scholarly journals The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37 Targeted Radioimmunotherapy in Activated B Cell like Diffuse Large B Cell Lymphoma Cell Lines

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2574-2574
Author(s):  
Gro Elise Rødland ◽  
Katrine Melhus ◽  
Roman Generalov ◽  
Sania Gilani ◽  
Francesco Bertoni ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin®) is currently being evaluated as monotherapy in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL), as well as in a phase 1b trial in combination with rituximab for patients with relapsed/refractory FL. Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines: U-2932 and RIVA. Both cell lines are representative for TP53 deficient Double Expressor (DE) DLBCL. Importantly, resistance was not a consequence of reduced binding of the radioimmunoconjugate to cell surface expressed CD37. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in both resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to radioimmunotherapy (RIT), alongside topoisomerase and histone deacetylases (HDAC) inhibitors. Kinetic studies of the effect of mono- and combination therapy of U-2932 and RIVA cells with JNJ-7706621 and 177Lu-lilotomab satetraxetan are suggestive of a model in which radiation damage induced G2-arrested lymphoma cells eventually enter mitosis (repair or escape) and mitotic entry, progression and exit are impaired by JNJ-7706621 mediated inhibition of CDK1/2 and AURKA/B. Extended residence-time of cells in mitosis due to chromosome condensation and congression defects as well as spindle and mid-spindle assembly failure is likely pivotal for the increased sensitivity to persistent 177Lu-lilotomab satetraxetan deposited DNA damage, ultimately promoting cytokinesis failure (multinucleation, aneuploidy, increased cell size) and cell death. In conclusion, CD37-targeting 177Lu-lilotomab satetraxetan RIT showed activity in several ABC-DLBCL lymphoma cell lines. CD37-independent RIT-resistance was identified in two cell lines representative of aggressive DE ABC-DLBCLs with inactive TP53, and reversed by subsequent inhibition of CDK1/2 and AURKA/B by JNJ-7706621. These findings may be of potential relevance for ongoing clinical trials of 177Lu-lilotomab satetraxetan in relapsed, ASCT-non-eligible DLBCL, and may also be more generally applicable to other 177Lu-based RITs and alternative radionuclide utilizing targeted therapies. Future pre-clinical investigations are required to elucidate the potential application of CDK1/2 and AURKA/B inhibitors as a strategy to revert RIT resistance in TP53 deficient cancers. Disclosures Rødland: Nordic Nanovector ASA: Patents & Royalties, Research Funding. Melhus:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Generalov:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Bertoni:Nordic Nanovector ASA: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants; Jazz Pharmaceuticals: Other: travel grants; NEOMED Therapeutics 1: Research Funding; Acerta: Research Funding; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership, Patents & Royalties. Syljuåsen:Nordic Nanovector ASA: Patents & Royalties, Research Funding. Patzke:Nordic Nanovector ASA: Employment, Patents & Royalties.

Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1637-1637 ◽  
Author(s):  
Andreas Viardot ◽  
Mariele Goebeler ◽  
Richard Noppeney ◽  
Stefan W. Krause ◽  
Stefan Kallert ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

scholarly journals CD19-Loss with Preservation of Other B Cell Lineage Features in Patients with Large B Cell Lymphoma Who Relapsed Post-Axi-Cel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 203-203 ◽  
Author(s):  
Sattva S Neelapu ◽  
John M. Rossi ◽  
Caron A. Jacobson ◽  
Frederick L. Locke ◽  
David B. Miklos ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Cell Lineage ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Cd19 Expression ◽  
Large B Cell

