scholarly journals Longitudinal Analyses of Diagnostic-Relapse Biopsies of Diffuse Large B Cell Lymphoma Reveal a Poor Risk Subset of ABC Patients Based on the Expression of a 30 Gene Panel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2769-2769
Author(s):  
Findlay Bewicke-Copley ◽  
Koorosh Korfi ◽  
Shamzah Araf ◽  
Emil Arjun Kumar ◽  
Thomas E C Cummin ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Gene Mutations ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma

Background: Although diffuse large B cell lymphoma (DLBCL) can be cured using immuno-chemotherapy, 40% of patients experience relapse or refractory disease. Large-scale profiling studies have mainly focused on DLBCL at diagnosis, resolving different outcome groups based on gene expression (e.g. cell-of-origin (COO) or molecular high grade), MYC/BCL2 translocations (double-hit lymphoma) or gene mutations and copy number aberrations (Schmitz et al, NEJM 2018; Chapuy et al, NatureMedicine 2018). In comparison, longitudinal studies have been hindered by the limited availability of sequential biopsy samples. To date, the relapse-specific gene mutations identified are limited and inconsistent across studies. In our study, we have focussed attention on the changes in gene expression profile (GEP) accompanying DLBCL relapse. Methods: We retrospectively collected archival paired diagnostic/relapse formalin fixed paraffin embedded tumor biopsies from 38 de novo DLBCL patients collected from multiple UK sites treated with rituximab-based immuno-chemotherapy, where partial or complete remission was reported following treatment. COO classification was performed by the Lymph2Cx assay on NanoString to distinguish activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit was used to measure the expression levels of > 20,000 genes on the paired samples. Results: COO remained stable from diagnosis to relapse in 17 ABC-ABC pairs, 11 GCB-GCB pairs and 4 unclassified (UNC)-UNC pairs. Frank COO switching was observed in 6 cases (1 ABC-GCB, 2 ABC-UNC, 2 GCB-UNC, 1 UNC-ABC). Pairs with stable COO were taken forward for further analysis. Gene expression analysis using the limma R package identified 163 and 136 genes as differentially expressed (DE) (p <= 0.01 and absolute log2FC > 1) between the diagnostic and relapse biopsies in ABC and GCB tumors respectively, with only a one gene overlap. Gene Set Enrichment Analysis further suggested that ABC and GCB relapses are mediated via different mechanisms, with tumor growth and proliferation signatures enriched in ABC relapses, whilst adaptive immunity-related signatures accompanied GCB relapses. Next, we aimed to utilise our relapse-specific genes to identify outcome predictors at diagnosis using publicly available GEP datasets. In order to increase our discovery power and accuracy, a larger set of DE genes from the paired differential analysis (796 genes in ABC pairs and 387 from GCB pairs) were selected (p <= 0.05) and subsequently used in a training cohort (GEP from Reddy et al, Cell 2017). The Prediction Analysis for Microarrays R (PAMR) algorithm identified a 30-gene signature within DE genes from ABC pairs (Fig1.A), capable of separating the 249 ABC cases into 136 low and 113 high-risk cases with significantly inferior overall survival (Hazard Ratio (HR)=1.89, log-rank p=0.0017, measure of goodness-of-fit C-index=0.71; Fig1.B). No equivalent signature was found in the GCB cases using this approach. The prognostic significance of this 30-gene discriminator was successfully validated using a linear predictor in two independent GEP datasets: 1) a population-based cohort (Lenz et al, NEJM 2008) with 93 R-CHOP-treated ABC cases identifying 47 low and 46 high-risk cases (HR=1.92, p=0.046, C-index=0.77; Fig1.C) and 2) a clinical trial dataset (REMoDL-B, Davies et al, Lancet Oncol 2019) with 255 ABC cases identifying 110 low and 145 high-risk ABC cases (HR=1.95, p=0.0051, C-index=0.70; Fig1.D). Conclusions: Here we describe a 30-gene discriminator in ABC-DLBCL, derived from genes differentially expressed between diagnosis and relapse, that allowed the definition of clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis. The clinical translation of such a tool may be useful to guide therapy for this unfavourable subgroup of ABC-DLBCLs. Validation of this signature is currently underway in additional datasets and further study is required to understand the contribution of these genes in DLBCL pathology. Disclosures Korfi: Roche: Consultancy. Burton:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rule:TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Crosbie:Janssen: Honoraria. Scott:Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Roche/Genentech: Research Funding. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Acerta Pharma: Honoraria, Research Funding; ADCT Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Okosun:Gilead Sciences: Honoraria, Research Funding. Johnson:Epizyme: Honoraria, Research Funding; Novartis: Honoraria; Kite: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Boehringer Ingelheim: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Incyte: Honoraria. Fitzgibbon:Epizyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Speakers Bureau.

