scholarly journals Clinical Relevance of MYC/BCL2 and Cell of Origin in Patients with Relapsed Diffuse Large B-Cell Lymphoma Treated with Autologous Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2021-2021
Author(s):  
Yingjun Wang ◽  
Ken H. Young ◽  
Denái R. Milton ◽  
Celina Ledesma ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Cell Of Origin ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Significant Difference ◽  
Bcl2 Expression

Purpose: Dual expression of MYC and BCL2 proteins (Double Expressor Lymphoma-[DEL]) and MYC, BCL2 and /or BCL6 translocations (Double Hit Lymphoma-[DHL]) as well as the cell-of-origin (COO) are important prognostic factors in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who are treated with standard chemo-immunotherapy. Data are limited regarding the prognostic impact and interdependence of these biomarkers on outcomes in pts with relapsed DLBCL treated with autologous stem cell transplantation (ASCT). Methods: Data from Pts with relapsed DLBCL who underwent ASCT at our center and in whom archived tumor material was available were analyzed. Cutoff values of 40% for MYC and 70% for BCL2 were established by immunohistochemistry (IHC). FISH cases for MYC and BCL2 were considered for evaluation if at least 200 tumor cell nuclei per core displayed reliable signals in the sections. COO classification was achieved by IHC methods according to both the Visco-Young and Choi algorithms. The majority of pts (81%) underwent chemo-mobilization of stem cells with rituximab for in-vivo purging; rituximab was also given on days+1 and +8 with BEAM conditioning (J Clin Oncol 2005; 23:2240-7; Clin Cancer Res 2018; 24:2304-11). The study was IRB-approved at our center. Results: 303 pts were evaluated; 169 (56%) met the criteria for DEL and 3 (1%) for DHL; 8 (3%) met criteria for both (DEL/DHL) and 97 (32%) for neither (non-DEL/non-DHL). Because of small size, the 3 pts with only DHL were excluded from this analysis. In addition, 8 pts (3%) had atypical DHL and their outcomes were analyzed separately. GCB classification was successful in 269 pts, and 119 pts (44%) were of the GCB subtype. Median age of the whole group was 60 years (range, 18-80); the male gender predominated (65%). The median number of prior lines of therapies was 2. At ASCT, 90% of pts had chemo-sensitive disease (64% CR, 26% PR), and 6% had small volume SD; IPI was ≥ 2 in 17% of pts and PET was positive in 26%. There were no statistically significant differences in pt characteristics between the subgroups of non-DEL/non-DHL, DEL, or DEL/DHL, with the exception of GCB distribution: 46% and 41% of non-DEL/non-DHL and DEL, respectively, were classified to be of the GCB subtype, whereas all 8 DEL/DHL were classified as non-GCB (P=0.002). With a median follow-up time among survivors of 50 months (range, 4-217 months), the 4-year overall survival (OS) rates of non-DEL/non-DHL, DEL and DEL/DHL subgroups were 65%, 59%, and 25%, respectively. There was no significant difference in OS between non-DEL/non-DHL and DEL subgroups (P=0.39), however a significant difference in OS was observed between the two subgroups compared to the DEL/DHL pts (P=0.034; Figure 1). Progression-free-survival (PFS) rates were higher for the non-DEL/non-DHL (4-year rate: 51%) and DEL (4-year rate: 49%) compared to DEL/DHL (4-year rate: 25%) subgroups, though not statistically different (P=0.22). A higher risk of non-relapse mortality was observed in the DEL/DHL group compared to the other 2 groups (hazard ratio [HR]=3.8, P=0.017). The 4-year OS and PFS rates for the atypical DHL were 67% and 33%, respectively. We also evaluated the interaction of COO with BCL-2 protein expression; we found that pts who had BCL2 (+) expression, had worse OS (HR=1.82; P=0.049) and a trend for worse PFS (HR=1.58; P=0.08) compared to BCL2 (-) pts. This interaction was more prominent however in GCB pts. The 4 year OS rates of GCB/BCL2(-) and GCB/BCL2(+) were 87% and 56%, respectively (P=0.030). The 4-year PFS rates were 88% and 47%, respectively (P=0.007) (Figure 2). The OS and PFS rates within non-GCB subgroups were similar regardless of BCL2 expression. Conclusions: Our study shows that pt subgroups who have both DEL/DHL DLBCL have inferior survival. Interestingly, we also found that pts who have DEL and non-DEL/non-DHL have similar outcomes after ASCT. BCL2 expression is an important prognostic factor in GCB lymphoma. Investigational studies combining targeted therapies in this setting are warranted. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; 47 Inc: Research Funding. Qazilbash:Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Genzyme: Other: Speaker. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

