Relapsed/refractory Diffuse Large B-cell Lymphoma Research Articles

Overall Survival Following First and Second Relapse of DLBCL Treated with Therapies Including Autologous Transplant and CAR-T Cells: Results from the Lion Prospective Observational Registry

Background: Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma (NHL) and is curable with first-line conventional chemotherapy, but a significant fraction of patients relapse or do not respond to initial therapy. There are a variety of treatments available for relapsed/refractory (RR) disease, including platinum-based salvage chemotherapy often used historically both with or without autologous stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy emerging more recently as a second-line option. We report survival data following 2 nd and 3 rd line therapy for RR DLBCL in a large contemporary prospective cohort. Methods: We selected patients (pts) from the Lymphoma Innovations ORIEN Network (LION) with diffuse large B-cell lymphoma, not otherwise specified and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (“double-hit” lymphoma) who had previously received R-CHOP chemotherapy. All patients had signed written consent. Clinical data were abstracted from medical records using standardized protocol. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2 nd (OS2) or 3 rd (OS3) line treatment until death, censoring patients alive at last follow-up. Comparisons of OS were performed using the log-rank test. Results: A total of 328 patients with RR DLBCL who received 2 nd line treatment were included, 177 of whom went on to receive 3 rd line therapy. Baseline characteristics included male sex in 205 pts (65%), stage III/IV disease in 244 pts (81%), and extranodal involvement in 183 pts (63%). Second line treatments included platinum-based salvage chemotherapy both with (99 pts) and without (88 pts) autologous stem cell transplant, rituximab plus gemcitabine and oxaliplatin (30 pts, grouped distinctly from platinum-based salvage chemotherapy), CAR-T therapy (43 pts), polatuzumab vedotin (17 pts), and other classes of treatment (51 pts). Median OS2 for 2 nd line platinum-based salvage chemotherapy with autologous transplant was 110.4 months compared with 50.4 months for platinum-based salvage chemotherapy without transplant. OS2 for platinum-based salvage chemotherapy with autologous transplant was 96.5% (95% CI 90-99) at 12 months, 90.7% (95% CI 81-96) at 24 months, and 79.3% (95% CI 67-88) at 60 months compared with 77.1% (95% CI 66-85) at 12 months, 65.5% (95% CI 52-76) at 24 months, and 38.1% (95% CI 21-55) for platinum-based salvage without transplant. OS2 for rituximab plus gemcitabine and oxaliplatin was 81.7% (95% CI 58-93) at 12 months, still 81.7% (95% CI 58-93) at 24 months, and 70.1% (95% CI 37-88) at 60 months. OS2 for CAR-T cell therapy was 75% (95% CI 50-89) at 12 months and 62.5% (95% CI 36-80) at 24 months, it could not be calculated at 60 months. OS2 for polatuzumab vedotin was 73.5% (95% CI 36-91) at 12 months and could not be calculated at 24 or 60 months. OS3 for platinum-based salvage chemotherapy with autologous transplant was 100% at 12 months and 83.3% (95% CI 27-98) at 24 months compared with 70.7% (95% CI 34-90) at both 12 and 24 months for platinum-based salvage without transplant. OS3 for rituximab plus gemcitabine and oxaliplatin was 75% (95% CI 13-96) at 12 months and 50% (95% CI 6-85). OS3 for CAR-T therapy was 86.3% (95% CI 75-93) at 12 months, 65.8% (95% CI 50-78) and 46.3% (95% CI 22-68) at 60 months. OS3 for polatuzumab vedotin was 53.4% (95% CI 24-76) at 12 months and 40.1% (95% CI 12-67) at 24 months. Conclusions: We observed a statistically significant difference by log-rank in OS2 in patients receiving platinum-based salvage chemotherapy followed by autologous stem cell transplant compared to other therapies in a contemporary cohort of pts with RR DLBCL. This difference is likely driven in part by transplant being a surrogate marker for efficacy of salvage chemotherapy. OS3 was also highest at 12, 24, and 60 months in patients receiving platinum-based salvage chemotherapy followed by transplant. Other therapies including CAR-T cells, polatuzumab vedotin, and rituximab plus gemcitabine and oxaliplatin did not demonstrate significantly different rates of overall survival in the 2 nd or 3 rd line setting.

Treatments for Relapsed-Refractory Diffuse Large B-cell Lymphoma: A Preliminary Evaluation of the Place in Therapy of Glofitamab, a Bispecific Monoclonal Antibody.

Background and objectives Glofitamab, tafasitamab, loncastuximabtesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed-refractory diffuse large B-cell lymphoma(DLBCL). We studied the pattern of overall survival (OS) for these five agents. Methods We reconstructed patient-level data from the Kaplan-Meier OS graphs published in five pivotal trials. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were subjected to standard statistics to perform cross-trial indirect comparisons; mediansand hazard ratios (HRs) with 95% confidence interval(CI) were estimated for each treatment. Results Using glofitamab (a bispecific antibody) as a common comparator, our analysis of OS yielded the following results: a)tafasitamab plus lenalidomide, HR: 0.514(95% CI: 0.341 to 0.776; P=0.0015); b) polatuzumab vedotin, HR: 0.822(95% CI: 0.509to1.327); c) selinexor, HR: 1.170(95% CI: 0.852 to1.603); and d) loncastuximab tesirine, HR: 1.120(95% CI: 0.868 to1.659). Medians were estimated as follows: a) tafasitamab plus lenalidomide, 26.5 months (95% CI: 18.9 to NA); b) polatuzumab vedotin, 12.5 months (95% CI: 9.03to NA); c) glofitamab, 11.7 months (95% CI: 7.96 to 18.0); d) loncastuximab tesirine, 10.2months (95% CI: 6.97 to 11.6); and e) selinexor,10.1 months(95% CI: 6.72 to 14.2). Conclusions These comparative results represent an original finding generated by the Shiny method. Although these comparisons are indirect, our analysis offers a useful synthesis of the outcomes of these treatments. According to these results, glofitamab, despite its improved mechanism of action, does not seem to confer any OS advantage compared with the other four treatments.