A Phase III Study Of Enzastaurin In Patients With High-Risk Diffuse Large B Cell Lymphoma Following Response To Primary Treatment: The Prelude Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 371-371 ◽  
Author(s):  
Michael Crump ◽  
Sirpa Leppä ◽  
Luis E Fayad ◽  
Je-Jung Lee ◽  
Alice Di Rocco ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background Despite improvements in outcome following the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-CHOP), patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and International Prognostic Index (IPI) scores of 3-5 at diagnosis have a poor outcome. Enzastaurin is a potent inhibitor of PKCβ, a component of the B-cell receptor signaling complex, with preclinical activity and clinical activity in a phase II trial in patients with relapsed DLBCL, providing the rationale for this study in the primary therapy setting. Methods PRELUDE was a multi-national, randomized, double-blinded, placebo-controlled study. Patients were required to have a histologic diagnosis of DLBCL, pre-treatment IPI score ≥3, and a complete response (CR) or CRu by International Working Group Criteria, or a negative FDG-PET scan after 6–8 cycles of R-CHOP. Patients were randomly assigned in a 2:1 ratio to receive either enzastaurin 500 mg daily or an identical placebo as maintenance therapy, for a planned treatment duration of 3 years. The primary endpoint was DFS, defined as lack of disease progression or death. Assuming a 2-year DFS rate in the control group of 70%, the primary analysis had 80% power to detect a HR of 0.67, eg, a 2-year DFS rate of 79% in the enzastaurin group. Secondary endpoints included overall survival (OS) and event-free survival (EFS). Data were analyzed 3 years after the last enrolled patient initiated treatment. Results From May 2006–April 2010, 758 patients were enrolled (enzastaurin, n=504; placebo, n=254). Median age at enrollment was 64 years (range 21-89); at diagnosis, 65% of patients had stage IV disease, 48% had B symptoms, and 25% had a mass >10 cm; baseline disease and patient characteristics were well balanced between treatment arms. Fifty-seven percent had a negative PET scan following completion of R-CHOP. Median follow-up time for all patients was 48 months (range 0.03–80). At the time of analysis, 209 events had occurred. The DFS HR for enzastaurin vs. placebo was 0.92 (95% CI: 0.69, 1.22; 2-sided log-rank p=0.54). DFS at 24 and 48 months were 79% and 70% for the enzastaurin arm, and 75% and 71% for placebo, respectively. OS at 24 and 48 months was 87% and 81% for enzastaurin, and 89% and 82% for placebo; HR for enzastaurin vs. placebo was 1.04 (95% CI: 0.74, 1.47; 2-sided log-rank p=0.81). Percent of ITT population patients on therapy at 12, 24, and 36 months was 70.6%, 60.6%, and 20.1% for enzastaurin; 72.3%, 60.6%, and 22.1% for placebo. Biomarker subgroup analysis was performed and will be available at time of presentation. Treatment emergent AEs (all grades) that were possibly study drug-related and significantly different between enzastaurin and placebo included chromaturia (18.5% vs. 0.4%), QTc prolongation (10.8% vs. 3.6%), and diarrhea (10.3% vs. 2.8%). There were no significant differences in number of patients with at least 1 grade 3 or higher AE between treatment arms. No significant differences were observed in the frequency of deaths while on therapy. Conclusion Enzastaurin did not improve DFS, EFS, or OS in patients with high-risk DLBCL and CR following R-CHOP treatment. Disclosures: Crump: Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Leppä:Eli Lilly: Research Funding. Ogura:Eli Lilly: Research Funding. Rifkin:Millenium, Celgene, ONYX: Membership on an entity’s Board of Directors or advisory committees. Mackensen:Eli Lilly: Consultancy. Offner:Eli Lilly: Membership on an entity’s Board of Directors or advisory committees. Smith:Genentech, Celgene, Spectrum, Seattle Genetics, Gilead, Amgen/Micronet: Consultancy. Tobinai:Eli Lilly: Research Funding. Hahka-Kemppinen:Eli Lilly: Employment. Thornton:Eli Lilly: Employment. Shi:Eli Lilly: Employment. Lin:Eli Lilly: Employment. Kahl:Genentech: Consultancy. Savage:Eli Lilly: Consultancy.

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.

scholarly journals Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 96-96 ◽  
Author(s):  
Dahlia Sano ◽  
Loretta J. Nastoupil ◽  
Nathan H. Fowler ◽  
Luis Fayad ◽  
F. B. Hagemeister ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Age Groups ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

Phase 1b/2a Open-Label, Multiple-Dose, Dose-Escalation Study To Evaluate The Safety and Tolerability Of Intravenous Infusion Of SNS01-T In Patients With Relapsed Or Refractory Multiple Myeloma, Mantle Cell Lymphoma, Or Diffuse Large B Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1950-1950 ◽  
Author(s):  
John A Lust ◽  
Charles Barranco ◽  
Saad Z Usmani ◽  
Frits van Rhee ◽  
Mehdi Hamadani ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Pro Inflammatory Cytokines

