scholarly journals Phase I/II Study of MAK683 in Patients with Advanced Malignancies, Including Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1422-1422
Author(s):  
Vincent Ribrag ◽  
Jean-Marie Michot ◽  
Lara Igleias ◽  
Daniel Tan ◽  
Brigette Ma ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Biomedical Research ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Advanced Malignancies ◽  
Large B Cell

Abstract Introduction: Polycomb repressive complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Enhancer of zeste homolog 2 (EZH2) in conjunction with embryonic ectoderm development (EED) is a catalytic subunit of PRC2 and functions as a histone methyltransferase for H3K27. H3K27me3 appears to be a unifying component in many malignancies, inducing transcriptional repression. EED is a core component of PRC2 that modifies the epigenetic status of target genes, including cell cycle control genes. Dysregulation of this pathway leads to tumorigenesis in several diseases. MAK683 is a specific oral inhibitor that impairs EED binding to H3K27me3. This is a Phase I/II study of MAK683 in adult patients with advanced malignancies for whom no effective standard treatment is available. Here, we present data from a subset of patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients with DLBCL received escalating doses of MAK683 in fasted conditions. Patients were administered MAK683 10, 20, 40, 80, 120, 240, 300, 500, and 800 mg once daily (QD) or 60, 80, 120, 150, and 300 mg twice daily (BID) orally in 28-day cycles until unacceptable or dose-limiting toxicities (DLTs) had developed, disease progression, or death. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended Phase II dose (RP2D). Results: As of March 5, 2021, 31 patients with an Eastern Cooperative Oncology Group Performance Status of 0-2 were treated. Median age was 70 years (range: 33-84) and patients were heavily pre-treated, with a median of 4 (range: 1-16) prior lines of therapy. Overall, 30 patients (97%) discontinued treatment due to progressive disease (26 patients, 84%), adverse events (3 patients, 10%), and physician's decision (1 patient, 3%). In total, 21 (68%) patients experienced ≥1 treatment-related adverse event (TRAE) of any grade, and the most common (≥20%) TRAEs were thrombocytopenia (29%) and anemia (23%). Grade 3/4 TRAEs were reported in 14 (45%) patients, with ≥15% of patients reporting thrombocytopenia (19%), neutropenia, and decreased neutrophil count (16% each). DLTs were reported in 7 patients, all of which were hematological and therefore may be related to the underlying disease in this subset of patients. Patients in both the QD dosing group (120 mg, 240 mg, and 800 mg; n=1 each) and BID dosing group (60 mg, n=1; 80 mg, n=2; 150 mg, n=1) reported DLTs. There were no treatment-related deaths in this study. Overall response rate was 16% (95% CI: 5─34) and the disease control rate was 29% (95% CI: 14─48). Two patients (6%) achieved a complete response (CR) and 3 patients (10%) achieved a partial response. Four patients (13%) reported stable disease. Pharmacokinetic data showed rapid absorption of MAK683 across all dosing regimens tested and drug exposure increased with dose. Conclusions: MAK683 was generally well tolerated and there were preliminary signs of activity in patients with treatment-resistant DLBCL. The use of MAK683 as a novel strategy for the inhibition of EED may have potential in relapsed/refractory DLBCL. Disclosures Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, 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; Incyte: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Michot: GSK: Honoraria; MSD: Consultancy, Honoraria; Celgene: Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Igleias: Merck Serono, MSD, BMS, Lilly, Roche, Bayer, Sanofi: Consultancy. Tan: Novartis, Bayer, Boehringer Ingelheim, MSD, Astra Zeneca, Eli-Lilly, Loxo: Consultancy; Astra Zeneca, Pfizer, Novartis: Research Funding; Merck, Pfizer, Novartis, Takeda, Bayer, Boehringer Ingelheim, Roche: Honoraria. Ma: Novartis, Merck, Y-Biologies, Taiho, Daiichi: Honoraria, Speakers Bureau; Novartis, Inglheim: Research Funding. Wainberg: Plexxikon, BMS, EMD Serono: Research Funding; Roche, Novartis, BMS, Merck, Pfizer, Lilly, Bayer, Astra Zeneca, Daiichi, Astellas, Amgen: Consultancy. Fan: Novartis Institutes for Biomedical Research: Current Employment. Suenaga: Novartis Pharma K.K.: Current Employment. Cheng: Novartis: Current Employment. Lai: Novartis: Current equity holder in publicly-traded company; Novartis Institutes for Biomedical Research: Current Employment. Yokota: AstraZeneca, Chugai Pharma, MSD, Syneos Health, Lilly, Incyte, Novartis, GlaxoSmithKline, Ascent: Research Funding; Abbott Japan, Ono Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Merck Biopharma, MSD, Rakuten Medical, Eisai: Honoraria; Merck Biopharma, MSD, Rakuten Medical: Membership on an entity's Board of Directors or advisory committees.