Polatuzumab Vedotin Combined with R-ICE (PolaR-ICE) As Second-Line Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction: Currently, the standard of care for patients (pts) with relapsed/refractory (RR) diffuse large B-cell lymphoma (DLBCL) who relapse > 1 year after frontline treatment is salvage chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) in appropriately selected, chemosensitive pts. Following first-line therapy (tx) with a rituximab-containing anthracycline-based regimen in the modern era, response rates to platinum-based chemoimmunotherapy are suboptimal. More effective salvage regimens for RR DLBCL remain an unmet need. Polatuzumab vedotin (Pola) is an antibody-drug conjugate directed against CD79b that is safe and effective when combined with chemotherapy in frontline and relapsed, transplant-ineligible DLBCL pts [Tilly NEJM 2022, Sehn, JCO 2020]. We evaluated the safety and efficacy of Pola combined with rituximab, ifosfamide, carboplatin, and etoposide (RICE) as second-line tx in RR DLBCL in a multicenter phase 2 study. Methods: Adult transplant-eligible pts with ECOG ≤ 2 who had biopsy-proven RR DLBCL following frontline CD20-directed anthracycline-based chemoimmunotherapy were eligible. Pts with DLBCL not otherwise specified (NOS), transformed indolent lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma (HGBCL) NOS, and HGBCL with MYC and BCL2 rearrangements were eligible. Pts with central nervous system lymphoma, peripheral neuropathy (PN) ≥ grade (gr) 2 or prior tx of RR DLBCL were excluded. Participants received PolaR-ICE: 1.8mg/kg Pola day (d) 1, rituximab 375mg/m2 d1, etoposide 100 mg/m2 IV d1-3, carboplatin AUC 5 (750 mg max) IV d2, ifosfamide IV 5000 mg/m2 d2 (inpatient) or divided between d1-3 (outpatient) every 21d for 2 cycles followed by PET-CT. G-CSF prophylaxis was mandatory. Pts in CR were eligible to proceed directly to ASCT or could receive a 3rd cycle of PolaR-ICE at investigator's discretion. Pts with partial response (PR) [or stable disease, MD discretion] received a 3rd cycle of PolaR-ICE. After ASCT, pts in ongoing response who had recovered from ASCT toxicities were eligible to receive Pola consolidation (1.8mg/kg) in 21d cycles starting d+30-60 to complete a cumulative 6 doses of Pola. A safety lead-in of up to 8 pts were enrolled according to the IQ rolling 6 design, with a de-escalation dose available (Pola 1.4mg/kg). Following the lead-in, a 2-stage design was employed with 20 pts enrolled (including lead-in) and since 8+ CRs were observed, the study proceeded to enroll a total of 40 pts. The co-primary endpoints were safety and CR rate according to 2014 Lugano classification. ORR, PFS and overall survival were secondary endpoints. Results: 41 pts were enrolled; baseline characteristics are shown in Table 1. 37 pts were evaluable for response: 1 pt died prior to response assessment, 1 pt was inevaluable for response and replaced, 1 pt had clinical progressive disease (PD) and counted in ORR evaluation as PD, and 1 pt is pending response evaluation. 40 pts have toxicity data available, including 22 pts who received 3 cycles of PolaR-ICE, 16 treated with 2 cycles to date, and 2 pts who received 1 cycle to date. Of 38 pts (37 evaluable + 1 clinical PD), 35 had an objective response after 2 cycles of PolaR-ICE for an ORR of 92%, 21 (55%) had a CR, 14 (37%) had a PR, 1 had stable disease and 2 had PD. The end of salvage (PolaR-ICE x 2 or 3) ORR was 89% and CR rate 61% (1 PR became PD and 2 PR converted to CR with a 3rd cycle). To date, 21 pts proceeded to ASCT and 13 pts received consolidation Pola. The most common treatment-emergent adverse events (TEAE, all gr) related to PolaR-ICE were anemia (78%), nausea (70%), thrombocytopenia (70%), leukopenia (50%), fatigue (48%), neutropenia (48%), lymphopenia (38%), constipation (35%), hypertension (30%), and hypophosphatemia (28%). The most common gr ≥ 3 TEAEs were anemia (43%), thrombocytopenia (43%), neutropenia (43%), and no other non-hematologic TEAE occurred in more than 2 (5%) pts. 1 pt underwent Pola dose reduction due to gr 4 cytopenias, gr 2 nausea. Gr ≥ 3 infection/febrile neutropenia/sepsis occurred in 3 (8%) pts. 1 pt had a study treatment-related gr 5 AE due to sepsis. PN occurred in 10 (25%) pts, all gr 1 except one gr 2 event. Conclusion: PolaR-ICE produced a high ORR with CR in a majority of pts and the safety profile was similar to RICE, without added toxicity due to Pola. Longer follow-up is needed to assess the durability of responses and outcomes following ASCT/Pola consolidation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Recurrent Copy Number Alterations Contribute to a Unique Genetic Landscape in Relapsed-Refractory DLBCL

Introduction Patients with diffuse large B-cell lymphoma (DLBCL) are generally treated in the frontline setting with a standard immunochemotherapy regimen (R-CHOP), but for the 30-40% of patients who develop relapsed disease (relapsed-refractory DLBCL, rrDLBCL), prognosis is generally poor. While some novel therapies for rrDLBCL have measurably improved patient outcomes, there remains a notable proportion of patients for whom treatments fail or are not viable. Under the expectation that mutations contributing to treatment resistance will be selected for, and thus be enriched upon relapse, we sought to comprehensively explore the genetic features of rrDLBCL in comparison to the general DLBCL patient population. Methods We applied whole genome sequencing (WGS) and whole exome sequencing (WES) to 107 tumour tissue biopsies and/or liquid biopsies collected from patients at relapse following R-CHOP and, in some cases, one or more salvage therapies. We supplemented this with rrDLBCL cases from previous publications for a total of 155 cases with exome data. Following Illumina sequencing, read alignment, and quality control, single nucleotide variants and small insertions/deletions (cumulative simple somatic mutations, SSMs) were detected using a consensus of 3/4 variant callers (Strelka2, MuTect2, SAGE, and LoFreq). We subsequently performed ultra-low pass WGS (lpWGS) (0.3-0.5x coverage) on 67 rrDLBCL liquid biopsies for a total of 222 cases with copy number variant (CNV) information. CNVs were identified using ichorCNA (lpWGS), Sequenza (WES), and Battenberg (WGS), and regions recurrently perturbed were identified using GISTIC2. The frequency of SSMs and CNVs was compared to a diagnostic cohort comprised of WES from Schmitz et al. (2018 NEJM) and BC cases we previously subjected to WGS. The genetic subgroup of each case was assigned using LymphGen. Results Comparing the landscape of SSMs between diagnostic and rrDLBCL revealed four genes mutated at significantly (Q < 0.1) higher rates among rrDLBCLs: KMT2D (40.7% of rrDLBCLs), TP53 (32.3%), STAT6 (7.1%), and MYC (9.03%). Three genes (TMEM30A, TET2, and BCL10) were significantly depleted for mutations at relapse (Figure 1A). Although our rrDLBCL cohort was generally balanced in terms of molecular subgroups (56 GCB, 52 ABC, 16 UNC), the prevalence of genetic subgroups varied, with EZB comprising more cases than any other class (26.3%), and a limited number classified as BN2 (7.5%), MCD (8.3%), ST2 (3.8%) or A53 (6.0%). Although MYC mutations, indicative of a MYC translocation, were enriched in rrDLBCL, we did not observe an over-representation of EZB-MYC+ cases. 42.1% of cases were unclassified via LymphGen, including 54.5% of ABC-rrDLBCLs. Large arm-level or whole chromosome gains were common, particularly those involving chromosome 7 (47.7% of rrDLBCLs) or encompassing 18q23 (including BCL2, 44.1%), as were deletions affecting 6q23.3 (TNFAIP3, 45.0%) and 17p13 (TP53, 37.4%). We observed recurrent CNVs perturbing established DLBCL genes, including gains of REL and BCL2, and deletions of CDKN2A/CDKN2B, RB1, and PTEN. Comparing the frequency of recurrent CNVs to our diagnostic cohort revealed 14 regions significantly enriched for CNVs at relapse (Figure 1B). These included deletions of TP53, PTEN, and gains involving STAT6, MIR17HG and BCL2. We also noted several recurrent events that appeared exclusively in rrDLBCL that have not been previously described. These include recurrent deletions affecting the MHC Class I regulator IRF2 (4q34.3, 21.6% of rrDLBCLs) and the RNA splicing regulator HNRNPD (4q13.2, 22.5%) and gains perturbing the B-cell maturation factor IKZF3/Aiolos (17q21.1, 20.7%), and B-cell differentiation regulator TCF3 (19p13.3, 12.6%), with the latter event predominating in ABC-rrDLBCL. Conclusions This cohort of rrDLBCL contained fewer BN2 cases and more EZB, which may relate in part to an enrichment of transformations from FL. The prevalence of fewer BN2 cases at relapse is consistent with the notion that these cases have superior outcomes afforded by R-CHOP. The depletion of mutations in TET2 and a low rate of ST2 cases could imply that such cases are also less likely to relapse on standard therapy. The frequent observation of deletions affecting HNRNPD points to an under-appreciated role of RNA-binding proteins in DLBCL relapse. Recurrent deletions of IRF2 could further explain immune evasion observed in rrDLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trends in the Use of Hematopoietic Stem Cell Transplantation in the Management of Relapsed/Refractory Diffuse Large B Cell Lymphoma. a Retrospective Analysis of the Lymphoma Working Party of the EBMT