Background: Axi-cel is the first, personalized autologous anti-CD19 CAR T cell therapy approved for the treatment of patients with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies (YESCARTA. Prescribing Information. 2017). With a median follow-up of 27.1 months in ZUMA-1, the overall response rate was 83%, and 39% of the treated patients had ongoing response (Locke et al. Lancet Oncol. 2019). To gain insights into the mechanism of secondary treatment failure post-axi-cel, as well as define alternative targets and product optimization approaches, we analyzed tumor biopsies obtained prior to axi-cel therapy and at relapse. Methods: Tumor tissue samples from patients in Cohorts 1 and 2 of ZUMA-1 who had responded and subsequently relapsed were assessed in a post-hoc analysis for protein expression of B cell linage markers (CD19, CD20, PAX5, CD79a, and CD22) by multiplex immunohistochemistry (IHC), followed by multiplex immunofluorescence (IF) staining and confocal microscopy in representative cases. Pretreatment tissue samples were available from 96 patients, and 21 were available post-relapse. Paired pretreatment and post-relapse samples were available for 16 patients. CD19 and CD20 H-scores were derived based on proportion and intensity of antigen expression. Scores of 0 - 5 were considered negative, and scores of 6 - 300 were considered positive. CD19 splice variants were assessed by RNA sequencing. Results: Among all patients with available post-relapse samples, 7/21 (33%) showed loss of CD19 expression. Analysis of the 16 paired pretreatment and post-treatment samples showed loss of CD19 expression in 4 patients (25%) who relapsed post-axi-cel (Figure). Nineteen post-relapse tumor samples were evaluable for other B cell lineage markers and showed preservation of CD20, CD22 and CD79a, and the B cell lineage transcription factor PAX5, even in samples with loss or substantial reduction of CD19 expression. Multiplex IF showed that CD19 and CD20 were expressed on the cell membrane, and analysis uncovered the presence of malignant cells with different relative expression levels of these two antigens within a given biopsy. Interestingly, among the 96 pretreatment tumor samples, IHC analysis demonstrated that CD20 was robustly expressed in nearly all samples, alongside CD19, despite all patients having previously relapsed after receiving rituximab-based regimens. The CD19 and CD20 expression levels in these tumor biopsies obtained pre-axi-cel did not correlate with each other. RNA sequencing showed alternative splicing of CD19 with loss of exon 2 and/or exons 5/6 in diffuse large B cell lymphoma tumors at baseline and/or relapse, similar to what has been described previously in B cell acute lymphoblastic leukemia (Sotillo et al. Cancer Discov. 2015). In addition, several novel splice junctions have been identified. Data on the correlation between H-scores and CD19 splice forms and clinical outcomes, including response and progression-free survival, will be presented. Conclusions: In this cohort of patients relapsing after axi-cel, loss of CD19 expression was common by IHC as compared to pretreatment, likely due to alternative splicing and selection of variants devoid of target epitope. Additionally, the data showed that expression of alternate B cell lineage antigens was largely preserved. In particular, CD20 cell surface expression was strong in most tumors despite prior rituximab-based treatments. Altogether, these data point to strategies to improve efficacy of anti-CD19 CAR T cell products through co-targeting or sequential targeting of alternate B cell antigens. Disclosures Neelapu: Novartis: Consultancy; Cell Medica: Consultancy; Poseida: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; BMS: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding; Karus: Research Funding; Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Kite, A Gilead Company: Employment. Jacobson:Celgene: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor. Miklos:AlloGene: Consultancy; Celgene-Juno: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Becton Dickinson: Consultancy; Miltenyi: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Precision Bioscience: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Rodig:Kite, a Gilead Company: Research Funding; Bristol Myers Squib: Consultancy, Honoraria, Other: Travel Expenses, Speakers Bureau; Merck: Research Funding; Affirmed: Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Milletti:Gilead: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Roche: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Kite, a Gilead Company: Employment. Chang:Kite, a Gilead Company: Employment, Equity Ownership. Xue:Kite, a Gilead Company: Employment. Plaks:Gilead: Equity Ownership. Kim:Kite, a Gilead Company: Employment. Bot:Kite, a Gilead Company: Employment, Equity Ownership.