scholarly journals Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Yuliya Linhares ◽  
Mitul D Gandhi ◽  
Michael Chung ◽  
Jennifer Adeleye ◽  
David Ungar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

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

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

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

An International Collaborative Study of Outcome and Prognostic Factors in Patients with Secondary CNS Involvement By Diffuse Large B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Tarec Christoffer El-Galaly ◽  
Chan Yoon Cheah ◽  
Mette Dahl Bendtsen ◽  
Gita Thanarasjasingam ◽  
Roopesh Kansara ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Systemic Disease ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Cns Involvement ◽  
First Line ◽  
Advisory Committees ◽  
Large B Cell Lymphoma

Abstract Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically <6 months. However, data in patients that develop SCNS following primary therapy that contains a rituximab-based-regimen as well as the impact of more intensified treatment for SCNS are limited. Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS. Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy's and St. Thomas' Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records. Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87%) patients and 112 (40%) had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27%) or without upfront CNS prophylaxis (N=205, 73%) (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15%). In multivariable analysis, performance status >1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, P<0.01]). The 2yr post-SCNS survival for patients treated with HDMTX and/or platinum-based regimens (N=163) was 29% (95% CI 22-37). For patients with isolated parenchymal SCNS, single modality treatment with radiotherapy resulted in 2-yr OS of 19% (95% CI 8-35). For the subgroup of 49 patients treated with HDMTX- and/or platinum-based regimens for isolated SCNS after 1st line DLBCL treatment and with performance status 0 or 1, the 2yr post-SCNS survival was 46% (95% CI 31-59). Overall, 9% of the patients received HDT with ASCT as part of salvage therapy at the time of SCNS. Amongst 36 SCNS patients without systemic involvement and in CR following intensive treatment (HDMTX and/or platinum-based treatments), 11 patients consolidated with HDT had similar outcomes to 25 patients treated without consolidating HDT (P=0.9, Fig 1) Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status >1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS. Disclosures El-Galaly: Roche: Consultancy, Other: travel funding. Cheah:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Speaker's Bureau. Kansara:Celgene: Honoraria. Connors:Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.