Background. Both autologous (auto-HSCT) and allogeneic stem cell transplantation (allo-HSCT) represent accepted treatment strategies for patients with relapsed / refractory (RR) diffuse large B cell lymphoma (DLBCL). Nevertheless, both transplant modalities have evolved over time and the advent of new drugs might have modified indications and timing of HSCT. Aims. We analyzed the transplant activity for patients with RR DLBCL reported to the EBMT registry over the last three decades. Methods. Patients were included if they had RR (primary refractory or relapsed disease) DLBCL, were above 18 years of age and had undergone auto-HSCT as 1st HSCT or allo-HSCT either as a 1st HSCT or after a prior auto-HSCT between January 1990 to December 2019. Minimal essential data-A were retrieved from the EBMT database. Results. 5454 patients [4329 auto-HSCT and 1125 allo-HSCT (556 1st allo-HSCT and 569 allo-HSCT after an auto-HSCT)] were registered in the EBMT database during the study period. The number of auto-HSCT steadily increased from 284 in the 1990-2000 period up to a maximum of 1751 in the 2015-2019 time period; the number of allo-HSCT also increased from 65 up to a peak of 585 in the same time periods. With regards to autologous recipients, there was a significant increase in age at HSCT [48.8 yrs (1990-2000) vs 57 yrs (2015-2019), p<0.0001], time between diagnosis and HSCT became shorter [17.7 mo (1990-2000) vs 14 mo (2015-2019), p<0.0001], performance status at HSCT improved (>=80% [86 (1990-2000) vs 92 (2015-2019), p<0.02], peripheral blood (PB) has become the universally used stem cell source [87% (1990-200] vs 99% (2015-2019), p<0.0001] and total body irradiation has almost been abandoned [12.9% (1990-2000) vs 0.4% (2015-2019), p<0.0001]. A significantly higher proportion of patients have undergone the autologous procedure in complete remission (CR) [19% (1990-200] vs 40% (2015-2019), p<0.0001]. 36-mo overall survival (OS) has significantly improved over time [48.3% (1990-2000) vs 57.8% (2015-2019), p=0.003] as well as non-relapse mortality (NRM) [7.3% (1990-12000) vs 5.9% (2015-2019), p=0.04]. Time between diagnosis and HSCT has decreased over time also in allogeneic recipients [25.5 mo (1990-2000) vs 19.2 mo (2015-2019), p<0.01]]. PB has become the universal source of stem cells [43% (1990-2000) vs 92% (2015-2019), p<0.0001], and there has been a more frequent use of reduced intensity conditioning protocols [43% (1990-2000) vs 63% (2015-2019), p<0.0001] as well as of matched unrelated donors and haploidentical donors [21% (1990-2000) vs 49% (2015-2019) and 0% (1990-2000) vs 19.5% (2015-2019), respectively, p<0.0001]. 36-month OS estimates have also improved [33.0% (1990-2000) vs 43.9% (2015-2019), p<0.08)] as well as those for progression free survival [28.1% (1990-2000) vs 38.6% (2015-2019), p=0.01], with no changes in NRM [31.3% (1990- 2000) vs 22% (2015-2019), p=0.44]. Summary/Conclusion. Transplantation activity, the clinical pattern of patients undergoing this treatment and the characteristics of the procedure have significantly changed over the study period; long-term outcome has significantly improved both in auto-HCT and allo-HCT recipients. Improvement of supportive measures as well as in the experience of the transplant centers and a better selection of patients could account for these changes. The introduction of new cellular therapy modalities (CART cells) initially as third line or more therapy and later on as second line therapy in patients with primary refractory or early relapsed DLBCL has already started to modify this therapeutic landscape.

Abstract A22: Cost effectiveness of second line Axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma

Abstract Background In patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL), CAR T has been shown to be effective in patients with at least 2 prior lines of therapy. ZUMA-7 study demonstrated that axi-cel improved event free survival (EFS) compared to standard of care (SOC) salvage chemoimmunotherapy in primary refractory/early relapse DLBCL leading to its recent FDA approval in this setting. We evaluated the cost effectiveness of second line axi-cel. Methods We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapse DLBCL by developing a Markov model (20-year horizon) to model the cost-effectiveness of axi-cel in the second-line setting compared to SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150,000/quality-adjusted life-year (QALY). Results Assuming a 5-year EFS of 35% with second line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of 100,000 and 150,000 ($93,547/QALY). Axi-cel was no longer cost effective if its 5-year EFS was 26.4% or lower. One-way sensitivity analysis demonstrated that second-line CAR T is cost effective up to a cost of $972,061 at a WTP of $150,000. Second-line axi-cel was the cost-effective strategy in 73% of the 10,000 Monte-Carlo iterations at a WTP of $150,000. Conclusions If the absolute benefit in EFS is maintained over time, second line axi-cel for aggressive RR-DLBCL is cost effective when compared to SOC at WTPs of $100,000 and $150,000/QALY. However, its cost effectiveness is highly dependent on long-term outcomes. Routine usage of second-line CAR T would add significantly to healthcare expenditures even when used in a high-risk subpopulation. Further reductions in cost of CAR T are needed. Citation Format: Swetha Kambhampati, Monica Saumoy, Yecheskel Schneider, Lihua E. Budde, Alexey Danilov, Matthew Mei, Leslie Popplewell, Tanya Siddiqi, Jasmine Zain, Stephen Forman, Larry Kwak, Steven Rosen, Alex Herrera, Nikhil Thiruvengadam. Cost effectiveness of second line Axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A22.

