nooruddin ◽

Zenggang Pan ◽

Lilyana Gross ◽

Weitzenkamp David ◽

Bradley M. Haverkos ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Board ◽

Post Transplant ◽

Large B Cell Lymphoma ◽

Improved Outcomes ◽

Germinal Center B Cell

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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Immunophenotypic characteristics of Diffuse Large Bcell Lymphoma

Bioresearch Communications ◽

10.3329/brc.v8i1.57043 ◽

2021 ◽

Vol 8 (1) ◽

pp. 1049-1052

Author(s):

SM Mahbubul Alam ◽

Ahmed Khaled

Keyword(s):

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

Molecular Subtype ◽

B Cell Lymphoma ◽

Cell Of Origin ◽

Large B Cell Lymphoma ◽

Germinal Center B Cell ◽

Wide Range ◽

Large B Cell

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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A Novel Autochthonous Mouse Model Serves As a Preclinical Evaluation Platform and Explores Dual BTK and BCL2 Inhibition for Activated B Cell-like Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood-2021-146871 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 712-712

Author(s):

Ruth Flümann ◽

Pascal Nieper ◽

Tim Lohmann ◽

Ilmars Kisis ◽

Martin Peifer ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Clinical Activity ◽

Large B Cell Lymphoma ◽

Gene Sets ◽

Support Research ◽

Privately Held

Abstract Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Both biologically and clinically, DLBCL represents a highly heterogeneous disease. DLBCL has been subdivided into germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCL, on the basis of gene expression profiling, which separates DLBCL according to the presumed cell of origin (COO). This COO-based classifier distinguishes sub-entities displaying distinct biological features, pathogenesis and clinical response to frontline therapy. In addition to this classic transcriptome-based stratifier, recent genomic analyses of human DLBCL samples led to the discovery of partially overlapping genetically-defined DLBCL subsets. A study by Schmitz et al. employed a supervised clustering approach, allowing the classification of ~50% of the cases into four genetically-defined DLBCL subtypes, one of which is being characterized by co-occurring MYD88- and CD79B mutations as well as high expression of BCL2 (termed MCD). In a second approach by Chapuy et al., patient samples were clustered in an unsupervised manner. Also in this study, a cluster with recurrent mutations in MYD88 (specifically p.L265P) and CD79B, as well as gains of 18q (the location of BCL2) was identified (termed C5). We previously reported the formation of B cell lymphoma in mice that were engineered to express Myd88 p.L252P in combination with overexpression of BCL2 (Myd88 p.L252P/wt;R26 LSL.BCL2/wt;Cd19 Cre/wt, abbr. MBC) in a B cell-specific manner. While the developing lesions display many features of human ABC DLBCL, their B220 -/CD138 + immunophenotype reflects plasmablastic characteristics. To refine this mouse model, we incorporated additional C5/MCD lesions by engineering a B cell-specific loss of Prmd1 or Spib overexpression generating Prdm1 fl/fl;Myd88 p.L252P/wt;R26 LSL.BCL2/wt;Cd19 Cre/wt (PPMBC) and Myd88 p.L252P/wt;R26 LSL.BCL2/LSL.Spib;Cd19 Cre/wt (SMBC) compound animals. Both, the B cell-specific