scholarly journals Repurposing dasatinib for diffuse large B cell lymphoma

2019 ◽  
Vol 116 (34) ◽  
pp. 16981-16986 ◽  
Author(s):  
Claudio Scuoppo ◽  
Jiguang Wang ◽  
Mirjana Persaud ◽  
Sandeep K. Mittan ◽  
Katia Basso ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Multikinase Inhibitor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

scholarly journals Targeting NF-κB with First in Class N-Quinoline Benzenesulfonamides (NQBS) Reveals Potent Activity in Models of Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4435-4435
Author(s):  
Matko Kalac ◽  
Michael Mangone ◽  
Alison Rinderspacher ◽  
Shi-Xian Deng ◽  
Luigi Scotto ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
B Cell ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Research Funding ◽  
Nuclear Translocation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The first two authors contributed equally to this work Identifying pharmacologic strategies to inhibit the activation of NF-κB and its target genes has been a major research pursuit. To date, no direct inhibitors of the NF-κB subunits have been explored in the clinic. Based on the constitutive activation of NF-κB in diffuse large B-cell lymphoma (DLBCL), we used this disease model to develop drugs targeting NF-κB. Using a fluorescence-based high throughput screening (HTC) approach, a unique N-quinoline-benzenesulfonamide (NQBS) scaffold was identified as potential small molecule inhibitor of the NF-κB pathway. A confocal microscopy based HTC assay performed in human umbilical vein endothelial cells (HUVEC) identified hit compounds that contained a unique NQBS core structure. The assay screened for compounds that inhibited nuclear translocation of NF-κB subunits in TNFα-induced HUVEC cells. To date over 100 NQBS analogs have been synthesized with varying potency and cytotoxicity in inhibiting growth of DLBCL lines (OCI-Ly10, RIVA, HBL-1 and OCI-Ly3). Cytotoxicity assays demonstrated that the most potent compounds exhibit IC50s in the 0.5 to 1.5 µM range. These most potent NQBS analogs identified as CU-O42 CU-O47 and CU-O75 were also able to induce apoptosis and caspase activation. Apoptosis was preceded by exclusion of the NF-κB proteins from the nucleus. To analyze the localization of NF-κB proteins within the cell compartments before and after the treatment with CU-O42, CU-O47 and CU-O75, we used confocal microscopy, electromobility shift (EMSA) and ELISA assays. Control cells tested positive for p50/p65 both within the cytoplasm and the nucleus. Following treatment with CU-O42 NF-κB was sequestered within the cytoplasm of the cell which occurred as early as 3h after exposure. In addition, all three analogs reduced the nuclear levels of NF-κB in a concentration-dependent manner when measured by EMSA and ELISA. Furthermore, CU-O47 and CU-O75 were able to