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.

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 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.

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.

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.

scholarly journals Preliminary Results from a Phase I Trial of Pembrolizumab Plus Vorinostat in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 759-759 ◽  
Author(s):  
Alex F. Herrera ◽  
Lu Chen ◽  
Leslie L. Popplewell ◽  
Lihua E Budde ◽  
Matthew Mei ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Pd1 Blockade ◽  
Expansion Cohort ◽  
Large B Cell

Introduction: Up to 20-40% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) and most treated pts with follicular lymphoma (FL) will have relapsed or refractory (RR) disease. Despite recent therapeutic advances, a minority of pts with transplant-ineligible RR HL or DLBCL, or RR FL will achieve durable remission with currently available treatments (tx). Effective novel therapies for pts with RR HL, DLBCL, or FL remain an unmet need. Although responses to PD1 blockade have been observed in pts with RR HL, DLBCL, and FL, there is room for improvement. Despite a high overall response rate (ORR) to anti-PD1 monotherapy in RR HL, the complete response (CR) is low and most patients with RR DLBCL or FL will not respond. Histone deacetylase inhibitors (HDACi) have immunomodulatory effects, including enhancing antigen presentation, recruiting T-cells into tumors, and promoting T-cell function. Preclinical models in melanoma and lung cancer demonstrated enhanced anti-tumor activity when HDACi were combined with PD1 blockade. We conducted a phase I study to determine the safety and efficacy of pembrolizumab plus vorinostat in RR DLBCL, FL, and HL. Methods: Adult pts with RR HL, DLBCL, or FL who had failed ≥ 1 prior line of tx and were transplant-ineligible were enrolled to receive IV pembrolizumab and oral vorinostat in 21-day cycles. Pts were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then onto an expansion cohort with tx at the recommended phase 2 dose (RP2D). In DL1, vorinostat was administered at 100mg BID on days 1-5 and 8-12 and in DL2, vorinostat was administered at 200mg BID on days 1-5 and 8-12. Pembrolizumab dose was 200mg every 3 weeks in all DLs. Tx could continue for a maximum of 2 years. The primary endpoint was safety and determination of the RP2D. Responses were assessed using PET-CT (DLBCL, HL, FL) or CT (FL) by investigators according to the 2014 Lugano Classification. Results: 30 pts were enrolled, including 12 in the dose escalation and 18 in the expansion cohort. At baseline, 67% were male, 73% were Caucasian, the median age was 44 years (range 19-79), the median number of prior tx was 4 (range 1-7), 9 pts had DLBCL, 9 had FL, and 12 had HL. Among DLBCL pts, 4 had primary mediastinal large B-cell lymphoma (PMBL), 4 were non-GCB by Hans criteria, 3 had double-expressor lymphoma, and 3 had prior CAR T-cells. Among HL pts, 11 had prior BV, 7 had prior PD1 blockade, and 3 were refractory to prior PD1 blockade. Additional baseline characteristics are shown in Table 1. In 28 pts with tx data, the median number of cycles was 5 (range 1-16). Of 6 pts treated at DL1, 1 had a DLT (Grade 4 Stevens-Johnson syndrome, SJS) and 1 out of 6 pts had a DLT in DL2 (Grade 3 pulmonary embolism, PE); therefore, DL2 was chosen as the RP2D. In all pts, including the expansion cohort, the most common adverse events (AEs) were nausea (61%), fatigue (57%), hypertension (54%), anemia (50%), leukopenia (50%), hyponatremia (43%), diarrhea (43%), neutropenia (39%), and thrombocytopenia (39%). Grade (gr) 3-4 AEs included 2 pts with gr 3 neutropenia, 1 pt had Gr 4 SJS, and 1 pt each with gr 3 hypertension, anemia, thrombocytopenia, hyperkalemia, lymphopenia, or PE. Immune-related AEs included the Gr 3 SJS and 5 (18%) pts with thyroiditis. 2 patients had vorinostat dose reduction - 1 for neutropenia, 1 for GI toxicity. 12 pts remain on tx; tx was discontinued for toxicity in 3 pts (SJS, PE, elevated creatinine), stem cell transplant in 3 pts, patient preference in 2 pts, and insufficient response in 10 pts. Among 27 evaluable pts, the ORR was 59% and the CR rate was 30% (Table 2). The 9 pts with DLBCL had an ORR of 56% with a CR of 33%, including 2 CR, 1 PR, 1 PD in the 4 PMBL pts (1 had been refractory to CAR T-cells). The 9 pts with FL had an ORR of 22% and CR rate of 11%, and the 9 pts with HL had an ORR of 100% with a CR rate of 44% - both evaluable HL pts who were previously refractory to PD1 blockade responded (2 PR). The median follow-up time in all pts was 4 months (mo, range 1-11). The median duration of response, progression-free survival (PFS), and overall survival (OS) in all patients were 6 mo, 8 mo, and not reached. The overall 6 mo PFS and OS were 59% and 76%, including 67%/71% in DLBCL, 33%/40% in FL, and 80%/100% in HL. Conclusions: Pembrolizumab and vorinostat was tolerable and produced objective responses in pts with RR DLBCL, FL, and HL. A majority of DLBCL pts and all HL pts responded, including pts who had progressed on prior anti-PD1 tx. Disclosures Herrera: AstraZeneca: Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding. Popplewell:City of Hope: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Mei:Seattle Genetics, Inc.: Research Funding. Chen:Autolus Therapeutics: Employment. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy.