loss of Prdm1 and Spib overexpression on the MBC background resulted in a marked reduction of CD138 + cells in the spleens of 10 weeks old animals compared to control (Fig. 1A), accompanied by a decrease in serum immunoglobulins, indicative of a plasma cell differentiation block and in agreement with the reported function of PRMD1 and SPIB as transcription factors regulating plasma cell differentiation. Both PPMBC and SMBC mice developed lymphoma significantly earlier than MBC animals. These tumors largely displayed a B220 +/CD138 - immunophenotype. As transcriptional profiling is the gold standard for differentiation between GCB and ABC DLBCL, we generated germinal center- and activated blood B cell gene sets from healthy donors. We then performed gene set enrichment analyses between SMBC/PPMBC tumors and either MBC or Kmt2d fl/fl;VavP-Bcl2;Cɣ1 Cre/wt (KBC) lymphomas, the latter being reminiscent of human GCB DLBCL. While both PPMBC and SMBC samples were enriched for GCB gene signatures when compared to MBC, they enriched for ABC gene sets in comparison to KBC, potentially suggesting a developmental stage between KBC and MBC lesions (Fig. 1B). We next aimed to employ our PPMBC model of C5 DLBCL as a pre-clinical tool, in order to derive therapeutic approaches for this disease. In this regard, we note BCL2 has emerged as a potential therapeutic target in DLBCL. The BCL2 inhibitor venetoclax produces response rates of ~18% in relapsed/refractory DLBCL (Davids et al., 2017). Similarly, in a phase I/II clinical trial involving 80 patients with relapsed/refractory DLBCL, ibrutinib induced complete or partial remissions in 37% of ABC-DLBCL patients, but in only 5% GCB-DLBCL patients (Wilson et al., 2015). Building on these observations, we asked whether single agent or combined venetoclax and ibrutinib treatment might display pre-clinical activity in the PPMBC setting. Indeed, combination treatment with ibrutinib and venetoclax resulted in a significant survival benefit compared to single compound or untreated animals (Fig. 1C). Given this preclinical activity, we treated 6 relapsed/refractory (r/r) non-GCB DLBCL patients (determined by Hans algorithm) in an off-label setting and observed tumor shrinkage in 5 of 6 patients (Fig. 1D). Thus, our clinical data corroborate our preclinical observations and suggest that combined venetoclax and ibrutinib may display clinical activity in a subset of r/r non-GCB DLBCL. Figure 1 Figure 1. Disclosures Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Calado: Myricx Pharma: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties: Cancer Treatments. WO patent WO 2020/128475 A1 (2020). Pasqualucci: Sanofi: Research Funding; Astra Zeneca: Research Funding. von Tresckow: Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; AstraZeneca: Honoraria, Other: congress and travel support; Kite-Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Chapuy: Gilead: Honoraria; BMS: Honoraria; Regeneron: Consultancy; Gilead Sciences: Research Funding; Astra Zeneca: Honoraria. Reinhardt: CDL Therapeutics: Current holder of individual stocks in a privately-held company; Gilead: Research Funding; Merck: Consultancy; Vertex: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy. OffLabel Disclosure: Treatment of DLBCL patients with ibrutinib and venetoclax.