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 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

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 PD-1 Blockade for Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 706-706 ◽  
Author(s):  
Yi-Bin Chen ◽  
Philippe Armand ◽  
Robert A. Redd ◽  
Jad Bsat ◽  
Reid W Merryman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Disease Relapse ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The leading cause of death after high-dose chemotherapy and autologous stem cell transplantation (ASCT) for relapsed / refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains disease relapse. Except for specific subsets, DLBCL appears to have relatively low susceptibility to single-agent PD-1 blockade. However, administering PD-1 blockade early after ASCT could leverage the remodeling immune landscape and minimal residual disease state to increase the therapeutic effect of PD-1 blockade and decrease the relapse rate after ASCT. A prior study with pidilizumab showed encouraging results in this setting (Armand et al. JCO 2013;31:4199-206), but the specificity of that antibody is still under investigation. We therefore conducted a phase 2 multi-center single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab (pembro) in patients with chemosensitive DLBCL after ASCT. Another arm of this study enrolled pts with R/R classical Hodgkin lymphoma and will be presented separately. Methods: Patients ≥ 18y with R/R DLBCL who had received no more than 3 lines of prior therapy and had undergone ASCT with chemosensitive disease were enrolled on this study. In addition to meeting standard eligibility criteria for pembro treatment, pts had to have recovered from ASCT toxicities and had to begin study treatment within 60 days of stem cell infusion, with a goal of starting treatment within 21 days of hospital discharge. All patients received pembro 200mg IV every 3 weeks for 8 cycles. PET-CT scans were obtained at post-ASCT baseline, after 3 and 7 cycles, then at 12 and 18 months post-ASCT. The primary endpoint was the progression-free survival rate (PFS) at 18 months after ASCT, assessed using the International Harmonization Project 2007 criteria, with the approach considered promising if 22 patients were alive and in remission at 18 months. Results: 31 pts were enrolled and 2 withdrew consent before starting treatment. Among the 29 eligible pts, median age was 57 (22-76). Prior to ASCT, 18 (62%) were in CR and 11 (38%) were in PR. At study baseline (post-ASCT), 25 (86%) were in CR. 18 pts (62%) completed all 8 cycles of pembro per protocol. 11 pts (38%) stopped pembro early for pt choice (n=1, after febrile neutropenia), toxicity (n=6, including 3 pts with gr3 pneumonitis, 1 with g3 hepatitis, 1 with gr4 aplastic anemia) or progressive disease (n=4). 23 pts (79%) experienced a total of 57 gr3 or higher adverse events (AEs). The most common gr4 AE was neutropenia (n=6, 21%). Concerning related AEs, 9 pts (31%) experienced 14 gr3-4 AEs at least probably related to pembro including neutropenia (4 gr3, 1 gr 4) and pneumonitis (2 gr3). 10 pts (34%) experienced at least one immune-related AE of gr2 or higher severity including pneumonitis (n=1 gr2, n=2 gr3), transaminitis (n=1 gr2, n=1 gr3) and rash (n=1 gr2, n=1 gr3). There were no treatment-related deaths. Among the 29 eligible pts, 1 patient withdrew consent after cycle 1 and 1 pt was lost to follow-up after the 12m assessment (in CR). 27 pts (93%) were evaluable for the primary endpoint. 10 patients (34%, 95% CI: 18-54%) experienced disease relapse at a median of 5 months (3-18) after ASCT, and all other evaluable patients (n=17, 59%, 95% CI: 39-76%) were in CR at the 18m timepoint. 2 pts have died, both of whom had relapse at 3m after ASCT. Correlative studies including immune reconstitution and MRD analyses are ongoing. Conclusions: Pembrolizumab administered after ASCT in patients with R/R DLBCL is feasible with toxicity similar to its use in the R/R setting for other hematological malignancies. The high rate of neutropenia on this study, which is not a common AE of pembro in other settings, may be related to the burden of prior therapy or possibly to an accentuated toxicity of pembro in this specific patient population. The 18-month progression-free rate did not meet the protocol-specified primary objective, and therefore does not support a larger confirmatory study. Future studies in this setting should likely focus on specific subsets of DLBCL, e.g. primary mediastinal BCL, EBV+ DLBCL, T cell histiocyte rich LCL, which may be especially sensitive to PD1 blockade. Disclosures Chen: REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Armand:Pfizer: Consultancy; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy; Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Herrera:Seattle Genetics: Research Funding; KiTE Pharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding. LaCasce:Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Seattle Genetics: Consultancy, Honoraria. Jacobson:Pfizer: Consultancy; Precision Bioscience: Consultancy; Kite: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Humanigen: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Rodig:Merck & Co., Inc.: Research Funding; Affimed Inc.: Research Funding; KITE Pharma: Research Funding; Bristol-Meyers-Squibb: Research Funding. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Healthcare Resource Utilization and Costs in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma: A U.S. Real-World Observational Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2133-2133
Author(s):  
Xiaoqin Yang ◽  
François Laliberté ◽  
Guillaume Germain ◽  
Monika Raut ◽  
Mei Sheng Duh ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Healthcare Costs ◽  
Research Funding ◽  
Index Date ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Icd 10 ◽  
Large B Cell