Abstract Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, apoptosis, and inflammation, and is the only known protein to be modified by hypusination. Hypusinated eIF5A, the predominant form of eIF5A in cancer cells, is involved in cell survival and activation of inflammatory pathways. In contrast, accumulation of the unhypusinated form of eIF5A is associated with apoptosis and mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic. SNS01-T was designed to treat B-cell cancers and consists of two active components: a plasmid DNA expressing the pro-apoptotic eIF5AK50R under the control of a B cell-specific promoter, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced cellular delivery. The mode of action of SNS01-T is siRNA-mediated inhibition of hypusinated eIF5A and simultaneous over-expression of pro-apoptotic eIF5AK50R to induce cell death. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. The safety and tolerability of intravenous administration of SNS01-T is being investigated in a first-in-human Phase1b/2a study in patients with relapsed or refractory multiple myeloma (MM), mantle cell lymphoma (MCL) or diffuse large B cell lymphoma (DLBCL). Eligible patients are being enrolled sequentially into four cohorts at increasing doses. Each patient receives an intravenous infusion of SNS01-T twice weekly for 6 consecutive weeks. Eligible patients must have been diagnosed with MM according to IMWG criteria, or with MCL or DLBCL with histologic confirmation. Patients also must have measurable disease, have relapsed or refractory disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include analysis of pharmacokinetics, immunogenicity, pro-inflammatory cytokines, and therapeutic efficacy. The required 3 patients per cohort have completed the dosing schedule in cohorts 1 and 2 from a total of 10 patients enrolled (9 patients with MM and 1 with DLBCL). Of the ten patients enrolled, four completed the full treatment period, two did not complete dosing but were evaluable for safety, and four (three in cohort 1 and one in cohort 2) discontinued treatment after fewer than 8 doses and were not evaluable. There were no drug-related serious adverse events or dose limiting toxicities in either cohort 1 or 2. In cohort 1 (0.0125 mg/kg SNS01-T), two of three evaluable patients did not progress on treatment and were considered stable at week 3 and week 6, the end of the dosing regimen. The third patient progressed after receiving 10 of the 12 doses and was evaluable for safety. In cohort 2 (0.05 mg/kg), 3 patients (2 with MM and 1 with DLBCL) were evaluable for safety. Stabilization of serum monoclonal protein levels was observed in one MM patient of cohort 2. Two patients (1 with MM and 1 with DLBCL) progressed after receiving 8 of the 12 doses and were evaluable for safety. Results from ongoing pharmacokinetic studies, immunogenicity studies, and quantification of pro-inflammatory cytokines will be discussed. The planned dose levels for the third and fourth groups are 0.2 and 0.375 mg/kg, respectively. The results to date of this first-in-human clinical trial indicate that SNS01-T can be administered safely and the MTD has not yet been reached (Clinical Trials.gov Identifier: NCT01435720). Disclosures: Barranco: Senesco Technologies: Consultancy. Usmani:Celgene, Onyx, Millenium: Consultancy, Research Funding, Speakers Bureau. van Rhee:Jansen&Jansen: Research Funding. Thompson:Senesco Technologies: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Taylor:Senesco Technologies: stock options Other. Dondero:Senesco Technologies: Employment. Browne:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Siegel:Celgene, Millenium, Onyx (same for all): Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Ibrutinib for Transformed Lymphoma; A Report of 4 Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5115-5115
Author(s):  
Amy Sharma ◽  
Sadia Riaz ◽  
Jonathan E. Kolitz ◽  
Jacqueline C. Barrientos ◽  
Steven L Allen
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large Cell Lymphoma ◽  
Large B Cell