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The Anti-CD19 Antibody-Drug Conjugate Loncastuximab Tesirine Achieved Responses in Patients with Diffuse Large B-Cell Lymphoma Who Relapsed after Anti-CD19 CAR T-Cell Therapy

Blood ◽

10.1182/blood-2021-153591 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2489-2489

Author(s):

Paolo F. Caimi ◽

Kirit M. Ardeshna ◽

Erin Reid ◽

Weiyun Z. Ai ◽

Matthew A. Lunning ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Antibody Drug Conjugate ◽

Non Hodgkin Lymphoma ◽

Large B Cell Lymphoma ◽

Car T ◽

Principle Investigator ◽

Large B Cell

Abstract Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) that is resistant to chimeric antigen receptor T-cell (CAR-T) therapy have poor outcomes (Chow VA, et al. Am J Hematol. 2019;94:E209-E13). The majority of patients with DLBCL who relapse after CAR-T therapy do so with disease that continues to express CD19 surface antigen (Shah NN, Fry TJ. Nat Rev Clin Oncol. 2019;16:372-85); however, it is unknown whether treatment with CD19-targeted agents is an effective strategy for patients with prior failure of anti-CD19 CAR-T therapy. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) which had encouraging phase 1 antitumor activity and acceptable safety in non-Hodgkin lymphoma (Hamadani M, et al. Blood. 2021;137:2634-2645). In the Phase 2 LOTIS-2 trial (NCT03589469) the efficacy and safety of Lonca was evaluated in patients with relapsed or refractory (R/R) DLBCL after ≥2 lines of systemic treatments (Caimi PF, et al. Lancet Oncol. 2021;22:790-800). The overall response rate (ORR) was 48.3%. The aim of this post-hoc analysis of the LOTIS-2 trial was to investigate the antitumor activity of Lonca in patients with DLBCL relapsed or refractory after CAR-T therapy. Methods: The methodology of the LOTIS-2 trial has been published. Briefly, patients were treated with Lonca (0.15 mg/kg for the first 2 cycles then 0.075 mg/kg for subsequent cycles) administered as a single 30-minute infusion, once every 3 weeks for up to 1 year, or until progressive disease or unacceptable toxicity. Patients with previous anti-CD19 CAR-T therapy were required to have persistent CD19 expression, evaluated by local review of immunohistochemistry of a post-CAR-T biopsy. The primary endpoint was ORR, defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), determined by independent review. Secondary endpoints included overall survival (OS), progression free survival (PFS), and duration of response (DOR). PET/CT imaging was performed 6 and 12 weeks after the first Lonca dose and every 9 weeks thereafter. Response was assessed using the Lugano 2014 criteria. Kaplan Meier survival analysis was performed from initiation of Lonca treatment. Results: The characteristics of 13 patients with DLBCL with disease relapse or progression after anti-CD19 CAR-T therapy are shown in table 1. The median time interval between CAR-T infusion and Lonca treatment was 7 months (range, 45-400 days). Ten (77%) patients received Lonca as the first therapy after CAR-T failure, 3 patients received other treatments prior to Lonca (chemoimmunotherapy [R-GemOx], n = 1; allogenic stem cell transplant, n = 1; chemoimmunotherapy [R-GemOx] followed by venetoclax + bromodomain inhibitor, n =1). The ORR to Lonca was 46.2% (n=6; CR, 15.4% [n = 2]; PR, 30.8% [n = 4]) after a median of 2 cycles (range, 1-9). Of the 6 patients who achieved a response to Lonca, 5 had a previous response to CAR-T and 1 had prolonged, stable disease for >1 year after CAR-T. With a median follow-up of 8 months, the median OS and PFS were 8.2 and 1.4 months, respectively (Figure 1); the 1-year OS estimate was 33.3%. The median DOR to Lonca was 8 months. Conclusions: Lonca achieved a response in 6 out of 13 patients who had failed prior CAR-T therapy. Five out of 6 responding patients had previously presented at least a partial response after CAR-T therapy. These data suggest that in patients without CD19 antigen loss, repeat therapy with another agent targeting this antigen can result in disease control. Prior response to anti-CD19 therapy may be associated with subsequent response to a second anti-CD19 treatment. Further studies are needed to confirm the feasibility and value of repeated anti-CD19 treatments in patients with B-cell non-Hodgkin lymphoma. Funding: This study was funded by ADC Therapeutics; medical writing support was provided by CiTRUS Health Group. Figure 1 Figure 1. Disclosures Caimi: Amgen Therapeutics.: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Honoraria. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding; Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees. Reid: Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator, Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Lunning: Myeloid Therapeutics: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Verastem: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Kite, a Gilead Company: Consultancy; TG Therapeutics: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Solh: ADCT Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; Partner Therapeutics: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Hamadani: Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau.

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Therapeutic Targeting of the Bcl-6: p53 Axis with Histone Deacetylase Inhibitors in Diffuse Large B-Cell Lymphoma,

Blood ◽

10.1182/blood.v118.21.3733.3733 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3733-3733 ◽

Cited By ~ 1

Author(s):

Jennifer E Amengual ◽

Matko Kalac ◽

Luigi Scotto ◽

Patrick A Sleckman ◽

Enrica Marchi ◽

...

Keyword(s):