Treatments for relapsed-refractory diffuse large B-cell lymphoma: comparison of overall survival outcomes observed with four novel agents.

Tafasitamab, loncastuximab, tesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed/refractory B-cell lymphomas. We studied the patterns of overall survival (OS) for these four agents. PATIENTS AND METHODS: We reconstructed patient-level data from the published Kaplan-Meier OS graphs. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were then subjected to standard statistics to perform between-treatment comparisons, and hazard ratios (HRs) and 95% confidence intervals (CI) were estimated. Using tafasitamab plus lenalidomide as a common comparator, our analysis of OS yielded the following results: a) Polatuzumab vedotin vs. tafasitamab + lenalidomide: HR=1.60 (95%CI, 0.94-2.74, p=0.0831); b) Selinexor vs. tafasitamab + lenalidomide: HR=2.28 (95%CI, 1.54-3.38, p<0.001); c) Loncastuximab tesirine vs. tafasitamab + lenalidomide: HR=2.35 (95%CI, 1.55-3.56, p<0.001). All three values favored tafasitamab + lenalidomide. These comparative OS results represent the original findings. Although these comparisons were indirect, our analysis offered a useful synthesis of the outcomes reported thus far for these four treatments.

TTI-622-01: A phase 1a/1b dose-escalation and expansion trial of TTI-622 in patients with advanced hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL).

TPS7595 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don’t eat me" signal to suppress macrophage phagocytosis. Overexpression of CD47 on cancer cells serves as a mechanism of immune surveillance evasion, and is associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Preclinical studies demonstrate that TTI-622 induces macrophage-mediated phagocytosis of different malignant cell lines, including DLBCL cells, decreases tumor growth and improves survival in a DLBCL xenograft tumor model. Anti-CD47 antibody enhances rituximab stimulated macrophage-mediated phagocytosis of non-GCB DLBCL cell lines (Bouwstra et al, Cancer Immunol Res. 2019). The ongoing phase 1a part of this study has been previously described. Here we describe 2 cohorts within the phase 1b part of the study that are intended to determine the safety and preliminary efficacy of TTI-622 when given in combination with anti-CD20 targeting agent in patients with CD20+ relapsed/refractory (RR) DLBCL. Methods: TTI-622-01 is a multi-center Phase 1a/1b study. Phase 1a was designed to determine the MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of QW, Q2W, and Q3W single-agent TTI-622 in R/R lymphoma using a 3+3 dose escalation schema. Phase 1b, ongoing, will determine the safety, recommended dose and preliminary efficacy of TTI-622 in combination with select approved anticancer treatments for patients with hematological malignancies including, but not limited to anti-CD20 therapy in patients with CD20+ RR DLBCL. Secondary objectives are to further characterize safety, PK and immunogenicity of TTI-622 when combined with approved therapies. Patients will be enrolled in 2 cohorts exploring different doses of TTI-622 in combination with anti-CD20 therapy. Cohorts will open in a staggered manner. In each cohort 3 patients will be dosed and followed for 28 days before expanding enrolment to additional 27 patients per cohort. Key eligibility criteria include: age ≥18 years; relapsed and/or refractory disease after ≥1 prior line of therapy; not eligible for or have progressed after high dose chemotherapy (HDT)/auto-SCT; ≥1 site of measurable disease (Lugano 2014 classification); ECOG PS ≤2; adequate organ functions, no known CNS involvement; no prior anti-CD47 or anti-SIRPα therapy. Patient recruitment is planned or ongoing at 40 sites worldwide. Clinical trial information: NCT03530683.

CAR T Therapy Referral for Diffuse Large B Cell Lymphoma (DLBCL) By U.S. Community Hematology/Oncology (cH/O) Practices: Perceptions and Patterns

IntroductionChimeric antigen receptor T-cell (CAR T) therapy has resulted in a treatment paradigm shift for certain hematologic malignancies, with United States Food and Drug Administration approval of several products for patients with relapsed/refractory (RR) aggressive B cell lymphomas (BCL). Although most BCL patients are initially treated by cH/O physicians, current delivery of CAR T is limited to major academic centers. Consequently, there is a dearth of reporting on the complex aspects of cH/O involvement before and after CAR T therapy administration, which complicates determination of the magnitude of potential benefits. To appropriately incorporate this therapeutic option, and optimize patient care, communication and cooperation between cH/O and the CAR T center is critical; at a minimum, the referring cH/O's access to all aspects of the CAR T therapy continuum is paramount. To that end, this study surveyed cH/O physicians to determine: 1) whether adequate data were recorded and available to the cH/O; 2) timing of referral, leukapheresis, and CAR T infusion; 3) treatment prior to CAR T referral, and 4) physician perceptions on patient eligibility, barriers to access, and noncompliance.MethodsThis retrospective, observational, multicenter chart review assessed adult patients with RR DLBCL who received CAR T therapy in 2019. Patients with ≥6 months of post-CAR T therapy administration follow-up were identified by cH/O physicians participating in the Cardinal Health Oncology Provider Extended Network (OPEN). cH/O physicians provided their perceptions and experience with CAR T therapy via survey and abstracted patient data using electronic case report forms. Patient demographic/clinical/treatment characteristics and physician perceptions were summarized descriptively.ResultsSurveyed Perceptions: Top barriers to CAR T referral: patient choice (39%), location of CAR T center (31%), and preference for other therapy (31%); 39% reported no specific barriers. Rapid disease progression (69%) was the main reason patients would not undergo CAR T therapy after referral, followed by patient ineligibility (62%), patient choice (62%), and insurance coverage/patient cost (46%). Chart Abstraction: Data on 65 RR DLBCL patients were collected from 13 cH/O practices in all 4 U.S. regions (Table). Median duration of follow-up from CAR T therapy referral was 15 months. Median age at RR DLBCL diagnosis was 60 years, and most patients were male (63%) and White (79%). Most patients (92%) received anti-CD20 monoclonal antibody (mAb) + CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as 1L therapy. At referral, 80% of patients (48/60) had lactate dehydrogenase levels above the upper limit of normal. Prior to CAR T infusion, all patients were reported to receive lymphodepletion treatment with fludarabine + cyclophosphamide. Median intervals among patients with and without disease progression, respectively, were: 9 weeks (8 vs 10) from CAR T referral to CAR T infusion, which comprised 5 weeks (4 vs 6) from CAR T referral to leukapheresis and 4 weeks (both groups) from leukapheresis to CAR T infusion.ConclusionsThe cH/O physicians' perceived barriers to CAR T therapy for their patients appear to conflict with the patient data; 69% thought that rapid disease progression precluded CAR T therapy but the reported 9-week interval from referral to CAR T infusion suggests reasonably timely intervention. This highlights the critical need for early referral with a commitment to prompt patient evaluation by the treatment center. The cH/O physician is vital for CAR T referrals and treatment decisions, and the recent increasing access to patients via telemedicine may help better integrate the cH/O, the patient, and the treatment center to promote access of patients to CAR T cell therapies, particularly when limited other options are available. [Display omitted] DisclosuresPorter: DeCart: Membership on an entity's Board of Directors or advisory committees; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Klink: Cardinal Health: Current Employment, Current holder of stock options in a privately-held company. Balanean: Cardinal Health: Current Employment; Georgia State University: Other: former student and employee. McAllister: Cardinal Health: Current Employment. Feinberg: Cardinal Health: Current Employment.