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

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

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

scholarly journals The Analysis of HIV-Associated Lymphoma in Japan

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5315-5315
Author(s):  
Shotaro Hagiwara ◽  
Kentaro Yoshinaga ◽  
Masayuki Shiseki ◽  
Junji Tanaka ◽  
Seiji Okada
Keyword(s):  
Board Of Directors ◽  
Burkitt Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background. The recent advance of antiretroviral therapy decreased the morbidity of opportunistic infections. However, the incidence of HIV-associated lymphoma remains high. Also, the outcome of the HIV-associated lymphoma is unclear in the era of rituximab. In order to address these clinical questions, we performed a nation-wide epidemiological study. Methods. Patients with HIV-associated lymphoma were extracted from the database of Japanese society of hematology blood disease registry from January 2012 to December 2015. We analyzed the patient's age, sex, subtypes of lymphoma, the international prognostic index (IPI) for diffuse large B cell lymphoma, and overall survival. Results. Eighty-one patients were extracted from the database. Eighty patients were available for the survival analysis. Seventy-six (93.8%) patients of them were male. The median age was 52.5(25-88) year-old. However, there were two peaks of age; the first peak was 38-40-year-old and the second was 59-62-year-old. Sub-types of lymphomas were diffuse large B cell lymphoma (DLBCL)(48.1%), Burkitt lymphoma(19.8%), primary CNS lymphoma(8.6%), plasmablastic lymphoma(7.4%), peripheral T cell lymphoma(3.7%), Hodgkin's lymphoma(3.7%), primary effusion lymphoma(2.5%), MALT lymphoma(1.2%), Follicular lymphoma(1.2%) and Adult T cell lymphoma/leukemia(1.2%). Extra-nodal involvement at the diagnosis was observed in 61.7%. The involved sites were the brain, stomach, small bowel, colon, thyroid and the others. In DLBCL, the patients with IPI high and high-intermediate risk was 51.3%. The median observation period was 26 months. Estimated 3 years overall survival (OS) in all cases was 68.8+/-0.63%. Although there was no statistical significance, however, the 3 years, OS of Burkitt lymphoma tended to be better than that of DLBCL (84.6%+/-10.0 versus 67.7+/-8.8%). Log-rank analysis showed the OS in DLBCL patients with IPI high-intermediate and high risk was significantly worse than the patients with low, and low-intermediate risk (p<0.001). Estimated 3 years OS was 90+/-9.5% vs. 38.0+/-13.0%, respectively. The outcome of patients with primary CNS lymphoma remains poor, estimated 3 years OS was 45.7+/-22.4%. Conclusion. Our study showed diversity in the pathological subtype of HIV lymphoma. In the era of rituximab, the outcome seemed to be improved in patients with DLBCL and Burkitt lymphoma. However, the survival remains short in patients with poor prognostic factors and primary CNS lymphoma. Figure. Figure. Disclosures Hagiwara: Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Shiseki:NOVARTIS Pharma: Honoraria, Research Funding; Bristol-Myers Sqibb: Honoraria; Otsuka: Speakers Bureau. Tanaka:Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria; Pfizer: Honoraria.

scholarly journals Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4082-4082
Author(s):  
Beth A. Christian ◽  
Ying Huang ◽  
Sabarish Ayyappan ◽  
Robert A Baiocchi ◽  
Jonathan E Brammer ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Advisory Committees ◽  
Oral Agents ◽  
Grade 3 ◽  
Aggressive B Cell Lymphoma