Abstract Introduction Large cell lymphoma transformed from an indolent lymphoproliferative disorder typically carries a worse prognosis than de novo diffuse large B cell lymphoma. When transformation to large cell lymphoma occurs in CLL (Richter's syndrome), traditional anthracycline or platinum based therapy is associated with a median survival of <12 months. Better, more targeted therapies are needed. We describe 4 patients with transformation to large cell lymphoma who responded to ibrutinib. Cases: Patient A, age 68 at transformation, was a 64 year old male at diagnosis with CLL Rai stage 1. He was initially asymptomatic with a performance status of 0. 4 years later he developed dyspnea on exertion after one block and was found to have a left pleural effusion with diffuse lymphadenopathy with increased PET avidity. Biopsy of a supraclavicular node was positive for extracavitary primary effusion lymphoma, HHV8+, CD5-, CD10-. Patient was given R-CHOP x 6 cycles; he relapsed after 18 months and was given ibrutinib 560mg daily with monthly rituximab x 6 and achieved a PR with reversion to CLL. He is currently continuing ibrutinib in this remission for 10+ months. Patient B, age 90 at transformation, was a 68 year old female at diagnosis of CLL, Rai stage 0. She developed stage III CLL 18 years after diagnosis, was treated with BR x 6 cycles. 2 years later she developed Richter's transformation which was CD10+. Although she achieved a PR after 4 months of ibrutinib 560mg with monthly rituximab, her PS was 4 and she was transferred to hospice and expired 4.5 months after initiating ibrutinib/rituximab. Patient C, age 87 at relapse, was a 73 year old male at diagnosis when he originally presented with stage 1 DLBCL transformed from marginal zone lymphoma. He had 3 cycles of R-CHOP and RT to involved area and was disease free for 14 years until he had worsening thrombocytopenia. This was monitored for 3 years until age 87 when CT/PET showed increasing SUV in multiple lymph nodes and the spleen. Biopsy showed diffuse large B cell lymphoma, CD10-. He was started on ibrutinib 560mg with monthly rituximab x 6. He achieved a CR by CT/PET except for persistent splenic disease. He underwent splenectomy and continues in CR on ibrutinib at 9+ months. Patient D is an 83 year old female with large cell transformation from marginal zone lymphoma at diagnosis. She had stage IV disease with large cells involving pleural fluid and bone marrow. She was CD10-. She received R-CHOP x 3 with progressive disease. At that time ibrutinib 560mg alone was initiated. She has a CR based on recent CT/PET findings and is continuing ibrutinib at 18+ months. Conclusion: All of the above patients responded to ibrutinib given with or without rituximab with symptomatic and objective remissions; all of the CD10 negative cases are alive and still responding 9-18 months after initiating therapy. Studies examining the efficacy of ibrutinib in diffuse large B cell lymphoma are underway. This report supports the need for further study of ibrutinib in the transformed setting, particularly in the elderly where patients may not be appropriate for aggressive therapies. Disclosures Off Label Use: Ibrutinib was used to treat transformed large cell lymphoma.. Kolitz:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Barrientos:Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Allen:Millennium: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Equity Ownership; Onconova: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees.

Ibrutinib in Combination with R-Gemox-D in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: Phase II Clinical Trial of the Geltamo Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Beatriz Rey Búa ◽  
Ana Jiménez Ubieto ◽  
Jose Javier Sanchez Blanco ◽  
Pau Abrisqueta ◽  
Antonio Gutierrez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
New Combination ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Relapsed Disease

BACKGROUND Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), non-candidates for autologous stem-cell transplantation (ASCT), have few treatment options. Ibrutinib is an oral Bruton's tyrosine kinase inhibitor that has shown increased antitumor activity in patients with DLBCL of different subtype from germinal center B-cell like (non-GCB). In the present phase II clinical trial (NCT02692248), we investigated the efficacy and toxicity of the combination of Ibrutinib with the R-GEMOX-D regimen (rituximab, gemcitabine, oxaliplatin and dexamethasone), in patients with non- GCB DLBCL. METHODS We included patients with histological diagnosis of non-GCB DLBCL (according to Hans algorithm), with relapsed or refractory disease after at least 1 line of immunochemotherapy and non-candidates for ASCT. Patients received an induction treatment consisting of 6 (in case of complete remission [CR] after cycle 4) or 8 (in case of partial response [PR] or stable disease after cycle 4) cycles of R-GEMOX-D at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles, and the secondary objectives were: CR rate, progression-free survival (PFS), overall survival (OS) and toxicity. Analyses were performed in the intention to treat population (data cut-off 10th April 2020). RESULTS Sixty-four patients (59.4% male) were included between March 2016 and November 2018. Median age was 67 (25-84) years. Patients had received a median of 2 previous lines of treatment; 56.3% were refractory (&lt;PR) to the last regimen, whereas 43.7% had relapsed disease after a previous CR. Eleven (17.2%) patients had received a previous ASCT. IPI at study entry was 0-1, 2-3, and 4-5 in 9.4%, 67.2%, and 20.3% of patients, respectively (missing data in 2 patients). Of the 64 patients who started study treatment, 44 and 35 patients, respectively, were evaluated for response after 4th cycle and at the end of induction. Twenty-four (37%) patients started maintenance with ibrutinib, 7 of whom continue or have completed it. Causes of withdrawal from the trial (n=57) were progression (n=40), adverse event (n=6), transplantation (n=5), withdrawal of consent (n=3) and other causes (n=3). ORR and CR rate after 4th cycle were 53.2% and 35.9%, respectively. Patients with relapsed disease had significantly higher ORR (67.9% vs 41.7%, p=0.037) and CR rate (57.1% vs 19.4%, p=0.002) than patients with refractory disease. At the end of induction, ORR and CR rate were 35.9% and 29.7%, respectively. After a median follow-up of 22 months (range: 1 to 39 months), the estimated 2-year PFS and OS were 21% and 25%, respectively (Figure 1A and 1B), being significantly better in patients with relapsed disease (Figure 1C and 1D). In the multivariate analysis, status of lymphoma at study entry significantly influenced PFS (HR 0.45; 95% CI 0.25-0.82; p=0.009) and OS (HR 0.51; 95% CI 0.27-0.94; p=0.0031) independently from the IPI and the number of previous treatment lines. The most frequent adverse events (AE) (present in at least 20% of patients) were thrombocytopenia (67.2%), diarrhea (51.6%), neutropenia (46.9%), anemia (37.5%), fatigue (34.4%), nausea (29.7%) and paresthesia (20.3%). The most frequent grade 3-5 AE (present in at least 10% of patients) were thrombocytopenia (46.9%), neutropenia (35.9%), diarrhea (15.6%) and anemia (14.1%). Three patients presented a grade 5 AE, two of them related (aspergillosis and pneumonia, respectively) and one unrelated (heart failure). CONCLUSIONS The combination of ibrutinib with R-GEMOX-D as salvage therapy for patients with non-GCB DLBCL is associated with high response rates, especially in relapsed patients. The vast majority of refractory patients progress very early, so this regimen could be considered as a bridge to other consolidation therapies. Biological studies analyzing cell of origin by gene expression profiling, minimal residual disease and mutational spectrum are in progress. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Giné:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. Grande:Janssen: Research Funding. Caballero:Roche: Other: travel; Gilead: Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Other: travel; Takeda: Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. OffLabel Disclosure: Off-label use of a new combination in the context of a clinical trial. New combination (Ibrutinib + R-GEMOX)