Tumor Suppressor ◽

B Cell ◽

Cell Lines ◽

Germinal Center ◽

Research Funding ◽

Cell Lymphoma ◽

Hdac Inhibitors ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Abstract 3733 Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's Lymphoma. Despite advances in treatment, 1/3 of patients die from their disease. Gene expression profiling has delineated three subtypes with different genetic features known to be prognostic: the Activated B-cell (ABC), Germinal Center (GC), and grey zone types. For example, ABC DLBCL is addicted to NFkB over-expression. The oncogene, BCL6, encodes a transcription factor that functions as a transcriptional repressor within normal germinal center B-cells. Constitutive activation of Bcl-6 leads to GC-type DLBCL by turning off genes expressing cell cycle dependent kinase inhibitors, and essential tumor suppressor genes, like p53. There is a critical inverse relationship between Bcl-6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl-6 is required for maintaining its effects as a transcriptional repressor. Conversely, acetylation of p53 is activating when class III histone deacetylases (HDAC), also known as sirtuins, are inhibited by drugs such as niacinamide. HDAC inhibitors are presently approved for T-cell lymphoma and may require the targeting of additional pathways to be effective in B-cell lymphomas. Trichostatin A and niacinamide modulate Bcl-6 in lymphoma cell lines. One therapeutic strategy that could favorably shift the relationship between oncogenes and tumor suppressors is the pharmacologic modification of Bcl-6 and p53 using HDAC inhibitors. Eight DLBCL cell lines were screened (4 ABC: Su-DHL2, HBL-1, OCI-Ly10, RIVA; 4 GC:OCI-Ly1, OCI-Ly7, Su-DHL6, Su-DHL4) with four class I/II HDAC inhibitors (romidepsin, vorinostat, panobinostat and belinostat) in combination with niacinamide (sirtuin inhibitor) at two dose levels each at three time points. Cell growth inhibition was measured by luminescence cell viability and apoptosis flow cytometry assays. Synergy was measured by the relative risk ratio (RRR) calculation where values <1 represent synergy. Synergy was achieved in significantly greater number and intensity in the GC versus ABC cell lines. Specifically, romidepsin in combination with niacinamide achieved the greatest synergy. To analyze mechanism of action, DLBCL cell lines were treated with combinations of class I/II HDAC inhibitors and niacinamide. Cells of both GC and ABC subtypes treated with the combination resulted in increased acetylation of p53, and increased p21 and BLIMP-1 content compared to controls. These results did not correlate with cytotoxicity as the ABC cell lines did not achieve the same synergy as the GC cells. GC cells treated with the same combinations resulted in acetylation of Bcl-6 compared with controls as measured by immunoprecipitation and Western blotting assays; ABC cells do not express Bcl-6. This finding correlated with cytotoxicity implying that a rational second pathway must be targeted to shift the balance between oncogene and tumor suppressor activity to achieve effective cell kill. p300 content was also increased suggesting that treatment with HDAC inhibitors recruit or upregulate its production and activity leading to increased acetylation. Using a novel double transgenic mouse model of aggressive spontaneous B-cell lymphoma (l-myc overexpressing crossed with CD19-tagged mCherry luciferase), in vivo effects of the drug combination were studied. These mice express equal basal amounts of Bcl-6 and p53 as GC cell lines. Mice treated with niacinamide 20 mg/kg and romidepsin 2.3mg/kg IP for 5 hours achieved increased acetylation of Bcl-6 and p53, and accumulation of p21 and BLIMP1 compared with controls. Importantly, mice treated with the combination of niacinamide 40 mg/kg and romidepsin 2.3 mg/kg IP achieved decreased tumor burden as measured by bioluminescence signal intensity compared to mice treated with each drug alone and controls. Presently, we are translating these concepts and observations in a proof-of-principle phase I trial evaluating the safety of vorinostat plus niacinamide in lymphoid malignancies. By targeting the specific pathogenetic features of DLBCL, it may be possible to tailor future treatment platforms for discrete subtypes of DLBCL. Disclosures: Off Label Use: The drugs evaluated are not approved for use in DLBCL. O'Connor:Celgene: Consultancy, Research Funding; Merck: Research Funding; Novartis: Research Funding; Spectrum: Research Funding.

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Safety and Efficacy Of Obinutuzumab (GA101) Plus CHOP Chemotherapy In First-Line Advanced Diffuse Large B-Cell Lymphoma: Results From The Phase 2 Gather Study (GAO4915g)

Blood ◽

10.1182/blood.v122.21.1820.1820 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1820-1820 ◽

Cited By ~ 12

Author(s):

Andrew D Zelenetz ◽

Mehrdad Mobasher ◽

Luciano J Costa ◽

Ian Flinn ◽

Christopher R. Flowers ◽

...