Objective Responses Achieved in Patients with MYC-Altered Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with the Dual PI3K and HDAC Inhibitor CUDC-907

IntroductionPatients with relapsed/refractory (RR) diffuse large B-cell lymphoma (DLBCL) characterized by translocation or amplification of MYC or increased expression of MYC protein (MYC-altered) are reported to have a dismal prognosis (Blood. 2012 May 17;119(20):4619-24. and Haematologica. 2013 Oct;98(10):1554-62.). CUDC-907, a first-in-class oral dual inhibitor of HDAC and PI3K enzymes, has demonstrated downregulation of MYC mRNA and protein levels in MYC-altered DLBCL cell lines, as well as anti-tumor activity in multiple MYC-driven animal cancer models. In a Phase 1 study, objective responses were reported in a number of patients with MYC-altered RR DLBCL treated with CUDC-907. This Phase 2 study is designed to further explore the efficacy of CUDC-907 in this population. Clinical trial information: NCT02674750.Patients and MethodsUp to 200 RR DLBCL patients may be enrolled to enrich for a total of 100 patients with confirmed MYC-altered disease by central immunohistochemistry (IHC) testing. Following central testing, patients are placed into one of three groups; Group A consists of patients with MYC translocation and/or amplification by fluorescent in situ hybridization (FISH) without MYC protein expression ≥40% by IHC, Group B (n = 100) of patients with MYC protein expression ≥40% by IHC (regardless of FISH results), and Group C of patients that do not qualify for Group A or B. Central testing of BCL2 and BCL6 gene and protein expression status are also being performed. Key eligibility criteria include confirmed availability of viable biopsy tissue (fresh or archival) for central testing, ECOG score ≤1, 2-4 prior lines of therapy for DLBCL, and ineligible for/failed prior autologous stem cell transplantation. Transformed follicular lymphoma patients are also eligible. All patients receive 60 mg of CUDC-907 orally once a day on a 5 days on/2 days off schedule in 21-day cycles. The primary endpoint is to assess the objective response rate (ORR) in Group B. The evaluable population in this analysis are defined as any patient who received at least one dose of CUDC-907 and had a post-baseline disease assessment.ResultsAs of 29 June 2017, 68 patients received CUDC-907; 5 in Group A, 44 in Group B, and 19 in Group C. All patients with MYC translocations also had MYC protein expression ≥40% by IHC (n = 16). There were 17 patients with MYC amplifications, 12 of which also had MYC protein expression ≥40% by IHC, making all 5 Group A patients MYC amplifications only.The most frequently reported adverse events were diarrhea (64.1%), nausea (42.2%), thrombocytopenia (35.9%), fatigue (31.3%), hypokalemia (29.7%), and vomiting (25%). The most frequently reported Grade ≥3 treatment-related adverse events were thrombocytopenia (18.8%), neutropenia (14.1%), diarrhea (14.1%), anemia (6.3%), and hypokalemia (6.3%).Seven objective responses (3 CR and 4 PR) were reported in Group B and none in Groups A or C. The ORR in evaluable Group B patients was 19.4% (7/36). One of the PRs was reported in a double-hit lymphoma patient (both MYC and BCL2 translocations present). Responses showed encouraging durability considering the follow-up time with a range of 0.8 to 6.9+ months. Four of the responses were ongoing as of the data-cut, including 2 CRs. One of the CR patients discontinued study treatment early to pursue a stem cell transplant. The median duration of treatment for responders was not reached (95% confidence interval, 4.7 months to not reached).ConclusionsThe biologic rationale, tolerable safety profile, and evidence of anti-tumor activity in MYC-altered RR DLBCL support the continued development of CUDC-907 in this poor-prognosis patient population. DisclosuresLandsburg:Takeda: Research Funding; Curis: Consultancy, Research Funding. Ramchandren:Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Pagel:Pharmacyclics: Consultancy; Gilead: Consultancy. Lugtenburg:Roche: Research Funding; Takeda: Research Funding; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; BMS: Honoraria; Servier: Honoraria; Sandoz: Honoraria.

Phase 1/2 study of the novel SUMOylation inhibitor TAK-981 in adult patients (pts) with advanced or metastatic solid tumors or relapsed/refractory (RR) hematologic malignancies.

TPS2667 Background: SUMOylation, a posttranslational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in regulating type I interferon (IFN-I)-dependent innate response and functions to constrain the innate immune response, which can impair tumor immune surveillance. TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme subunit 2 (SAE2). Inhibition of SAE2 by TAK-981 disrupts SUMOylation, thereby allowing innate immune system activation. In ex vivo assays, TAK-981 increased phagocytic activity of monocyte-derived macrophages, increased natural killer cell cytotoxicity, and induced markers of dendritic cell activation and maturation via IFN-I signaling. In syngeneic mouse models, TAK-981 resulted in antitumor activity, including complete remissions, and a sustained, protective antitumor immune response. Methods: This first-in-human study of single-agent TAK-981 comprises two parts. Phase 1 primary objectives are to determine safety and tolerability, and to select a recommended phase 2 dose (RP2D); secondary objectives are to assess preliminary antitumor activity, characterize pharmacokinetics (PK), and explore pharmacodynamic (PD) biomarkers. This phase will enroll ̃70 pts with untreatable locally advanced or metastatic solid tumors or RR lymphoma. The phase 2 primary objective is to evaluate preliminary efficacy at the RP2D in ̃132 pts with non-squamous non-small cell lung cancer, cervical cancer, microsatellite-stable colorectal cancer, or CD20+ RR diffuse large B-cell lymphoma or follicular lymphoma. Pts receive TAK-981 via a 1-hour intravenous infusion on days 1, 4, 8, and 11 in 21-day cycles until unacceptable toxicity, pt withdrawal, or death. Dose escalation is proceeding from 3 mg, guided by an adaptive 3+3 design combined with Bayesian logistic regression modelling with overdose control, plus consideration of other safety, clinical, PK, and PD data. The RP2D will be based on the maximum tolerated dose (MTD) or on a biologically effective dose (BED) that is ≤MTD. The BED is defined as a dose at which there is evidence of drug-target engagement and inhibition of SUMOylation, plus: induction of cytokines/chemokines and/or IFN-I signature in tumor or blood; evidence of increased T cell infiltration in tumor; or antitumor activity. PK/PD modeling in the BED range is ongoing and will be used in RP2D determination. Clinical trial information: NCT03648372.