Background: Around a third of patients with diffuse large B-cell lymphoma (DLBCL) either relapse following first-line (1L) chemoimmunotherapy (CIT) or are refractory to 1L CIT. Among patients with relapsed or refractory (R/R) disease eligible for second-line (2L) therapy, fewer than half survive beyond 5 years. Refractory DLBCL entails a poorer prognosis than relapsed DLBCL; however, literature on healthcare resource use (HRU) for these two populations is sparse. This study sought to describe HRU and healthcare costs in U.S. patients with relapsed and refractory DLBCL. Methods: A retrospective claims analysis was conducted using the Optum® ClinformaticsTM DataMartTM database (01/2013-03/2018). Adult patients with ≥1 hospitalizations or ≥2 outpatient (OP) visits with an ICD-10-CM diagnosis code for DLBCL after 10/01/2015 were included. Patients were defined as (1) incident if they had no prior ICD-9-CM diagnosis code for unspecified DLBCL or primary mediastinal large B-cell lymphoma (PMBCL), or as (2) prevalent if they had a prior ICD-9-CM code for unspecified DLBCL or PMBCL. For incident cases, the index date was defined as the date of the first ICD-10 code for DLBCL or other lymphoma (after 10/01/2015); for prevalent cases, the index date was the date of the first unspecified ICD-9 code for DLBCL or PMBCL. Patients with an ICD-10 code for PMBCL at any time, or an ICD-9/ICD-10 code for Hodgkin lymphoma, multiple myeloma, and other selected lymphomas during the 12 months before the index date were excluded. Patients with DLBCL were classified as relapsed if they initiated 2L ≥90 days after the last dose of the 1L therapy and as refractory if they initiated 2L <90 days after the last dose of 1L therapy. The 12-month period prior to the index date was defined as the baseline period. HRU (including hospitalizations, OP, ER, and other visits) and associated costs, including pharmacy costs, were evaluated per patient per year (PPPY) from the initiation of 1L up until end of data availability or end of continuous health plan enrollment. Results: A total of 139 and 68 incident DLBCL patients were identified as relapsed and refractory, respectively, with median (interquartile range [IQR]) age of 74 (68-81) and 72 (67-78), and mean Quan-Charlson comorbidity index score of 3.1 in both cohorts. The mean (SD) number of baseline all-cause hospitalizations was 0.35 (0.67) for relapsed and 0.40 (0.98) for refractory patients. Mean total baseline healthcare costs were $21,195 for relapse and $29,754 for refractory patients. R/R patients with prevalent DLBCL (153 relapsed; 21 refractory) had similar baseline characteristics. In incident DLBCL patients, those with relapsed and refractory DLBCL were observed for 495 and 346 days, respectively. On average, 1.7 and 2.4 hospitalizations PPPY occurred in relapsed and refractory patients, respectively. The table shows the breakdown of HRU by type of visits. Although hospitalizations were qualitatively higher in refractory patient, mean ± SD total healthcare costs were in similar range (relapsed= $164,631 ± 115,503; refractory= $159,729 ± 102,442). Corresponding OP costs (relapsed= $99,748 ± 85,350; refractory= $86,505 ± 59,081) were mainly driven by DLBCL anti-cancer therapy costs and were qualitatively higher among relapse compared to refractory patients ($41,768 ± 46,135 and $29,454 ± 32,242, respectively). In prevalent DLBCL, evaluation periods of relapsed and refractory patients lasted 964 and 786 days, respectively. Patients with relapsed DLBCL had 1.1 hospitalizations PPPY, and those with refractory DLBCL had 1.9 hospitalizations PPPY. Corresponding mean ± SD total healthcare costs were $112,653 ± 79,617 and $95,465 ± 50,167 PPPY, respectively. More pronounced results (i.e., higher rates of hospitalizations and corresponding healthcare costs for refractory compared to relapse patients) were observed in a sensitivity analysis when HRU and costs were assessed up to 6 months post-index date, which suggests that refractory patients are more likely to be hospitalized early on. Conclusions: In this U.S. real-world study, patients with R/R DLBCL incurred substantial HRU and costs, thereby imposing a considerable burden on the healthcare system. There was a trend towards higher hospitalizations for refractory patients, suggesting a worse prognosis; however total healthcare costs were similar, offset by higher anti-cancer therapy costs among relapsed patients. Disclosures Yang: Merck & Co.: Employment. Laliberté:Janssen Scientific Affairs, LLC: Research Funding; Merck & Co., Inc.: Research Funding. Germain:Janssen Scientific Affairs, LLC: Research Funding; Merck & Co., Inc.: Research Funding. Raut:Merck & Co., Inc.: Employment. Duh:Analysis Group, Inc., a consulting firm that has received research funding from Shire, a Takeda company, to conduct this study: Employment; Shire: Research Funding; Merck: Research Funding. Sen:Merck & Co., Inc.: Employment. Lejeune:Merck & Co., Inc.: Research Funding. Desai:Merck & Co., Inc.: Employment. Armand:Merck & Co.: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Pfizer Inc: Research Funding; Otsuka: Research Funding; Bristol Myers Squibb Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Roche: Research Funding; Dana-Farber Cancer Institute: Employment; Sigma-Tau: Research Funding; Affimed: Research Funding; Serventa: Research Funding; Infinity Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.