Introduction: Venetoclax, a BCL2 inhibitor, has demonstrated efficacy both as a single agent and in combination with rituximabin several subtypes of B-cell non-Hodgkin lymphoma (NHL). The combination of obinutuzumab and lenalidomide has demonstrated safety and preliminary efficacy in follicular lymphoma (Fowler et al., JCO 2015; 35: 7531). We conducted a phase I study of obinutuzumab, venetoclax, and lenalidomide to determine the safety, maximum tolerated dose, and preliminary efficacy of the combination. Methods: Patients with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell (HGBCL), marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous (ASCT) but not allogeneic stem cell transplant were permitted. Prior lenalidomide or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required. Treatment consisted of obinutuzumab 1000 mg on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6 with escalating doses of lenalidomide days 1-21 and venetoclax days 1-28 of a 28 day cycle (Table 1). A 3+3 dose escalation schema was followed. The DLT period was 1 cycle and patients had to receive 80% of the doses of the oral agents and all doses of obinutuzumab to be considered evaluable for DLT. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection; grade 3 infection that fails to resolve within 7 days; and grade 3 or 4 non-hematologic toxicity. Patients without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed by CT or PET/CT every 3 months for 12 months and then every 6 months until disease progression. Results: 22 patients were treated. Median age was 61 years (range 31-78 years) with 16 males. Median prior therapies was 2 (range 1-10) and included 5 patients who had relapsed after chimeric antigen receptor T-cell therapy and 2 patients relapsed after ASCT. Median baseline lactate dehydrogenase was 259.5 U/L (range 147-5133, ULN 190 U/L). 16 patients had aggressive B-cell lymphoma including DLBCL, HGBCL, primary mediastinal and transformed FL, 5 patients had FL and 1 patient had marginal zone lymphoma. At dose level (DL) 1, one patient experienced a DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. No further DLTs occurred at DL 2-4. DL 4 was expanded and was determined to be the MTD. Four patients, 1 in each dose level, were not evaluable for DLT and were replaced including 3 who did not receiving 80% of the oral agents due to required dose reductions and 1 patient for disease progression. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n=20, 90.9%), thrombocytopenia (n=5, 22.7%), and anemia (n=3, 13.6%). Grade 3-4 infections (n=6, 27%) included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. Other grade 3-4 AEs occurring once each included dysgeusia, dyspnea, nausea, vomiting, and hyperhidrosis. No clinically significant tumor lysis has occurred. Patients have received a median of 3 cycles (range 1-12) of treatment. Three patients remain on therapy and 5 patients are on follow up. Dose reductions of lenalidomide occurred for 17 patients (77%) and of venetoclax for 11 patients (50%). Nine patients have achieved a response (41%), including 8 complete (CR) and 1 partial responses (PR). Responses have occurred at each DL and include 4 patients with FL (2 CR, 2 PR), 4 patients with aggressive lymphoma (4 CR) and 1 patient with MZL (CR). 14 patients are off of the study, 9 with progression, 2 for alternative therapy, and 1 each for DLT, physician preference, and a diagnosis of MDS in a patient with 3 prior lines of chemotherapy. Conclusions: Combined treatment with obinutuzumab, venetoclax, and lenalidomide administered up to 12 cycles is feasible with activity in multiple subtypes of relapsed NHL. Enrollment in expansion cohorts of FL and aggressive B-cell lymphoma is ongoing. Disclosures Christian: Celgene: Research Funding; Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding. Baiocchi:Prelude: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy. Awan:Gilead: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Obinutuzumab - off label use in relapsed aggressive B-cell lymphoma and indolent B-cell lymphoma Venetoclax - off label use in relapsed B-cell lymphoma

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

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

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

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

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

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

scholarly journals Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Idelalisib in Patients with B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5345-5345
Author(s):  
Franck Morschhauser ◽  
John Radford ◽  
Loic Ysebaert ◽  
Stephen E Spurgeon ◽  
Ebenezer A Kio ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Advisory Board ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a selective Bruton's tyrosine kinase (BTK) inhibitor. Idelalisib (IDELA), a first-in-class phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is approved for the treatment of CLL and follicular lymphoma (FL). Both have single agent activity in lymphoma and updated results from the combination of TIRA+IDELA from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) or two prior lines of therapy for FL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM) and no prior exposure to targeted inhibitors were eligible for enrollment. Patients were enrolled using a 3+3 dose escalation design with a fixed dose of IDELA at either 50 mg BID or 100mg QD and TIRA ranging from 20mg to 160mg QD. Cohorts were subsequently enrolled at multiple dose levels to evaluate disease-specific safety and efficacy. Results: As of March 5, 2018, 40 patients were enrolled on the combination. The median age was 65 (32-89) years and the disease subtypes were non-GCB DLBCL (n=17), FL (10), MZL (5), WM (5), SLL (2), and MCL (1). No maximum tolerated dose and no dose-response relationship was observed with daily dosing of both agents at the dose levels evaluated. For patients with non-GCB DLBCL (n=17), the median number of prior therapies is 3 (range 1-4). The median duration of treatment is 8 weeks (range 0.9, 44.1) with 2 patients still on treatment. 4/15 (27%) evaluable patients achieved a response; best overall response is shown in table 1. For the patients with indolent NHL (n=23), the median number of prior therapies is 3 (range 2-6). The median duration of treatment is 28 weeks (range 2.1, 120.0), with 5 patients still on treatment. 10/20 (50%) of the evaluable patients achieved a response with best overall response by indication shown in table 1. The most common treatment-emergent adverse events (AEs) are listed in table 2. Of the 40 patients who received treatment on study, AEs led to treatment interruption or discontinuation of both study drugs in 22 and 3 patients, respectively. There have been 7 deaths on study, 6 due to disease progression and 1 from an unknown cause. Conclusion: Once-daily dosing of GS-4059 up to 160 mg in combination with idelalisib 50 mg BID or 100 mg QD was generally safe and well tolerated. Early results show activity across all indications studied. Disclosures Morschhauser: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Radford:GlaxoSmithKline: Equity Ownership; BMS: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Ysebaert:Gilead Sciences, Inc.: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Spurgeon:Bristol Myers Squibb: Research Funding; MEI Pharma: Consultancy; Oncternal: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding. Salles:Merck: Honoraria; BMS: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria; Janssen: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Amgen: Honoraria; Epizyme: Honoraria; Novartis: Consultancy, Honoraria. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding.