scholarly journals Trial in Progress: A Multicentre, Parallel Arm, Open-Label Trial of Frontline R-CHOP/Polatuzumab Vedotin-RCHP and Glofitamab in Younger Patients with Higher Risk Diffuse Large B Cell Lymphoma (COALITION)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3571-3571
Author(s):  
Adrian Minson ◽  
Nada Hamad ◽  
Costas K. Yannakou ◽  
Shu Min Wong ◽  
Jason P Butler ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Line Treatment ◽  
Front Line ◽  
Advisory Committees

Abstract Background: R-CHOP remains a standard frontline treatment for patients with DLBCL and high-grade B-cell lymphoma (HGBL). A significant proportion of patients will have refractory disease or subsequently relapse, particularly those with high-risk features such as an elevated IPI score or rearrangements of MYC and BCL2 and/or BCL6 (double/triple hit (DH/TH)). This population remains in need of improved induction treatments that can reduce the requirement for subsequent therapies which are associated with significant toxicities and diminishing response rates. Rationale: Glofitamab is a novel full-length bispecific antibody with a unique 2:1 configuration (two CD20 binding domains and one CD3 binding domain). In combination with a single pre-dose of obinutuzumab, glofitamab has demonstrated &gt;70% complete remission in aggressive B-cell lymphoma at the recommended target dose in a phase 1 trial (Carlo-Stella, EHA 2021). Pre-clinical studies suggest that glofitamab's activity is retained in the presence of concomitant cytotoxic and CD20 antibody therapies, making it an attractive agent for combination with R-CHOP-like induction. Polatuzumab vedotin (pola) is an antibody-drug conjugate approved for R/R DLBCL in combination with BR, and is currently in evaluation for the front-line treatment of DLBCL in combination with RCHP in a randomised trial. The safety and preliminary efficacy of glofitamab in combination with R-CHOP, or pola-RCHP as a front-line treatment for high risk DLBCL is being evaluated. Study Design and Methods: This is a parallel-arm phase Ib/II trial. Treatment consists of an initial cycle of R-CHOP, followed by 5 cycles of combination induction treatment and 2 cycles of consolidation glofitamab monotherapy. Key inclusion criteria are: age 18-65 years, a diagnosis of DLBCL or HBGL, high-risk features (IPI ≥3 or NCCN-IPI ≥4 or presence of DH/TH), treatment naïve or after 1 cycle of R-CHOP, ECOG 0-3. The primary endpoint is the safety of the combination and secondary endpoints include complete response rates at interim and end of treatment FDG-PET assessments by Lugano criteria, progression free survival and overall survival. Correlative studies assessing baseline immunologic profiles, tumour phenotype and potential resistance mechanisms are planned. Approximately 40 patients will be treated in each arm across 12-14 Australian sites. The trial commenced recruitment in July 2021 (NCT04914741). The ability to recruit prior to either cycle 1 or cycle 2 allows seamless cross-referral from non-trial sites. Figure 1 Figure 1. Disclosures Minson: Hoffman La Roche: Research Funding; Novartis: Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Allogeneic Stem Cell Transplantation Provides Durable Remission in Patients with Primary Mediastinal Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2177-2177 ◽  
Author(s):  
Alex F. Herrera ◽  
Lu Chen ◽  
Sirin Khajavian ◽  
Matthew Lewis Chase ◽  
Justin Darrah ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a subset of aggressive B-cell non-Hodgkin lymphoma (B-NHL) with distinct biological and clinical features. Although most patients are cured with frontline chemoimmunotherapy with or without radiation therapy (RT), relapsed or refractory (rel/ref) PMBCL is much harder to control. Standard treatment of rel/ref PMBCL is similar to other aggressive B-NHLs, including salvage therapy and autologous (auto) stem cell transplantation (SCT) in chemosensitive patients. Recently, immunotherapy with PD-1 blockade and chimeric antigen receptor modified T-cells has proven to be effective in rel/ref PMBCL. Despite this, allogeneic (allo) SCT