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

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

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

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

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

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

10 Years Follow-up of the GELA LNH98.5 Study, First Randomized Study Comparing R-CHOP to CHOP Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3741-3741 ◽  
Author(s):  
Bertrand Coiffier ◽  
Christian Gisselbrecht ◽  
Andre Bosly ◽  
Raoul Herbrecht ◽  
Reda Bouabdallah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Randomized Study ◽  
B Cell Lymphoma ◽  
Chop Chemotherapy ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 3741 Poster Board III-677 LNH98.5 was the first randomized study with the addition of rituximab to CHOP in patients with diffuse large B-cell lymphoma. 399 patients were randomized, 197 in CHOP arm and 202 in R-CHOP arm. Patients were aged between 60 and 80 years (median 70 years), had disease stage II to IV, and no contra-indication to one of the drugs. 60% had poor risk lymphoma according to IPI. Response to treatment and early survival analyses were previously presented with 2 years and 5 years median follow-up (NEJM 2002;346:235 and JCO 2005;23:4117). With a median follow-up of 10 years, median age of surviving patients is 78 years, oldest patient being 91 years old. Only 4 patients were lost for follow-up, defined as not seen during the last 18 months, at 5, 7, 8, and 8 years. No event was observed in 105 of the 399 patients, 37 (19%) in CHOP arm and 68 (34%) in R-CHOP arm. Relapse was observed in 73 (59%) and 51 (34%) of CR patients, and death without progression in 16 and 33 patients, respectively. Death occurred in 71% and 56% of the patients, most of them from disease progression but 21 and 20 cancers were observed, representing half of the deaths without progression. Most frequent cancers were colon and lung; two MDS were observed in CHOP arm and one AML in R-CHOP arm. One patient with CHOP presented a multiple myeloma 10 years after DLBCL. During the last 3 years, 10 additional patients relapsed, 4 in CHOP arm and 6 in R-CHOP arm, these late relapses representing 4% of CR patients. Median overall survival was 37 months in CHOP arm and 7 y 9 m in R-CHOP arm with 10-y survival of 28% and 43%, respectively (p<0.001). Median survival from progression was 8 months in both arms. This analysis showed that the benefit of combining rituximab with CHOP chemotherapy persists with a median follow-up of 10 years and that over 40% of elderly patients are alive 10 years later confirming these patients could express long-term survival if treated like younger patients. However, late relapses do occur and new strategies should be developed to prolong the response of these patients. Disclosures: Coiffier: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Bosly:Roche: Research Funding, Speakers Bureau. Herbrecht:Roche: Research Funding. Bouabdallah:Roche: Research Funding. Morel:Roche: Research Funding. Van Den Neste:Roche: Research Funding. Bordessoule:Roche: Research Funding. Haioun:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tilly:Roche: Research Funding, Speakers Bureau. Salles:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Describing Treatment of Primary Mediastinal Large B Cell Lymphoma Using Rigorously Defined Molecular Classification: A Retrospective Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Carla Casulo ◽  
Myla Strawderman ◽  
Raphael Steiner ◽  
Carolyne Delage ◽  