Keyword(s):

Stock Options ◽

Research Funding ◽

Cell Lymphoma ◽

Dose Intensity ◽

B Cell Lymphoma ◽

Cell Of Origin ◽

First Line ◽

Large B Cell Lymphoma ◽

Direct Cell ◽

Anti Cd20

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and has an aggressive natural history. Rituximab (R), a type I anti-CD20 monoclonal antibody (mAb), plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), has improved patient (pt) survival and established a new standard of care. Nonetheless, 35%–40% of pts will relapse during/after first-line treatment and of these, <25% are cured with second-line therapy. Thus, there is a medical need to further improve cure rates, particularly in the first-line setting. Obinutuzumab (GA101; G) is a novel, glycoengineered type II anti-CD20 mAb with increased direct cell death and antibody-dependent cell-mediated cytotoxicity relative to R. Clinical activity of G in R/R DLBCL was confirmed in phase 1/2 studies. Phase 1b studies in indolent lymphoma found G-CHOP to be safe and effective. GATHER is a phase 2, open-label, multicenter study examining the safety and efficacy of G-CHOP in the first-line treatment of advanced DLBCL. Methods Pts with untreated CD20-positive DLBCL, clinical stage (CS) IIX (mass>7.5 cm), III, and IV, and International Prognostic Index (IPI) ≥2 (or any IPI if bulky disease) with measurable disease were treated with standard CHOP (day [d]1, 21-day cycles [c] 1–6) and G (1000 mg intravenously [IV]; d1, 21-d c 1–8 plus additional doses on d8 and d15 of c1). Prophylactic GCSF was not mandatory but allowed per ASCO guidelines. After the safety of regular-infusion G was established in the first 20 pts, Shorter Duration of Infusion (SDI) of G (SDI 120 min and SDI 90 min) was tested. Disease responses were assessed using FDG-PET and CT scans, according to the Cheson 2007 criteria, 6–8 weeks after completion of treatment. Efficacy endpoints were investigator- and independent central review facility-assessed overall response rate (ORR) and complete response (CR). G-CHOP Safety was measured by the incidence and severity of adverse events (AEs) and serious AEs and SDI safety by the incidence of grade (gr) 3/4 infusion-related (IR) AEs (any G-related AE during or within 24 h after infusion). Cell of origin and prognostic marker assessment was performed using mRNA (fluidigm microfluidic dynamic arrays) from baseline tumor samples. Results Eighty pts were enrolled in 13 months: 59% males; median age 60.5 years (range, 24–80); CS IIX 14%, CS III 35%, CS IV 51%; IPI low risk/low-intermediate risk 54%, high-intermediate risk/high risk 46%. Most AEs were gr 1/2. Gr ≥3 and serious AEs with highest frequency are summarized (Fig). IR AEs were in 51 pts (64%), most commonly in c1d1 (48 pts). The majority of IR AEs were gr 1/2; only 2 gr 3 IR AEs occurred, both in c1 d1. There were no gr ≥4 IR AEs. 288 SDI infusions (120-min in 24, 90-min in 264) were administered and associated with 3 gr 1/2 IR AEs and no gr ≥3 IR AEs. G-CHOP was delayed >5 d in 3/79 (4%) in c2, 7/78 (9%) in c3, 8/78 (10%) in c4, 5/77 (6.5%) in c5, and 7/74 (9.5%) in c6. Early treatment discontinuation occurred in 11 pts; 5 for failure to resolve an AE in ≤14 d. The median overall dose intensity of chemo agents across all 6 cycles was 100% (range 17%–104%). The ORR was 66/80 (83%) (44/80 [55%] CR, 22/80 [28%] PR); 1 pt was not evaluable, and 4 had missing data. Nine pts had progressive disease at the end of treatment, and there were 3 deaths from disease progression. Response assessment by an independent central review facility and analysis of efficacy in prognostic molecular subgroups (including cell of origin) will be presented. Conclusions G-CHOP was safely administered to pts with newly diagnosed DLBCL. Dose intensity of CHOP was maintained throughout treatment. Manageable, mild, and moderate IR AEs were frequent in the first cycle of G, but all pts continued the infusion after symptom resolution. Nonetheless, SDI of G was safe for all eligible pts. Neutropenia and febrile neutropenia appear to be the most important AEs. However, these could be addressed by prophylactic administration of G-CSF support. Preliminary efficacy is promising, but it is too early to evaluate progression-free and overall survival. The data provide further rationale for the ongoing randomized phase 3 study of G-CHOP vs R-CHOP in DLBCL. NCT01414855 Disclosures: Zelenetz: Cancer Genetics: Scientific Advisor, Scientific Advisor Other; Genentech, GSK, Roche: Research Funding; GSK, Celgene, Cephalon, Gilead, Seattle Genetics, Sanofi-Avenits USA: Consultancy. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Mobasher:Roche: Ownership of stock options, Ownership of stock options Other; Genentech: Employment. Costa:Genentech: Research Funding. Flinn:Genentech: Research Funding. Flowers:Celgene, Genentech, Oncology: Consultancy; Abbott, Celgene, Millennium/Takeda, Sanofi-Aventis, Spectrum, Janssen: Research Funding. Sandmann:Roche: Stock options, Stock options Other; Genentech, Inc.: Employment. Trunzer:F. Hoffmann-La Roche: Employment, Stock ownership Other. Vignal:F. Hoffmann-La Roche: Employment, Stock ownership Other.