retains an important potential role as it has curative potential for patients with advanced aggressive B-NHLs. However, there are scant modern data on alloSCT outcomes in patients with PMBCL, limited to case reports or small series. We therefore performed a multicenter retrospective study to evaluate alloSCT outcomes in patients with rel/ref PMBCL. Methods: We retrospectively studied consecutive patients with rel/ref PMBCL who underwent alloSCT at Fred Hutchinson Cancer Center, Dana-Farber Cancer Institute, Massachusetts General Hospital, or City of Hope between 1/2000 and 5/2014. Baseline and transplant characteristics are reported descriptively. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Incidence of relapse and non-relapse mortality were calculated using competing risks methods. Results: 28 patients with rel/ref PMBCL underwent alloSCT at participating institutions during the study period. Among these patients, median age at SCT was 36 years, 54% were female, median number of prior therapies was 4 (range, 2-7), 57% were refractory to frontline therapy, 86% received prior RT, and 71% had prior autoSCT. At alloSCT, 1 (4%) patient was in complete response (CR), 21 (75%) were in partial response (PR), and 6 (21%) were refractory to pre-alloSCT therapy (18 patients were assessed with PET). Most patients (86%) received reduced intensity conditioning, most commonly fludarabine/melphalan +/- ATG or Zevalin (25%), fludarabine/TBI200 (21%), or fludarabine/busulfan (14%). GVHD prophylaxis most frequently consisted of a calcineurin inhibitor (CNI) with mycophenolate mofetil (12, 43%), CNI with sirolimus +/- methotrexate (8, 29%), or CNI with MTX (4, 14%). 15 (54%) patients had a matched (8/8) related donor, 8 (29%) had a matched unrelated donor, 2 had a mismatched unrelated donor (7/8), and 3 had umbilical cord donors. All patients received peripheral blood stem cell grafts except for the 3 cord recipients. The median follow-up time in survivors was 5.0 (range 0.5-14.0) years. The 2 year PFS and OS in the cohort were 39% and 45%, respectively, while non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were 32% and 29%, respectively. The 5-year PFS, OS, NRM, and CIR were 34%, 45%, 32%, and 33%, respectively. The cumulative incidence of grade II-IV and III-IV acute GVHD were 39% and 4% at day 100, while the incidence of chronic GVHD at 1 year was 21% (18% extensive). Among patients in CR/PR at the time of alloSCT, the 2-year PFS and OS were 50% and 58%, respectively, as compared to a 2-year PFS and OS of 0% in patients who were refractory at the time of alloSCT (p=0.046 for PFS, p=0.014 for OS). One patient received post-alloSCT lenalidomide as maintenance therapy and remained in ongoing CR. Of the 9 patients who relapsed after alloSCT, 3 out of 4 patients exhibited a response to immunosuppression taper, while 4 out of 5 patients responded to subsequent systemic therapy. 2 patients underwent a donor lymphocyte infusion (DLI) and both developed subsequent GVHD - 1 patient had a CR documented 64 days after DLI while the other had continued disease progression. In the 9 patients who relapsed after alloSCT, the 2-year OS was 33%. Conclusions: AlloSCT can produce durable remissions in a subset of patients with heavily treated, rel/ref PMBCL. Patients with refractory disease at alloSCT had dismal outcomes. Despite the expanding treatment options available for these patients, alloSCT should be considered in the management of patients with rel/ref PMBCL who are sensitive to salvage therapy. Figure 1A PFS and OS After AlloSCT in Patients with Rel/Ref PMBCL Figure 1B PFS in Patients with Sensitive versus Refractory PMBCL at AlloSCT Disclosures Herrera: Merck, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding. Maloney:Roche/Genentech: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding; Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Chen:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Shadman:Acerta Pharma: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Beigene: Research Funding; Verastem: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Genentech: Consultancy.