inhibit TNFα induced luciferase expression in a HEK293T cell model where luciferase is controlled by an NF-κB promoter. A KINOMEscan platform (examining the activity of over 450 different kinases) showed that no NQBS analog screened (CU-O42 and CU-O75) inhibited any of the kinases in the assay. In addition, a proteasome inhibition assay tested negative for trypsin-like and chromotrypsin-like protease activity (CU-O42, CU-O47 and CU-O75). Stabilization of the inactive trimer of p50, p65 and IκBα was hypothesized as a potential mechanism of action of CU-O42 and CU-O75 through Internal Coordinate Mechanics (ICM) software. This binding hypothesis was further corroborated by cellular thermal shift assays (CETSA) with an increase of the IκBα melting temperatures (2.5-3°C) in whole cell lysates following rapid (30min) exposure to CU-O42 and CU-O75. Using a genome-wide regulatory network perturbation analysis (DeMAND) based on the RNA-Seq data collected from OCI-Ly10 cells treated with CU-O75, we identified IκBα as one of the potential targets of the compounds. Gene set enrichment analysis demonstrated NF-κB target gene downregulation using IC20 of CU-O75 at 24h (p=0.045). In vivo experiments were conducted in two models: (1) xenografts with human DLBCL cell lines of both ABC and GC subtype; and (2) myc cherry luciferase mouse model where mice spontaneously develop aggressive lymphomas. In both models, CU-O42 was able to inhibit tumor growth. Interestingly, in the xenograft model, malignant cell growth was inhibited in both ABC (HBL-1) and GC (OCI-Ly1) cells when compared to controls (p=0.01 and p=0.02). However, overall survival of mice with ABC xenografts treated with CU-042 significantly exceeded the survival of mice with GC xenografts (p<0.01) suggesting a more sustainable response in this subtype of disease, consistent with its dependency on NF-κB. Identification of a unique NQBS scaffold has led to the chemical synthesis of over 100 structural analogs with a potent inhibition on NF-κB nuclear translocation. They display potent activity across a panel of lymphoma cell lines, producing a survival benefit in mice implanted with an ABC-subtype of lymphoma. ICM, CETSA and DeMAND suggest that this is a direct effect mediated on the proteins within the p65/p50/IκBα complex. These findings point to a novel mechanism of action and warrant further research into potential clinical translation of this class of small molecules. Disclosures Califano: Thermo Fischer Scientific: Consultancy; Ipsen pharmaceuticals: Consultancy; Cancer Genetics Inc: Consultancy; Therasis Inc: Employment. O'Connor:Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Takeda Millennium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy; Bayer: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; Acetylon Pharmaceuticals, INC: Consultancy.