scholarly journals A Phase 2, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination with Either Rituximab or Lenalidomide in Patients with Refractory Large B-Cell Lymphoma (ZUMA-14)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4093-4093 ◽  
Author(s):  
Sattva S Neelapu ◽  
Mohamed A Kharfan-Dabaja ◽  
Olalekan O. Oluwole ◽  
Patel Krish ◽  
Ran Reshef ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Equity Ownership ◽  
Large B Cell

Background: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adult patients who have relapsed/refractory large B cell lymphoma (LBCL) and have had ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in patients with refractory LBCL, the objective response rate was 83% (complete response rate, 58%), with ongoing responses in 39% after a median follow-up of 27.1 months (Locke FL, et al. Lancet Oncol. 2019). Despite the success of axi-cel, approximately 60% of patients have no response or relapse after treatment, indicating that additional strategies are needed for patients with relapsed/refractory LBCL. Preclinical murine studies have shown that rituximab augmented the tumor-suppressing effects of anti-CD19 CAR T cells, and the combination led to higher rates of tumor reduction (Mihara K, et al. Br J Haematol. 2010; Rufener GA, et al. Cancer Immunol Res. 2016). The IMiD® immunomodulatory agent lenalidomide has shown activity in patients with relapsed/refractory diffuse large B cell lymphoma and has also been shown to enhance the antitumor functions of anti-CD19 and anti-CD20 CAR T cells in mice (Otahal P, et al. Oncoimmunology. 2016). In ZUMA-14, the aim is to investigate the efficacy and safety of axi-cel in combination with rituximab or lenalidomide in adult patients with refractory LBCL. Methods: This Phase 2 study (NCT04002401) has a planned enrollment of approximately 60 patients aged ≥ 18 years with refractory LBCL, defined as a response of either progressive disease or stable disease to previous chemotherapy or progressive disease or relapse ≤ 12 months after an autologous stem cell transplant. Patients with prior IMiD® treatment, including lenalidomide, prior CAR T cell therapy, and/or prior CD19-targeted therapy are excluded. After leukapheresis, patients will be assigned 1:1 to receive axi-cel with either rituximab (Cohort 1) or lenalidomide (Cohort 2). Patients will receive lymphodepleting chemotherapy of fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) on days -5 to -3 before axi-cel infusion (2 × 106 cells/kg) on Day 0. Cohort 1 will receive rituximab (375 mg/m2) every 28 days starting on Day -5 for a total of 6 doses. Cohort 2 will receive lenalidomide (10 mg) daily starting 7 days after leukapheresis through Day 3 and for 5 additional cycles (20 mg, first 21 days of each 28-day cycle) beginning after axi-cel infusion starting on Day 21. Patients may not receive any therapy other than conditioning therapy and rituximab or lenalidomide, as specified by cohort, between leukapheresis and axi-cel infusion. The primary endpoint is investigator-assessed complete response rate per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints include safety, objective response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (levels of blood CAR T cells over time). Exploratory endpoints for both cohorts include pharmacodynamic assessment of cytokine profiles and the rate of CD19-negative relapses. An additional exploratory endpoint for Cohort 2 is to investigate immunomodulation of the tumor microenvironment, including the number and activation of T cells and natural killer cells. Enrollment is expected to start in September 2019. Disclosures Neelapu: Cell Medica: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Acerta: Research Funding; Karus: Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Allogene: Consultancy; Poseida: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Krish:Celgene: Consultancy, Research Funding, Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding; Curis: Research Funding; MEI Pharma: Research Funding; Bristol Meyers Squibb: Research Funding; Xencor: Research Funding; Roche: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis: Consultancy, Research Funding. Reshef:BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Goyal:Kite, a Gilead Company: Employment. Kawashima:Kite, a Gilead Company: Employment, Equity Ownership. Milletti:Roche: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Gilead: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Kite, a Gilead Company: Employment. Oliva:Kite, a Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding. OffLabel Disclosure: ZUMA-14 is a clinical trial evaluating the investigational combination of axicabtagene ciloleucel with either rituximab or lenalidomide in refractory large B cell lymphoma

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4100-4100
Author(s):  
Tarsheen Sethi ◽  
Alexandra E. Kovach ◽  
Emily F Mason ◽  
Heidi Chen ◽  
Tamara Moyo ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Germinal Center ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Equity Ownership ◽  
Grade 3 ◽  
Large B Cell