Tina Faugh ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Molecular Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction Primary mediastinal large B cell lymphoma (PMBCL) is a rare non-Hodgkin lymphoma (NHL) with a female predominance; often presenting with a large anterior mediastinal mass. Though PMBCL has clinical and molecular features overlapping with Hodgkin lymphoma, it is a distinct entity defined by the World Health Organization classification. PMBCL is heterogeneously treated, and most patients receive front line therapy with either rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) with radiotherapy (RT), or the more intensive etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with rituximab (EPOCH-R) regimen. Diagnosis of PMBCL is made using clinicopathologic criteria and radiographic imaging, however gene expression profiling (GEP) studies reveal a characteristic genotypic signature distinct from diffuse large B cell lymphoma (DLBCL). Molecular classification of PMBCL using the Lymph3Cx assay from formalin-fixed paraffin-embedded tissue (FFPE) is feasible, reproducible, and highly concordant in a training and validation cohort (Mottok et al. Blood 2018). Using a multicenter cohort of patients, we sought to estimate the rate of mis-match among patients with a clinical diagnosis of PMBCL using Lymph3Cx, and describe treatment selections and outcomes for each group. Methods Patients were identified from a cohort of patients with newly diagnosed NHL from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource, and the Lymphoma Epidemiology of Outcomes cohort. Patients were enrolled between 2002-2019, and included if they had clinically defined PMBCL. FFPE was retrieved from hematopathology archives of participating academic centers. All diagnoses of PMBCL were based on expert hematopathology review at the time of therapy, and all cases underwent classification by GEP using the Lymph3Cx assay. Lymph3Cx was performed in the clinical lab at the Mayo Clinic in Arizona: Contiguous unstained sections were deparaffinized and macrodissected to enrich for tumor content before RNA isolation;100-200 ng of total RNA was used in an nCounter Elements XT, hybridized, and processed the following day using the nCounter FLEX system. Raw counts were processed through the Lymph3Cx algorithm and results reported as probability of PMBCL (≥0.90 as PMBCL, ≤0.10 as DLBCL all other results "Unclear PMBCL/DLBCL") (A. Mottok et al, Blood, 2018). For cases classified as DLBCL, the Lymph2Cx cell-of-origin classifier results was reported (Scott et al, JCO, 2016). Time to event endpoints were described with Kaplan-Meier plots by groups defined by mismatch status and compared with a logrank test. Binary outcomes will be presented with 90% exact confidence intervals. Results Fifty patients were identified. Median age was 35 years (range 19-70). Sixty four percent were women. Median follow up was 47 months. Treatments included R-CHOP (44%), EPOCH-R (44%), and MACOP-B [methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin] (6%), other (4%). Ten patients (20%) had events (defined as progression or death). Three patients in the entire cohort (6%) died. The Kaplan-Meier estimated survival at 47 months (median follow-up) is 92%. The Lymph3Cx assay yielded gene expression data of sufficient quality in 47/50 cases (94%, 90% CI=85.2, 98.3%). Of 47 cases clinically identified as PMBCL, 5 unclear were DLBCL/PMBCL and 1 was Germinal Center B cell subtype of DLBCL. Among these 6 patients, 4 received R-EPOCH (66%), 1 received R-CHOP (16.6%). One patient had missing treatment data. One patient had an event requiring subsequent therapy; all patients remain alive. Conclusions Using 47 patients with PMBCL defined by histology, clinical and radiographic findings, and molecular features, we demonstrate high concordance between clinical phenotype and molecular genotype of PMBCL by Lymph3Cx. Among the 6 patients not classified as PMBCL, most received R-EPOCH. Differences in outcome by mis-match status await longer follow-up and further accrual of subjects to our data base. Our data suggest molecular genotyping may have a role in mediastinal presentations of large cell lymphoma to optimize treatment decision making. Disclosures Maurer: Nanostring: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Flowers:AbbVie: Consultancy, Research Funding; Kite: Research Funding; Burroughs Wellcome Fund: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding; Bayer: Consultancy; National Cancer Institute: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Astellas: Consultancy; Bayer: Consultancy; Kite Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Consultancy; Roche: Other: Travel expenses; Seattle Genetics: Research Funding.

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