Differences In Treatment Patterns and Costs Among Diffuse Large B-Cell Lymphoma Patients Treated In The Clinic Vs. The Hospital Outpatient Setting

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1751-1751 ◽  
Author(s):  
Carolina Reyes ◽  
Stacey Dacosta Byfield ◽  
Laura K. Becker ◽  
Art Small
Keyword(s):  
Health Care ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Treatment Patterns ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Large B Cell

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin's Lymphoma (NHL) accounting for approximately 30% of newly diagnosed casesi. DLBCL is an aggressive form of NHL and without treatment, median survival estimates are <1 year.ii Rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is recommended first-line therapy for DLBCL patients and has been shown to improve overall survival compared with CHOP alone (previous standard therapy).iii In addition, published evidence suggests that receipt of granulocyte-colony stimulating factor (G-CSF) may improve outcomes among patients who initiate CHOP-based therapy.iv It is unclear whether differences in treatment and outcomes exist among cancer patients by site where care is delivered. This study examines differences in treatment patterns, health care resource use and costs among DLBCL patients receiving rituximab (R) or R+ chemotherapy in the office/clinic (OC) setting vs. the hospital outpatient (HOSP) setting. Methods This retrospective study used medical and pharmacy claims (1/2007 - 7/2012) from a national US commercial health plan to identify patients at least18 years old with ≥2claims for R. Patients were required to have evidence of DLBCL (≥1 claim with ICD-9-CM 200.78 or ≥2 claims with unique diagnosis codes from ICD-9-CM 200.70 to 200.77) and be enrolled in the health plan for ≥6 months before and after the index date (date of the first R claim). The follow-up period, that is, the episode of care (EOC), was the date of the first R infusion through 30 days after the last infusion prior to a gap in R administration of at least 7 months; those with less than 6 months of follow-up due to death were included. Patients with multiple cancers or receipt of R at both the OC and HOSP setting during the EOC were excluded. Differences in number of infusions, receipt G-CSF, healthcare utilization and per-patient per-month (PPPM) health care costs by cohort were examined. Results A total of 491 patients were identified, 65% OC (n=320) and 35% HOSP (n=171): by insurance type, 140 Medicare Advantage patients, 39% HOSP and 351 commercially insured patients, 33% HOSP. From 2007 to 2011/2012, the percentage of patients in HOSP increased from 32% to 43%. Descriptive results are shown in the Table. The cohorts had similar mean age, baseline Charlson comorbidity index scores and similar EOC lengths. However, compared to the OC cohort, the HOSP cohort had fewer infusions during the EOC and fewer infusions per month. In addition, fewer HOSP patients had evidence of combination therapy and receipt of any G-CSF during the EOC. HOSP patients also had significantly higher rates of emergency room visits, but not hospitalizations compared to OC patients. Total PPPM costs during the EOC as well as average costs of anti-cancer systemic therapy drugs plus administration costs incurred on days of rituximab infusions were significantly higher among the HOSP cohort compared to the OC cohort. Conclusions Increasing proportions of DLBCL patients receive infusions in the HOSP setting. HOSP patients had fewer infusions per month and incurred greater costs on the day of infusion compared to the OC cohort. There were fewer patients in HOSP with evidence of G-CSF during the EOC compared to OC patients. Overall, total PPPM costs were higher among the HOSP cohort compared to the OC cohort. Future research is warranted to assess the impact of these differences on clinical outcomes by site of care. [i] Armitage et al. JCO 1998;16(8):2780-95 [ii] Mey et al. Swiss Med Wkly 2012;140:w13511 [iii] NCCN Guidelines Version 1.2013 Diffuse Large B-cell Lymphoma [iv] Donnelly, et al, Leuk Lymphoma. 2000;39(1-2):67-75 Disclosures: Reyes: Genentech, inc: Employment, Equity Ownership. Dacosta Byfield:Genentech, Inc: Genentech contracted with OptumInsight to conducting the work described in the abstract. Stacey is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech., Genentech contracted with OptumInsight to conducting the work described in the abstract. Stacey is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech. Other; OptumInsight: Employment. Becker:Genentech, Inc: Genentech contracted with OptumInsight to conducting the work described in the abstract. Laura is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech., Genentech contracted with OptumInsight to conducting the work described in the abstract. Laura is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech. Other; OptumInsight: Employment. Small:Genentech, Inc: Employment, Equity Ownership.