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

scholarly journals A 220-Gene Targeted Next-Generation Sequencing Panel for the Detection of Variants in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma: Application to a Cohort of 85 Formalin-Fixed Paraffin-Embedded Diffuse Large B-Cell Lymphoma Biopsies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1470-1470
Author(s):  
Julia Friedman ◽  
Asha Guttapalli ◽  
Charles Ma ◽  
Venkata Thodima ◽  
Raghavendra Padmanabhan ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Large B Cell Lymphoma ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Equity Ownership ◽  
Gain Loss ◽  
Large B Cell

Abstract Background: Recent advancements in comprehensive sequencing technologies has enabled researchers to uncover numerous somatic variants within many disease types, but their respective contributions to disease pathogenesis and potential roles as outcome biomarkers are less well-defined. Even fewer studies have integrated somatic mutation events with genomic gain and loss events of respective genes, mostly due to the need to utilize a second platform to robustly assess genomic copy number. To further understand the roles of these genomic aberrations in the disease biology of mature B-cell neoplasms, we developed a next-generation sequencing (NGS) panel of 220 genes for profiling of Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), and secondarily for Chronic Lymphocytic Leukemia (CLL). Methods: The 220 genes represented in the panel included genes based on reported frequency of mutations, targets of therapeutic agents, involvement in disease-enriched pathways, prognostic value, and associated with targeted therapy resistance. Also included were genes that mapped to sites of genomic gain and loss commonly observed in these neoplasms. Of all the genes, 163 were enriched for DLBCL, 144 for FL, 44 for MCL, and 107 for CLL. Probes were designed to cover the coding exons of the 220 genes using a hybrid-capture approach (Nimbledesign, Roche, Inc.), with a total capture size of 0.92 Mb comprising 4086 target regions. Optimization of DNA fragmentation and library preparation was performed for DNA extracted from formalin-fixed paraffin-embedded (FFPE) biopsy material, being the most common intended tissue type and also for which tumor burden could be assessed. Sequencing was performed using a Miseq sequencer (Illumina, Inc.) with the goal to enable detection of somatic variants down to an allele variant frequency (AVF) of 5%. CLC Genomics Workbench (Qiagen, Inc.) was used for alignment and variant calling. Filtering was performed to exclude synonymous, intronic, and untranslated region variants, variants within homopolymer regions (>6), and variants detected below 5% AVF. Results: The average depth of coverage achieved across an initial sample set of over 50 FFPE DLBCL specimens was approximately 350X, with only one sample having more than 10% of the target regions not achieving a coverage of 60X or greater (within 95% of the target region). As part of a proof-of-concept study, we sequenced a cohort of 85 DLBCL FFPE samples from a single institution from patients undergoing biopsy as part of their routine clinical care. Clinical outcome, cell-of-origin subtype (by the Hans method) and genomic gain/loss data by array-CGH were available. All studies were performed with IRB approval. Of the 85 cases, 80 had also been submitted to bi-directional Sanger's sequencing for Exons 5-8 of TP53 to establish accuracy of variant detection. Of cases completed to date, additional TP53 mutations have been detected by NGS due to an AVF below that detectable by Sangers or only detected in one direction. In addition, of the 14 cases completely sequenced and filtered to date, EZH2 variants in four samples have been detected in the GCB subtype while four CD79B variants were in samples of the non-GCB subtype, consistent with previously reported associations. Furthermore, six of the eight samples which harbored an EZH2 or CD79B variants had mutations within the catalytic domain at Y646 (EZH2) or the ITAM residue Y196 (CD79B), both of which have clinical implications. Initial assessment of the ability of the panel to infer copy number showed concordance with aCGH in detecting large chromosomal aberrations. The sensitivity and specificity of this approach is currently being optimized. Conclusion: Overall then, a hybrid-capture NGS panel has been developed, targeting genes enriched for involvement in the most frequent subtypes of mature B-cell neoplasms and optimized for application to FFPE biopsy specimens. While emerging pathogenomic patterns observed in the cases sequenced to date have confirmed previously observed patterns, completion of the NGS analysis of the 85 DLBCL cohort will permit more complex integrated analysis of somatic variants and genomic gain/loss with pathologic and clinical outcome data. Disclosures Friedman: Cancer Genetics Inc.,: Employment, Equity Ownership. Guttapalli:Cancer Genetics, Inc.: Employment, Equity Ownership. Ma:Cancer Genetics, Inc.: Employment, Equity Ownership. Thodima:Cancer Genetics, Inc.: Employment, Equity Ownership. Kamalakaran:Cancer Genetics, Inc.: Employment, Equity Ownership. Houldsworth:Cancer Genetics, Inc.: Employment, Equity Ownership.

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

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

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

Sign in / Sign up

Export Citation Format

Share Document