Outcomes of Transplant-Eligible Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Salvage Chemotherapy: The Gustave Roussy Experience

IntroductionAfter failure of frontline therapy, patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) that does not respond to first-line salvage chemotherapy can be recommended second-line salvage chemotherapy. The available literature in this regard is weak, although many centers routinely offer this type of second-line salvage chemotherapy to their patients. Patients and MethodsThis retrospective study included transplant-eligible patients with RR-DLBCL treated at Gustave Roussy between January 2008 and April 2020. Eligible patients were those who received second-line salvage chemotherapy using R-DHAP or R-ICE in patients who experienced an insufficient partial response, stable disease, or progressive disease in response to first-line salvage chemoimmunotherapy using an alternative regimen. ResultsForty-six RR-DLBCL patients received second-line salvage regimen, which yielded an objective response rate of 33%, median progression-free survival of 2.1 months, and overall survival of 11.4 months. Twelve patients proceeded to autologous stem-cell transplantation (ASCT), of whom 70% remained alive 1 year after ASCT. To explore the impact of transplantation, a multivariate analysis (excluding response to the first-line salvage regimen because this covariate was totally embedded within the transplantation covariate), ASCT was associated with progression-free survival (hazard ratio = 0.16; 95% confidence interval, 0.06-0.42) and overall survival (hazard ratio = 0.27; 95% confidence interval, 0.08-0.88). ConclusionSecond-line salvage chemotherapy with R-DHAP or R-ICE followed by ASCT leads to a favorable outcome in almost one third of patients with RR-DLBCL and offers a median overall survival of approximately 1 year. These data support the administration of second-line salvage chemotherapy followed by ASCT.

The Copy Number Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma

Introduction Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) are treated with standard frontline immunochemotherapy (R-CHOP). However, for cases where R-CHOP fails (relapsed-refractory DLBCL, rrDLBCL), prognosis is extremely poor, with 2-year overall survival of 20-40%. The successful development of new therapies may be hampered by our limited understanding of the genetic and molecular mechanisms underpinning treatment resistance. For example, recent data from our group has highlighted novel mutations that emerge following treatment with R-CHOP. The contribution of copy-number variations (CNVs) towards treatment resistance has not yet been thoroughly explored. A more complete characterization of these genetic alterations may lead to new prognostic biomarkers or treatment strategies. Methods We analyzed exome sequencing data from 59 rrDLBCL cases derived from either tissue biopsies or liquid biopsies collected after relapse, including both unpublished and previously published cases (Schmitz et al. (2018) NEJM 378:1396-1407 and Morin et al. (2016) Clin Can Res 22(9)). We separately performed low-pass whole-genome sequencing (lpWGS, 0.1-1x coverage) on 45 rrDLBCL liquid biopsies with ctDNA levels insufficient for exome-based analysis, for a total of 104 cases with copy-number information. We identified CNVs from exome and lpWGS data using Sequenza and ichorCNA, respectively. Next, we identified significant peaks of recurrent gains and losses using GISTIC2. Comparison of these peaks to CNVs in a previously published diagnostic DLBCL cohort (Schmitz et al. (2018) NEJM 378:1396-1407) enabled the identification of events that were significantly more prevalent in rrDLBCL. Results Overall, the landscape of CNVs in rrDLBCL is reminiscent of diagnostic DLBCL, with recurrent amplifications of chromosome 7 (43/104, 41.3%) and 18q (42/104, 40.4%) and recurrent deletions of 6q (25/104, 24.0%) and 17p13 (39/104, 37.5%). We identified nine regions enriched for recurrent amplifications or deletions among rrDLBCLs. These include deletions of 17p13.1 (20.4% in diagnostic biopsies vs 41.3% of rrDLBCLs, q=8.53x10-5) and recurrent amplifications of 8q24 (18.5% vs 42.3%, q=5.72x10-7) and 7p22 (27.2% vs 57.9%, q=6.29x10-8). Many of these peaks represent focal events that are exceedingly rare in diagnostic DLBCL and do not contain established lymphoma-associated genes, including amplifications affecting 700kb of 6p11.2 (2.03% vs 7.69%, q=0.0178) and 500kb of 19p13.3 (6.7% vs 31.7%, q=9.99x10-10). Notably, the 6p11.2 amplifications were associated with inferior progression-free survival following R-CHOP (p=0.02), with most tumors harboring this alteration relapsing within 12 months. We also identified a novel, recurrent deletion affecting a 20mb region of 5q (2.78% vs 10.6%, q=0.00604) which was significantly deleted in rrDLBCL. For tumors with additional samples collected prior to R-CHOP and following salvage therapy, deletions of 5q appeared to emerge following frontline therapy and persisted after subsequent treatments, suggesting they may contribute to treatment resistance. Discussion The 17p13.1 deletion enriched in rrDLBCL encompasses TP53, which is a common target of somatic point mutations in rrDLBCL and associated with inferior treatment outcomes. The amplification of 8q24 and 7p22 include MYC and GNA12/CARD11, respectively, although these large events encompass numerous additional genes which may be the target of such events. Curiously, the focal 6p11.2 amplification only overlaps a handful of genes including miR_598, which has been predicted to target CD27 and CD38 and whose expression is upregulated in B-cell cell lines (Lawrie et al. (2008) Leukemia 22:1440-2446). Further investigation and validation of these events and their corresponding targets will provide insight into the biology of rrDLBCL and may reveal novel therapeutic targets. Disclosures Michaud: Epizyme: Current Employment. Daigle:Epizyme: Current Employment. Jain:Kite/Gilead: Consultancy; Novartis: Consultancy. Kuruvilla:Merck: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Honoraria; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Antengene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; TG Therapeutics: Honoraria. Crump:Servier: Consultancy; Roche: Consultancy; Kite/Gilead: Consultancy. Assouline:BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Bayer: Consultancy; Curis Inc: Consultancy. Johnson:AbbVie: Research Funding; Roche/Genentech, Merck: Honoraria; Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie: Consultancy. Scott:NanoString: Patents &amp; Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Janssen: Consultancy, Research Funding; Roche/Genentech: Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Morin:Celgene: Consultancy.