scholarly journals Survival Patterns in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma: Treatment Trajectories and Responses after the First Relapse

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1622-1622
Author(s):  
Ahmad S Halwani ◽  
Hsu-Chih Chien ◽  
Deborah Kay Morreall ◽  
Vikas Patil ◽  
Kelli M Rasmussen ◽  
...  
Keyword(s):  
B Cell ◽  
Treatment Regimen ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Aggressive Treatment ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
To Receive ◽  
Large B Cell

Background: Nearly 40% of patients with diffuse large B-cell lymphoma (DLBCL) are either refractory to or relapse (R/R) after initial first-line (L1) treatment. These patients frequently receive subsequent lines of treatment, although to achieve long-term remission requires aggressive chemoimmunotherapy followed by autologous bone marrow transplant (BMT). Few real-world studies have examined the treatments used in R/R DLBCL patients over the entire disease trajectory. Methods: Using the VA Cancer Registry System and electronic healthcare records (EHR), we identified Veterans diagnosed with DLBCL between January 1, 2000 to December 31, 2016 who relapsed or progressed after L1 RCHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab) ± etoposide and then proceeded to receive at least one additional line of treatment. Human annotation of EHR notes confirmed DLBCL diagnosis, treatment regimen(s) received (including BMT), and treating physician response assessment after each line. Treatment regimens were classified as aggressive (with intent to proceed to BMT) or non-aggressive per National Comprehensive Cancer Network (NCCN) guidelines. Eligible patients were followed until loss to follow-up, death or the end of the study period (March 31, 2019). Patients with a cancer diagnosis other than DLBCL were excluded from the study. Results: We identified 270 R/R DLBCL patients who received a second-line (L2) treatment after having previously received L1 with RCHOP ± etoposide. The mean age of patients was 64.6 years; 97.4% of patients were male. Of the 270 patients, 166 (61.5%) patients received an aggressive L2 treatment regimen. RICE (ifosfamide, carboplatin, and etoposide ± rituximab) and BR (bendamustine ± rituximab) were the most commonly used aggressive and non-aggressive regimens, accounting for 39.3% and 8.9% of L2 treatment, respectively. Compared with patients who received non-aggressive L2 treatment, aggressive L2 treatment patients were younger (61.4 versus 69.7 years). Following aggressive L2 treatment, 87 patients (52.4%) achieved complete or partial response (CR/PR), while CR/PR was achieved in 43 (41.3%) patients who received non-aggressive L2. Of the 29 (10.7%) patients who received BMT, 28 received an aggressive L2 regimen. Approximately half of all patients who received L2 therapy (121/270) proceeded to third-line (L3) treatment, of which 47 (38.8%) received an aggressive L3 regimen. Nearly half of those patients who received an aggressive L2 treatment (36, 47.4%) proceeded to an aggressive L3 regimen, while only 11 (18.8%) non-aggressive L2 patients proceeded to aggressive L3 treatment. Following L3 treatment, 7 (5.8%) patients proceeded to a BMT. The median overall survival (OS) in patients receiving L2 was 9.7 months (CI: 8.2-11.7 months). The median OS for patients treated with aggressive L2 was 9.7 months (CI: 8.1-12.2 months) compared with 9.7 months (CI: 6.8-12.9 months) in patients treated with a non-aggressive L2. The median progression-free survival (PFS) for patients treated with aggressive L2 was 5.6 months (CI: 4.6-7.9 months) and 4.9 months (CI: 3.5-8.4 months) for patients treated with non-aggressive L2. Median OS in patients receiving L3 was 6.3 months (CI: 5.1-8.7 months). The median OS for patients treated with aggressive L3 was 6.8 months (CI: 5.1-12.5 months) compared with 6.6 months (CI: 4.8-9.7 months) in patients treated with a non-aggressive L3. The median PFS for patients treated with aggressive L3 was 4.5 months (CI: 2.6-6.9 months) and 2.9 months (CI: 1.8-5.7 months) for patients treated with non-aggressive L3. Conclusions: Patients who receive aggressive L2 treatment tend to be younger, more likely to receive another aggressive therapy (if L3 treatment is needed), and were much more likely to proceed to BMT than patients who received non-aggressive L2 therapy. Patients who received aggressive L2 treatments resulted in higher response rates compared to less aggressive treatment. We did not find a difference in OS between patients who received aggressive and non-aggressive treatment, the cause of which may be multifactorial. Future studies will examine factors that may impact OS in these patient groups. Acknowledgments: The study was sponsored by Genentech, Inc. Masaquel, Halloran, DeLong-Sieg, Schulz, and Li are employees of Genentech and may receive stock options from Roche. Disclosures Halwani: Pharmacyclics: Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Kyowa Hakko Kirin: Research Funding; Miragen: Research Funding; Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding. Masaquel:Roche: Equity Ownership; Genentech: Employment. Halloran:Genentech, Inc.: Employment; Roche: Equity Ownership. Delong-Sieg:Genentech/Roche: Employment, Equity Ownership. Schulz:Roche: Equity Ownership; Genentech, Inc.: Employment. Li:Genentech: Employment; Roche: Equity Ownership. Sauer:University of Utah and SLC VA Medical Center: Employment.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3733-3733 ◽  
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.