scholarly journals Integrated Genetic and Topological Analysis Reveals a Hodgkin-like Mechanism of Immune Escape in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1579-1579 ◽  
Author(s):  
Gabriel K Griffin ◽  
Margaretha G.M. Roemer ◽  
Mikel Lipschitz ◽  
Jason Weirather ◽  
Christine J. Pak ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Specific Expression ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive large B cell lymphoma that typically presents with disseminated disease. In contrast to diffuse large B-cell lymphoma, not otherwise specified (DLBCL), TCRLBCL is characterized histologically by rare malignant B-cells within a robust but ineffective inflammatory background composed of numerous T cells and macrophages. TCRLBCL shows a "tolerogenic" immune signature by gene expression profiling, as well as frequent upregulation of PD-L1 (Van Loo et al. PMID: 19797726; Chen et al. PMID: 23674495). Although these features suggest that active immune evasion is central to TCRLBCL pathogenesis, its mechanistic basis is poorly understood. Accordingly, we performed an integrated analysis of tumor genetics and cell-cell interactions within the tumor microenvironment to comprehensively study PD-1:PD-L1 interactions in a multi-institutional cohort of TCRLBCL. Methods: 34 cases of TCRLBCL were identified from the pathology archives of four academic medical centers. Control cohorts containing 21 cases of DLBCL and 106 cases of classic Hodgkin Lymphoma (CHL) were used as comparators. An established fluorescence in situ hybridization (FISH) assay was used to identify copy number changes and structural rearrangements of CD274 (PD-L1) and PDCD1LG2 (PD-L2) on chromosome 9p24.1, which represents the primary genetic mechanism of PD-L1/L2 expression in CHL (Roemer et al. PMID: 27069084). Tumor-specific expression of PD-L1 and PD-L2 protein was assessed by immunohistochemistry (IHC) and scoring by two pathologists using a modified H-score (percentage of positive tumor cells [0-100%] multiplied by the mean staining intensity [0-3+]). The topology of PD-L1/PD-1 expression and cell-cell interactions in the tumor microenvironment was determined by multispectral immunofluorescence (IF) microscopy and spatial image analysis, as previously performed for CHL (Carey et al. PMID: 28893733). Results: By FISH, copy gain or amplification of PD-L1 and PD-L2 was identified in 22/34 (64.7%) cases of TCRLBCL (Figure 1A) and was associated with a 4.9-fold increase in tumor PD-L1 expression relative to cases with disomy or polysomy (mean PD-L1 H-score 72 vs 14.7, p = 0.02). A rearrangement of PD-L2 was identified in one case and associated with diffuse expression of PD-L2. These findings contrasted with those observed in the DLBCL cohort, which showed a low overall frequency of 9p24.1 copy gain/amplification (5/21 cases, 23.8%) and only minimal tumor PD-L1 expression (mean PD-L1 H-score 15.6), and were intermediate to those observed in CHL, which shows near universal copy gain/amplification of 9p24.1 (98/106 cases, 92%) and extensive tumor PD-L1 expression (mean PD-L1 H-score 143.7; Figure 1B). By multispectral IF, TCRLBCL showed prominent infiltration by PD-L1+ tumor-associated macrophages (TAM) (Figure 1C), which were 5.5-fold increased relative to DLBCL and 6.6-fold increased relative to CHL (p < 0.001). TCRLBCL also showed marked infiltration by PD-1+ T cells, which were 12.3-fold increased relative to DLBCL and 3.4-fold increased relative to CHL (p < 0.001). By spatial analysis, PD-L1+ TAMs in TCRLBCL were located in closer proximity to tumor cells than PD-L1- TAMs (p < 0.001, Figure 1D-E) and also showed frequent direct interactions with PD-1+ T cells. These findings contrasted with those in DLBCL, where no local enrichment of PD-L1+ TAMs or PD-1+ T cells was identified, and were similar but more prominent than those observed in CHL. Conclusion: TCRLBCL is characterized by recurrent gains of PD-L1 and PD-L2 on chromosome 9p24.1 in association with tumor-specific expression of PD-1 ligands, as well as prominent infiltration by PD-L1+ TAMs and PD-1+ T cells. PD-L1+ TAMs in TCRLBCL are enriched around individual tumors cells and also show frequent direct interactions with PD-1+ T cells, consistent with the establishment of an immunoevasive-niche. These findings contrast with those observed in DLBCL and are most similar to those identified in CHL. Relative to CHL, however, TCRLBCL shows less frequent gains of 9p24.1 and tumor cell expression of PD-L1, and a greater degree of infiltration by PD-L1+ TAMs and PD-1+ T cells. These findings suggest that the PD-1:PD-L1 pathway is central to immune evasion in TCRLBCL and highlight the need to test the clinical efficacy of PD-1 blockade in this patient population. Disclosures Griffin: Moderna Therapeutics: Consultancy. Freeman:Novartis: Patents & Royalties; AstraZeneca: Patents & Royalties; Dako: Patents & Royalties; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Patents & Royalties; Merck: Patents & Royalties; EMD-Serono: Patents & Royalties; Roche: Patents & Royalties; Xios: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Patents & Royalties; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Origimed: Membership on an entity's Board of Directors or advisory committees. Hodi:Merck: Consultancy. Shipp:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria. Rodig:KITE: Research Funding; Affimed: Research Funding; Merck: Research Funding; Bristol Myers Squibb: Research Funding.

scholarly journals Primary Mediastinal B-Cell Lymphoma: Evaluation of Clinicopathologic Diagnosis Compared to Gene Expression Based Diagnosis in a Clinical Trial with CD30+ B-Cell Lymphomas

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2959-2959
Author(s):  
Jakub Svoboda ◽  
Steven M. Bair ◽  
Christian Steidl ◽  
Marco Ruella ◽  
Daniel J. Landsburg ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Board Of Directors ◽  
Diagnostic Criteria ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Ffpe Tissue ◽  
B Cell Lymphomas ◽  
Advisory Committees