AML-058: First-In-Human Study of a Trail Receptor Agonist Fusion Protein, Eftozanermin Alfa, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Diffuse Large B-Cell Lymphoma

Aims Evaluate pharmacokinetic (PK) profile of Eftozanermin alfa (ABBV-621; eftoza) as monotherapy (eftoza-mono) or eftoza and venetoclax (eftoza-VEN); assess safety and tolerability, preliminary antitumor activity, and exploratory biomarkers. Methods In this phase 1 study, adults with relapsed/refractory (RR) acute myeloid leukemia (AML) or diffuse large B-cell lymphoma (DLBCL) received intravenous eftoza, 1.25, 3.75, or 7.5 mg/kg in AML eftoza-mono and 3.75 or 7.5 mg/kg in AML and DLBCL eftoza-VEN cohorts days 1, 8, and 15 of a 21-day cycle. VEN dose was 400 mg or 800 mg daily (oral). Results As of September 2019, 34 patients enrolled: 4 in AML eftoza-mono(median age 75 yrs; 1.25 [n=1], 3.75 [n=1], or 7.5 [n=2] mg/kg eftoza), 19 in AML eftoza-VEN(median age 72 yrs; 3.75 [n=10] or 7.5 [n=9] mg/kg eftoza), and 11 in DLBCL eftoza-VEN cohorts (median age 64 yrs; 3.75 [n=3] or 7.5 [n=8] mg/kg eftoza). Patients received eftoza for median 1 (AML eftoza-mono), 3 (AML eftoza-VEN), and 2 (DLBCL eftoza-VEN) cycles. Four patients in AML eftoza-VEN cohorts completed ≥5 cycles. Percentage of patients with treatment-emergent adverse events (TEAEs) was 100% for AML eftoza-mono/VEN, and 91% for DLBCL eftoza-VEN. Grade ≥3 TEAEs were in all AML eftoza-mono/VEN patients and 27% in DLBCL eftoza-VEN. Most common grade ≥3 TEAEs were increased alanine (n=4, AML eftoza-VEN) and aspartate (n=4, AML eftoza-VEN; n=1, DLBCL eftoza-VEN) aminotransferase. Serious eftoza-related AEs were in 5 patients (AML eftoza-VEN); none in >1 patient. Eftoza exhibited dose-proportional kinetics at weekly 1.25- to 7.5-mg/kg doses; PK was not affected by VEN. No responses were seen in AML eftoza-mono or DLBCL eftoza-VEN cohorts. Overall response rate in AML eftoza-VEN cohorts was 4/19 (21%), with 3 complete responses (CR; 3.75 mg/kg [n=2], 7.5 mg/kg [n=1]), and 1 CR with incomplete hematologic recovery (7.5 mg/kg); 4 had RD (3.75 mg/kg [n=2], 7.5 mg/kg [n=2]) and 3 PD (3.75 mg/kg [n=3]). Eftoza binding to death receptors on neutrophils was saturated by 2h post-dose in AML and DLBCL cohorts. There was time-dependent desaturation of the receptors for eftoza binding. In 63% of patients with RR AML ≥3, molecular aberrations were observed, with IDH1/2 and RAS being the most frequently mutated genes. Conclusions Eftoza-mono and eftoza-VEN were tolerated in patients with RR AML and DLBCL. Antitumor activity was observed in patients with AML treated with eftoza-VEN at 3.75- or 7.5-mg/kg doses. Abstract was previously published at EHA25.

Health-related quality of life (HRQOL) burden in patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) and non-Hodgkin’s lymphoma (RR-NHL).

e20070 Background: CAR T therapy is being investigated as 2nd line therapy in RR-DLBCL. To evaluate its impact on patients’ HRQOL, it is essential to understand the HRQOL of patients receiving current standard of care (SOC) therapy for DLBCL and NHL patients. Methods: A systematic literature review (SLR) of studies reporting HRQOL in RR-DLBCL patients was conducted in March 2019 (updated to include RR-NHL in May 2019) using EMBASE, MEDLINE, Cochrane (all from 2007), Northern Light and International Society for Quality of Life Research abstracts (both from 2017). A targeted literature review (TLR) for untreated or 1st line patients was conducted in July 2019 using PubMed. Search terms included diseases, lines of therapy and patient-reported outcome (PRO) measures. Abstracts and publications were screened for eligibility and data were extracted. Results: Of the 977 publications screened for the SLR, 26 met the inclusion criteria. Another 18 studies were included from the TLR. The most commonly used PRO measures were the SF-36 (10 studies), EORTC QLQ-C30 and FACT-Lym (8 studies each). The EORTC QLQ-C30 showed statistically significant or clinically meaningful changes in a greater number of domains (86%) than the FACT-Lym (75%) and SF-36 (62%). Additional results in table. Conclusions: While research is limited, RR-DLBCL patients receiving current SOC therapy report decreases in HRQOL and health utility. Further research is needed on how existing and future therapies may affect HRQOL among RR-DLBCL patients. [Table: see text]