Lenalidomide Efficacy in Activated B-Cell-Like Subtype Diffuse Large B-Cell Lymphoma Is Dependent Upon IRF4 and Cereblon Expression

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3287-3287
Author(s):  
Ling-Hua Zhang ◽  
Jolanta Kosek ◽  
Maria Wang ◽  
Carla Heise ◽  
Peter H Schafer ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership

Abstract Abstract 3287 Background: Durable responses with lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell (GCB)-like subtype (Czuczman, et al. British Journal of Haematology, 2011, 154, 477–481). Herein, the molecular mechanisms involved in the differential efficacy of lenalidomide in DLBCL subtypes were investigated. Methods: A panel of DLBCL cell lines, with 5 of ABC-subtype and 11 of non-ABC subtype, was collected and cell of origin subtype was confirmed based on literature, molecular and genetic analysis. The direct antiproliferative effect of lenalidomide on DLBCL cells was assessed using the 3H-thymidine incorporation assay and apoptosis analysis. The molecular mechanisms involved in the antiproliferative efficacy of lenalidomide in DLBCL subtypes were investigated by western blot, immunohistochemistry (IHC) and qRT-PCR analysis of key signaling events during B-cell receptor (BCR)-dependent NF-κB activation. The critical roles of interferon regulatory factor 4 (IRF4), and cereblon (CRBN) in lenalidomide efficacy were established by knock-in or knock-down of these proteins in sensitive ABC cells. Finally, a mouse xenograft model was used to confirm the antitumor effect of lenalidomide and the relevance of the molecular mechanism involved. Results: Using DLBCL cell lines, lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro at a concentration range of 0.01–100 μM (the median plasma concentration at Cmax for patients receiving 25 mg lenalidomide is 2.2 μM) and delay tumor growth in a human tumor xenograft model of OCI-Ly10 cells (lenalidomide 3–30 mg/kg, p.o. qdX28), with minimal effect on non-ABC-DLBCL cells. This tumoricidal effect of lenalidomide was associated with downregulation of IRF4, a survival factor in ABC-DLBCL cells. Treatment with lenalidomide for 1–3 days, similar to the inhibitors of PKCb and MALT1 (LY-333,531 and z-VRPR-fmk, respectively), was found to significantly (p<0.05) downregulate IRF4 protein levels in sensitive cell lines such as OCI-Ly10 and U2932. IRF4 inhibition by lenalidomide reduced CARD11-BCL-10-MALT1 complex activity of ABC-DLBCL cells (as measured by BCL-10 cleavage) and resulted in downregulation of B-cell receptor (BCR)-dependent NF-κB activity. An NF-κB-driven luciferase assay revealed that lenalidomide (1 μM) inhibited transcriptional activity of NF-κB up to 56% in the sensitive ABC-DLBCL cell lines OCI-Ly10 (p <0.05) and U2932 (p <0.01) after 2-day drug treatment. Lenalidomide also significantly (p <0.05) inhibited DNA binding by Rel A/p65, p50 and c-rel/p70 in 4 lines of ABC cells. While IRF4-specific siRNA mimicked the effects of lenalidomide reducing NF-κB activation, IRF4 overexpression conferred cell resistance to lenalidomide, indicating the crucial role of IRF4 inhibition in lenalidomide efficacy in ABC DLBCL. Furthermore, knockdown of CRBN in OCI-Ly10 (p <0.05) and U2932 (p <0.01) conferred resistance to lenalidomide as demonstrated by the abrogation of the inhibitory effects of lenalidomide on IRF4 expression, BCL-10 cleavage, NF-κB activity, and proliferation of these cells, whereas the activity of inhibitors to PKC β and IKKα/β (LY-333,531 and CC-415501, respectively) remained unaffected. These data indicate that antitumor effects of lenalidomide on ABC-DLBCL cells require the presence of cereblon. Conclusions: These data may provide a mechanism for the preferential efficacy of lenalidomide in ABC-DLBCL observed in clinical studies. These findings suggest that lenalidomide has direct antitumor activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-κB signaling pathway in a cereblon-dependent manner (also see Figure below). Disclosures: Zhang: Celgene Corp: Employment, Equity Ownership. Kosek:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Heise:Celgene Corporation: Employment, Equity Ownership. Schafer:Celgene: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership.