scholarly journals Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Entospletinib in Patients with B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5344-5344
Author(s):  
Gilles Salles ◽  
Martin J.S. Dyer ◽  
Daniel James Hodson ◽  
Krimo Bouabdallah ◽  
Loic Ysebaert ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Advisory Board ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a selective Bruton's tyrosine kinase (BTK) inhibitor. Entospletinib is a selective inhibitor of spleen tyrosine kinase (SYK). Both have single agent activity in lymphoma and updated results from the combination of TIRA+ENTO from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) or two prior lines of therapy for follicular lymphoma (FL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM) and no prior exposure to targeted inhibitors were eligible for enrollment. Patients were enrolled using a 3+3 dose escalation design with either ENTO 200mg or 400mg QD and doses of TIRA ranging from 20mg to 160mg QD. Cohorts were subsequently enrolled at multiple dose levels to evaluate disease-specific safety and efficacy. Results: As of March 5, 2018, 72 patients have enrolled on the combination. The median age was 67.5 years (range: 30-90) and the disease subtypes for patients enrolled were non-GCB DLBCL (n=32), FL (18), MZL (5), WM (7), SLL (2), MCL (8). No maximum tolerated dose and no dose-response relationship was observed with daily dosing of both agents at the dose levels evaluated. For patients with non-GCB DLBCL (n=32), the median number of prior therapies is 3 (range 1-7). The median duration of treatment is 8 weeks (range 2-98.1) with 6 patients still on treatment. 6/27 (22%) of the evaluable patients achieved a response; best overall response is shown in table 1. For patients with indolent NHL (n=40), the median number of prior therapies is 3 (range 1-6). The median duration of treatment is 36 weeks (range 0.1-116), with 29 patients still on treatment. 19/31 (61%) of the evaluable patients achieved a response with best overall response by indication shown in table 1. The most common treatment-emergent adverse events (AEs) are listed in table 2. Of the 71 patients who have received treatment on study, AEs led to treatment interruption or discontinuation of both study drugs in 10 and 1 patients, respectively. There have been 4 deaths on study, all due to disease progression. Conclusion: Once-daily dosing of TIRA up to 160 mg in combination with ENTO up to 400 mg QD was safe and well tolerated. Early results show activity in combination across all indications treated. Disclosures Salles: Novartis: Consultancy, Honoraria; Epizyme: Honoraria; Abbvie: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Merck: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Servier: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding. Hodson:Gilead Sciences, Inc.: Research Funding. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cartron:Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria. Davies:Acerta Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; ADC-Therapeutics: Research Funding; Janssen: Honoraria; Karyopharma: Membership on an entity's Board of Directors or advisory committees. Danilov:Aptose Biosciences: Research Funding; Gilead Sciences: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy. Fegan:Roche: Honoraria; Abbvie: Honoraria; Gilead Sciences, Inc.: Honoraria; Napp: Honoraria; Janssen: Honoraria. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Rule:Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Morschhauser:Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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