First-in-Human Study of Abbv-621, a TRAIL Receptor Agonist Fusion Protein, in Patients (Pts) with Relapsed/Refractory (RR) Acute Myeloid Leukemia (AML) and Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Apoptotic cell death can be triggered by activation of extrinsic and intrinsic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, binds to its death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) to selectively activate the extrinsic apoptotic pathway in cancer cells. ABBV-621 is a second-generation TRAIL receptor agonist with antitumor activity as monotherapy (621-mono) in preclinical models of AML and DLBCL. The intrinsic apoptotic pathway is regulated by the BCL2 protein family, commonly overexpressed in hematologic malignancies. Venetoclax (VEN), a highly selective small-molecule BCL2 inhibitor, has shown antitumor activity in combination therapy in AML and DLBCL. In preclinical and xenograft models of AML and DLBCL, the ABBV-621 and VEN combination (621-VEN) had antitumor activity superior to either agent alone. This first-in-human study evaluated ABBV-621 as single agent and in combination in pts with advanced solid tumors and hematologic malignancies (NCT03082209). Safety and tolerability of ABBV-621 in advanced solid tumors have previously been presented (Ratain et al. J Clin Oncol 2019;37[suppl]: abstr 3013). Here, we report preliminary data for 621-mono in pts with RR AML and for 621-VEN in pts with RR AML and DLBCL. Methods: Adult pts with RR AML or DLBCL (ECOG 0-2) were enrolled. Pts with AML received ABBV-621 at 1.25-, 3.75-, 7.5-mg/kg doses in the 621-mono and at 3.75-mg/kg dose in the 621-VEN arms. Pts in the DLBCL 621-VEN arm received ABBV-621 at 3.75- and 7.5-mg/kg doses. ABBV-621 was administered intravenously on D1, 8, and 15 of a 21-D cycle; in 621-VEN cohorts pts received 400 mg oral VEN daily, and could be escalated to 800 mg. The primary endpoint was safety. In addition, preliminary antitumor efficacy and ABBV-621 binding to decoy receptors on neutrophils from peripheral blood were assessed. Results: As of Jun 2019, 17 pts were enrolled. Pts in AML 621-mono arm (1.25 [1], 3.75 [1], 7.5 [2] mg/kg): 1 male; median (med) age, 75 yr (range 71-82); med prior treatments, 2.5 (range 1-4); med time on treatment, 15 D (range 1-70). Pts in AML 621-VEN arm (3.75 mg/kg [7]): 5 male; med age, 71 yr (60-79); med prior treatments, 2 (1-2); med time on treatment, 26 D (1-77). Pts in DLBCL 621-VEN arm (3.75 [3], 7.5 [3] mg/kg): 4 male; med age, 57 yr (40-75); stage 4 (3); med prior treatments, 2.5 (1 to ≥5); med time on treatment, 26 D (8-36). One pt in the AML 621-VEN 3.75-mg/kg dose cohort had increases in alanine aminotransferase, aspartate aminotransferase and bilirubin as dose-limiting toxicities. Sixteen pts experienced adverse events (AEs) irrespective of causality. A summary of AEs is shown in Table. One pt in the AML 621-mono 7.5-mg/kg dose cohort died due to AML progression, unrelated to ABBV-621. Antitumor activity was observed in 1 pt in the AML 621-VEN arm (with complex cytogenetics and TP53 mutation) who reached complete remission (CR). One pt in the DLBCL 621-VEN 3.75-mg/kg cohort had stable disease, 2 with AML had resistant disease (1 in 621-mono [7.5 mg/kg] and 1 in 621-VEN), and 7 had progressive disease (PD; 1 in AML 621-mono [1.25 mg/kg], 2 in AML 621-VEN, and 4 in DLBCL 621-VEN [2 each in 3.75- and 7.5-mg/kg] cohorts). Using flow cytometry, saturation of ABBV-621 binding to decoy receptors on neutrophils was observed at 2 h postdosing, followed by dose-dependent desaturation of receptors in pts with DLBCL at 48-168 h. In AML 621-VEN pts, ABBV-621 remained bound to decoy receptors for up to 168 h; in DLBCL 621-VEN pts, the duration of binding was higher at ABBV-621 7.5 mg/kg compared with 3.75 mg/kg. In AML, the baseline frequency of myeloblasts was higher in pts with PD than CR, while that of myelomonocytes was higher in the pt with CR. The frequency of myeloblasts and myelomonocytes expressing DR4 and DR5 at baseline was highest in the pt with CR (Figure). Conclusions: ABBV-621 was tolerated and showed antitumor activity in combination with VEN in pts with RR AML. Disclosures de Jonge: Faron Pharmaceuticals Ltd.: Consultancy. Carneiro:Actuate Therapeutics: Research Funding; Bayer: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; Medimmune: Research Funding; Astellas: Research Funding; AbbVie: Research Funding. Devriese:MSD: Consultancy. Penugonda:AbbVie: Employment, Other: Stock/stock options. Petrich:Abbvie: Employment, Equity Ownership. Nuthalapati:AbbVie: Employment, Other: Stock/stock options. Motwani:AbbVie: Employment, Other: Stock/stock options. Modi:AbbVie: Employment, Other: Stock/stock options. Chang:AbbVie: Employment, Other: Stock/stock options. Calvo:Celgene: Consultancy; Roche/Genentech: Consultancy, Other: travel/accommodations/expenses; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; PsiOxus: Consultancy; Amcure: Consultancy; START: Other: stock/ownership interests, Research Funding; Janssen-Cilag: Consultancy; EUSA Pharma: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Oncoart Associated: Other: stock/ownership interests; Guidepoint Global: Consultancy; Nanobiotix: Consultancy; HM Hospitales Group: Honoraria; AbbVie: Consultancy; BeiGene: Research Funding; Servier: Consultancy; International Cancer Consultants: Other: stock/ownership interests; Foundation INTHEOS: Other: president and founder; Gerson Lehrman Group: Consultancy; Pfizer: Consultancy. Moreno:Puma Biotechnology: Consultancy; Sanofi/Regeneron: Other: travel/accommodations/expenses.

Outpatient rituximab, ifosfamide, etoposide (R-IE) in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation

Patients with relapsed-refractory diffuse large B-cell lymphoma (RR-DLBCL) ineligible for autologous stem cell transplantation (autoSCT) have poor survival. Thirty transplant-ineligible patients older than 60 years were administered rituximab 375 mg/m2 day 1, ifosfamide 1333 mg/m2 days 1 to 3, and etoposide 80 mg/m2 days 1 to 3 (R-IE) every 21 days for 6 cycles plus 2 doses of rituximab. Revised international prognostic index 3–4 was seen in 53% and prior rituximab exposure in 60%. The complete and overall response rates were 55% and 76%, respectively. Median progression free survival (PFS) and overall survival were 23 and 24 months, respectively. Patients relapsing within 12 months of prior treatment had a median PFS of 2.5 months compared to 23 months for those relapsing beyond 12 months. Grade 3–4 thrombocytopenia and neutropenia occurred in one and eight patients, respectively. R-IE is an effective, well tolerated regimen in RR-DLBCL patients not fit for autoSCT.

Real world survival rates and healthcare utilization among SEER-Medicare patients treated with hematopoietic stem cell transplant (HSCT) for relapsed/refractory diffuse large b-cell lymphoma (RR-DLBCL).

e19502Background: Few elderly patients with RR-DLBCL are offered HSCT and little is known about their overall survival (OS) rates or economic burden. This study evaluated OS rates and healthcare re...

Overall survival (OS) and transplantation (ASCT) utilization in real-world patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL).

7545Background: Many patients (pts) with RR-DLBCL treated in the real-world are not offered ASCT despite its curative potential. Understanding the impact of ASCT on OS in the real world is critical...

Utility of routine surveillance imaging for diffuse large B-cell lymphoma post autologous transplant: A single center experience

Surveillance scans after autologous stem cell transplant (auto-HCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post auto-HCT whose recurrences were detected clinically versus with routine surveillance imaging. Among the 139 patients with RR DLBCL that underwent auto-HCT from 2000 to 2014 at our institution, 37 relapsed: 21 clinical and 16 radiological. The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p = 0.03), and median overall survival (OS) was 587 days and not reached, respectively (p = 0.006). Most patients with relapsed DLBCL after auto-HCT were diagnosed clinically and were likely to be detected earlier and have a shorter OS. Relapse in patients with aggressive disease will likely be detected when clinically apparent, and the outcome of these patients is independent of the way the relapse is diagnosed. Thus, universal scanning after auto-HCT appears to have little benefit.