The Synergistic Effect of Venetoclax Combined with a CDK9 Inhibitor in Primary Diffuse Large B Cell Lymphoma and Follicular Lymphoma Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2746-2746
Author(s):  
Xiaoxian Zhao ◽  
Darren C. Phillips ◽  
Andrew J. Souers ◽  
Juraj Bodo ◽  
Paul Tapang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Cdk9 Inhibitor ◽  
Large B Cell

Abstract The early phase studies have shown the high response rates in chronic lymphocytic leukemia (CLL) patients treated with the BH3 mimetic venetoclax (ABT-199). It indicated that inhibition of BCL-2 is a viable strategy for the treatment of lymphoid malignancies. Objective anti-tumor responses were also observed in patients with other common B-cell non-Hodgkin lymphomas (NHLs) such as follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), however the overall response rates are not as high as those in CLL patients. Targeting only one anti-apoptotic protein may lead to or uncover resistance owing to activity of other anti-apoptotic BCL2-family members in these settings. MCL-1 is associated with both intrinsic and acquired resistance to venetoclax and thus inhibition of MCL-1 is being explored through either direct inhibition or indirect targeting. Expression of MCL-1 is maintained via p-TEFb-mediated transcription, of which CDK9 plays a critical role. Here we aimed to investigate the combined effects of CDK9 inhibitor and venetoclax in primary DLBCL and FL cells. Inhibition of CDK9 via a small molecule A-1467729.0 (AbbVie) caused rapid loss in phosphorylation (Serine 2) of RNA polymerase II and MCL-1 expression in all tested primary cells of DLBCL and FL patients, confirming the intended effect of CDK9 inhibition. Primary samples from 12 NHL cases (6 DLBCL including 3 GCB/3 non-GCB and 6 FL) were tested for their ex vivo response to A-1467729.0 or venetoclax alone or in combination. Apoptosis assays showed negligible effects (<10% induction) of A-1467729.0 at concentrations of 1, 10, 50 and 100 nM in 11 of 12 samples, while venetoclax at same dose range induced dose-dependent apoptosis in all samples. At 10 nM, the range of venetoclax-induced apoptosis was 16.8% - 55.3% (median 27.9%). Co-treatment with venetoclax and A-1467729.0 demonstrated synergistic effects at multiple doses in all 12 samples as evidenced by flow cytometry based apoptotic assay and PARP cleavage. Quantitative flow cytometry (QFC) studies (molecules/cell) showed that DLBCL and FL patient samples had comparable levels of anti-apoptotic proteins including BCL-2, MCL-1 and BCL-xl. However, BIM levels were higher in DLBCL in comparison to FL samples. Immunohistochemical staining of BIM in formalin-fixed paraffin embedded tissues confirmed this trend. Interestingly, venetoclax was more potent in inducing apoptosis in DLBCL patient samples than FL patient samples ex vivo. QFC data revealed a correlation between 1) BCL-2/BIM ratio and IC50 of venetoclax; 2) BCL-2/(MCL-1+BCL-xl) ratio and IC50 of venetoclax in FL. Importantly, venetoclax and CDK9 inhibitor combination demonstrated superior anti-tumor efficacy in xenograft mouse model of B-cell NHL than either agent alone. In summary, small molecule inhibition of CDK9 in primary NHL cells results in rapid down regulation of MCL1 expression. A-1467729.0, in combination with venetoclax, demonstrates synergistic activity as shown by apoptosis induction in primary DLBCL and FL cells. QFC of BCL-2 family proteins may be a useful biomarker for predicting response to BCL-2 inhibition in FL. The in vitro synergy between CDK9 inhibitor and venetoclax was also seen in vivo xenograft studies. These data support further investigation for combination therapy with CDK9 inhibitor and venetoclax in B-cell NHL. Disclosures Phillips: AbbVie: Employment, Other: Shareholder, Patents & Royalties. Souers:AbbVie: Employment, Equity Ownership. Tapang:AbbVie: Employment, Equity Ownership. Albert:AbbVie: Employment, Equity Ownership.

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