Abstract Background: PMBCL is a unique subtype of aggressive B-cell lymphoma representing about 5% of lymphoma cases. The diagnosis is generally based on a combination of clinical features (e.g., mediastinal mass) and pathological findings on tissue biopsy (e.g., large neoplastic B-cells with variable CD30 positivity by immunohistochemistry). However, the histopathologic diagnostic criteria are not well defined and the distinction between PMBCL and diffuse large B-cell lymphoma (DLBCL) or gray zone lymphoma (GZL) involving the mediastinum can be challenging. Most PMBCL trials use the traditional diagnostic criteria for study entry. Specific treatment approaches based on results of these trials are designed for patients with PMBCL. In this study, we hypothesized that a gene expression based assay that characterizes the molecular signature of PMBCL using formalin-fixed, paraffin-embedded (FFPE) tissue may improve the diagnostic criteria and allow more accurate interpretation of results for lymphoma patients enrolled in clinical trials. Methods: This exploratory study compared the PMBCL diagnosis established by clinicopathologic criteria alone to the diagnosis assigned by a combination of clinicopathologic features and gene expression-based assay on FFPE tissue specimens of patients enrolled in a multisite phase I/II prospective trial using brentuximab vedotin (BV) in combination with rituximab - cyclophosphamide-hydroxydoxorubicin-prednisone (R-CHP) for CD30+ B-cell lymphomas (Svoboda, Blood 2017). The original diagnostic categories of PMBCL vs. DLBCL vs. GZL were assigned by investigators based on traditional clinicopathologic features. For exploratory Nanostring based diagnostic categorization, we used previously described and validated Lymph3Cx assay which consists of 64 probes with cut‐points defined at the 0.1 and 0.9 probability scores to distinguish between DLBCL and PMBCL (Mottok, Hematol Oncol 2017). The tissue was examined by a hematopathologist for adequate tumor content and nucleic acids were extracted from 10 mm FFPE scrolls or unstained slides. Survival curves were generated for PMBCL patients as categorized by investigator assessment alone and by investigator assessment plus molecular classification using STATA. Results: We enrolled 31 treatment-naïve patients with CD30+ B-cell lymphomas between January 2014 and April 2017 (NCT01994850). Based on investigator assessment, patients were categorized as PMBCL (N=23), DLBCL (N=6), and GZL (N=2). As of June 15, 2018, we obtained and analyzed diagnostic FFPE tissue using the Lymph3Cx assay on 14 pts with all 3 subtypes of CD30+ B-cell lymphomas: PMBCL (N=11), DLBCL (N=2), and GZL (N=1). Of 11 pts with PMBCL by investigator assessment alone, 8 pts (73%) had Lymph3Cx probability scores > 0.9 which was consistent with a diagnosis of PMBCL by gene expression; 2 pts (18%) scored in the indeterminate category (0.1 to 0.9); 1 pt (9%) scored as DLBCL (< 0.1). All 8 pts with a concordant diagnosis of PMBCL by investigator assessment and gene expression assay achieved complete remission (CR) and remain progression free after completing BV+R-CHP with median follow-up of 18 months. However, 1 pt re-classified as DLBCL by Lymph3Cx and 1 of 2 pts with an indeterminate score by Lymph3Cx achieved only partial responses and ultimately progressed; 1 pt with an indeterminate score remains in CR. None of the non-PMBCL pts in our exploratory analysis (2 DLBCL; 1 GZL) as assessed by investigators were categorized as PMBCL by Lymph3Cx. The CR rate for patients categorized as PMBCL by investigator assessment alone was 82% compared to 100% in those categorized as PMBCL by both investigator and gene expression assay (Table 1). The reportable progression free survival would also be different for these two cohorts (Figure 1). We will complete Lymph3Cx testing of diagnostic tissue for all 31 enrolled patients with CD30+ B-cell lymphomas enrolled on our clinical trial by the meeting. Conclusion: Preliminary results of this ongoing study suggest that a diagnosis of PMBCL by clinicopathologic assessment alone that is not supported by molecular classification may include non-PMBCL pts and affect treatment outcomes. We recommend that future clinical trials for PMBCL include gene expression based diagnostic assays to improve diagnostic accuracy and interpretation of results. Disclosures Svoboda: TG Therapeutics: Research Funding; Kyowa: Consultancy; KITE: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Tioma: Research Funding; Nanostring: Patents & Royalties: patent holding; Bristol-Myers Squibb: Research Funding. Ruella:University of Pennsylvania: Patents & Royalties. Landsburg:Curis: Consultancy, Research Funding; Takeda: Consultancy. Dwivedy Nasta:Takeda/Millenium: Research Funding; Incyte: Research Funding; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Other: DSMC. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Chong:Novartis: Consultancy. Schuster:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees.

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