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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 ◽

10.1200/jco.2012.30.15_suppl.e18517 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18517-e18517

Author(s):

Yabing Cao ◽

Ying Huang ◽

Sheng Ye ◽

Tongyu Lin

Keyword(s):

B Cell ◽

Germinal Center ◽

Survival Data ◽

Prognostic Value ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Germinal Center B Cell ◽

Large B Cell

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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Low absolute peripheral blood CD4+ T-cell count predicts poor prognosis in R-CHOP-treated patients with diffuse large B-cell lymphoma

Blood Cancer Journal ◽

10.1038/bcj.2017.37 ◽

2017 ◽

Vol 7 (4) ◽

pp. e558-e558 ◽

Cited By ~ 4

Author(s):

Y Kusano ◽

M Yokoyama ◽

Y Terui ◽

N Nishimura ◽

Y Mishima ◽

...

Keyword(s):

B Cell ◽

Peripheral Blood ◽

Blood Lymphocyte ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cd4 T Cell ◽

Large B Cell Lymphoma ◽

Cd4 T Cell Count ◽

Large B Cell

Abstract The absolute peripheral blood lymphocyte count at diagnosis is known to be a strong prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but it remains unclear as to which peripheral blood lymphocyte population is reflective of DLBCL prognosis. In this cohort, 355 patients with DLBCL treated with R-CHOP from 2006 to 2013 were analyzed. The low absolute CD4+ T-cell count (ACD4C) at diagnosis negatively correlated with the overall response rate and the complete response rate significantly (P<0.00001). An ACD4C<343 × 106/l had a significant negative impact on the 5-year progression-free survival and the overall survival as compared with an ACD4C⩾343 × 106/l (73.7% (95% confidence interval (CI)=66.7–79.5) versus 50.3% (95% CI=39.0–60.6), P<0.00001 and 83.3% (95% CI=77.1–88.0) versus 59.0% (95% CI=47.9–68.5), P<0.00000001, respectively). Multivariate analysis revealed that the ACD4C was an independent prognostic marker (hazard ratio=2.2 (95% CI=1.3–3.7), P<0.01). In conclusion, a low ACD4C at diagnosis served as an independent poor prognostic marker in patients with DLBCL.

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Combination of Nivolumab, Lenalidomide and Rituximab in Relapsed/Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma: Results from a Dose-Escalation Cohort

Blood ◽

10.1182/blood-2019-129634 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4100-4100

Author(s):

Tarsheen Sethi ◽

Alexandra E. Kovach ◽

Emily F Mason ◽

Heidi Chen ◽

Tamara Moyo ◽

...

Keyword(s):

B Cell ◽

Dose Escalation ◽

Germinal Center ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Grade 3 ◽

Large B Cell

Background: Ten to 15% of diffuse large B cell lymphoma (DLBCL) patients exhibit primary refractory disease (nonresponse or relapse within 3 months of therapy) and an additional 20-25% relapse following initial response. There is an unmet need for effective therapeutic regimens in relapsed/refractory (R/R) DLBCL. Lenalidomide is an immune modulator that reverses T cell dysfunction and also inhibits the NFκB pathway, which is constitutively active in non-germinal center (non-GCB) DLBCL. Lenalidomide and nivolumab, an anti-PD-1 antibody, each have single agent activity in R/R DLBCL. Here, we report the results of the dose-escalation cohort of this investigator-initiated, single-arm open-label study of the combination of nivolumab, lenalidomide and rituximab (NiLeRi) in R/R non-GCB DLBCL. Methods: Adult patients with R/R non-GCB DLBCL, as determined by the Hans algorithm, with adequate organ function and an ECOG performance status of ≤2 were eligible for the study. The primary objective was to evaluate the safety of NiLeRi, and determine the maximum tolerated dose (MTD) of lenalidomide in combination with fixed doses of rituximab and nivolumab, using a 3+3 dose escalation design. The secondary objectives were to determine efficacy in terms of overall response rate (ORR), progression free survival (PFS), and overall survival (OS) of patients treated with NiLeRi. All patients received nivolumab IV 3 mg/kg on days 1 and 15 and rituximab IV 375mg/m2 on day 1 of each 28-day cycle. Lenalidomide was initiated at 5 mg po once daily on days 1-21. Additional planned dose levels were 10 mg, 15 mg and 20 mg. Patients were evaluable for toxicity if they received all doses of nivolumab and rituximab and at least 16 doses of lenalidomide during cycle 1 or if they experienced a dose limiting toxicity (DLT), regardless of the number of doses. NiLeRi was given for 8 cycles and patients with partial response could receive lenalidomide and nivolumab for an additional 4 cycles. Response was assessed by PET-CT after 2, 5 and 8 cycles and defined by Lugano criteria. Results: Six patients with non-GCB subtype of DLBCL were enrolled in this study. The median age was 60.5 years (range 28-79), and 5 patients were male. The median number of prior lines of therapy was 4 (range 2-5), and the median IPI score was 3. None of the patients had bone marrow involvement. One patient each had been treated with autologous stem cell transplant (Auto-SCT) and CAR-T cell therapy. One patient withdrew consent before completing cycle 1 and was not evaluable for safety or efficacy. Safety: Five out of the six enrolled patients were evaluable for safety. All patients received lenalidomide 5 mg dose. Two patients experienced DLTs (grade 3 rash) resulting in lenalidomide discontinuation during cycle 2. The most common grade 3/4 toxicities were fatigue (20%), neutropenia (60%), thrombocytopenia (40%), and rash (40%). A total of 3 patients experienced grade 1/2 diarrhea and elevated liver enzymes. One patient experienced a grade 1 infusion reaction with rituximab. Efficacy: Patients who completed at least 1 cycle of therapy were evaluable for response, and this included 5 out of the 6 enrolled patients. The ORR and complete response (CR) rate were both 40%. Patients who responded did so early, with one patient achieving CR after 2 cycles and another patient achieving CR after 5 cycles. The best response seen in patients with primary refractory disease was PR. At a median follow up of 9.5 months, median PFS was 8.4 months (95% CI; 4.3 to not reached), and median OS was not reached. Discussion: This is the first study reporting the safety results of the combination of lenalidomide, nivolumab and rituximab in non-Hodgkin lymphoma. Rash was the most common DLT, limiting dose escalation of lenalidomide above 5mg in this cohort of patients. Two patients experienced durable CR early in the study after 2 and 5 cycles, respectively. This ORR and CR rate of 40% each in this small cohort of patients who had relapsed after multiple prior lines of therapy is encouraging. Correlative studies, including whole exome sequencing of patient samples, are underway, in an attempt to explore predictive markers for response and toxicity. Figure. Disclosures Mason: Sysmex: Honoraria. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership; Pfizer: Equity Ownership; Novo Nordisk: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership. Reddy:Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; KITE Pharma: Consultancy. OffLabel Disclosure: Nivolumab and lenalidomide are not FDA approved for use in diffuse large B cell lymphoma

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