Relapsed DLBCL Research Articles

CD19/BCMA Dual-Targeting Fastcar-T GC012F for Patients with Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma: An Update

Background CD19-directed CAR-T cell therapy is a valuable treatment option for relapsed/refractory B-cell non-Hodgkin's lymphoma (r/r B-NHL). It has been shown that a significant percentage of B-NHL clinical samples also express B cell maturation antigen (BCMA). To further improve safety and efficacy, we have been exploring utility of a CD19 and BCMA dual-targeting CAR-T, GC012F, manufactured through a novel next-day FasTCAR-T process, for treatment of r/r B-NHL. Here, we present updated results of this ongoing IIT trial with more patients and longer follow-up. Methods From October 2021 to June 2023, nine eligible refractory/ relapsed defuse large B cell lymphoma (r/r DLBCL) patients (pts) were enrolled in this study and treated with a single infusion of GC012F in escalating dosing cohorts after a standard lymphodepletion regimen over 3 days (20 - 30 mg/m 2/day Flu, 250 - 300 mg/m 2/day Cy). The primary objectives of this study were safety and tolerability assessment; the secondary objectives were pharmacokinetics and efficacy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASBMT 2019, and adverse effects were evaluated according to CTCAE 5.0. Efficacy assessment of GC012F was based on the Lugano criteria. Expansion of CAR-T cells and CAR copy numbers were analyzed by flow cytometry and qPCR, respectively. Results As of data cut-off of June 30 th, 2023, with a median of 372 days (range 131 - 625) of follow-up, all nine patients received single GC012F infusions at dose levels from 3.7×10 4 to 3×10 5 CAR-T/kg, and completed 3 months or longer time follow-up evaluations. The median age was 52 years (range 18 - 60). Among the enrolled patients, eight pts were Ann Arbor stage III/IV disease, one patient with double hit, and four pts had IPI score of 3. The lymphoma samples of all patient expressed CD19, and 7 out of 8 expressed various levels of BCMA. The median SPD was 2690.81 mm 2 (408.3 - 13325.96 mm 2). Patients received a median of 2 prior lines (range 2 - 3) of therapy including rituximab and anthracyclines. Two patients received prior auto-HSCT. All patients responded to GC012F treatments, 100% (9/9) pts achieved ORR at month 3 post GC012F infusion; 77.8% (7/9) CR at month 3, 66.7% (6/9) CR at month 6 and 62.5% (5/8) CR at month 9, respectively. Up to date, the longest duration of remission was 20.8 months. No dose-limiting toxicities were observed. Five patients experienced grade 1 CRS, and one patient in the highest dose group (3×10 5 CAR-T/kg) had grade 3 CRS within 2 days. No ICANS were observed. Of the nine treated patients, grade ≥ 3 hematologic toxicities were neutropenia (9/9), leukopenia (8/9), lymphocytopenia (8/9), and thrombocytopenia (7/9). All TEAEs were resolved after treatment with standard of care and supportive care. The median peak copy number of CAR-T cells in the peripheral blood was 71,000 copies/μg DNA (range 9263 - 185,039), and the median peak time was 14 days (range 9 - 21d). CAR-T geometric mean AUC 0-28 for patients was 658,538 copies/μg DNA × day (319,104 - 1,359,031; 95% CI). CAR-T cells were also detected in tumor biopsies from all five patients tested. Conclusion This first-in-human trial of GC012F, a CD19-BCMA dual targeting CAR-T product, for the treatment of r/r B-NHL showed a manageable safety profile and promising clinical responses. The ORR was 100% at month 3 with 77.8% (7/9) achieving CR. GC012F CAR-T cells were detected in the tumor biopsies, indicating the infiltration of CAR-T cells into the tumor lesions. Overall, based on the safety and efficacy results, CD19-BCMA dual targeting CAR-T product GC012F is a promising therapy for patients with refractory/ relapsed DLBCL.

The Role of High-Dose Regimens Followed By Autologous Stem Cell Transplantation for Salvage Chemotherapy-Sensitive DLBCL Patients

CONCLUSION INTRODUCTION： It has been reported that lisocabtagene maraleucel improved event-free survival and complete response rate compared with standard care as second -line therapy for early relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) patients(pts). However, CAR T-cell therapy could not be available for some candidates with rrDLBCL due to socioeconomical issues and manufacturing limitations. High-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a conventional curative treatment for salvage chemotherapy-sensitive DLBCL. We have devised AECC regimen (Usui, Clin Lymph; 2005, and Yano, Clin Lymph and Myeloma; 2007) for auto-SCT. Further, we have also used ranimustine (MCNU) based MEAM regimen due to not availability for carmustine in Japan. In this retrospective study, we compared the efficacy and safety of AECC with MEAM. METHODS： We retrospectively analyzed 68 pts with DLBCL who received AECC or MEAM followed by auto-SCT from January 2006 to December 2021 at the Jikei University Hospital and the Jikei University Kashiwa Hospital. AECC regimen consists of nimustine 200mg/m 2 on day -7 to day -6, etoposide (ETP) 30mg/kg on day -5 to day -4, cyclophosphamide 60mg/kg on day -3 to day -2, carboplatin 700mg/m 2 on day -3 to day -2. MEAM regimen consists of MCNU 300 mg/m 2 on day -7, ETP 200 mg/m 2 on day -6 to day -3, cytarabine 200 mg/m 2 q12 hrs on day -6 to day -3, and melphalan 140 mg/m 2 on day -2. In this study, early relapsed DLBCL (erDLBCL) was defined as DLBCL pts relapsed within 2 years from diagnosis. We retrospectively analyzed overall survival (OS), progression-free survival (PFS) and adverse events (AE). Thirty-five pts received AECC and 33 pts MEAM in DLBCL, respectively. AECC was mainly used from 2006 to 2013, and MEAM was used from 2014 to 2021. The patient characteristics between AECC and MEAM were as bellows; the median follow-up time for survival was 109 (0-193) vs 35(1-83) months ( P <0.01), the median age at auto-SCT was 54(25-65) vs 58 (40-68) years ( P = 0.01), 66% vs 61% were male ( P = 0.80), the median years from diagnosis to auto-SCT was 1.43(0.39-12.79) vs 1.67(0.39-22.40) years ( P = 0.41), the number of pts who receive 2 lines of therapy before auto-SCT were 18 vs 23 ( P = 0.144). Disease status at auto-SCT in the AECC and MEAM groups were 16 vs 12 pts in complete response (CR), 15 vs 21 pts in partial response (PR), and 4 vs 0 pts in stable disease or progressive disease (SD/PD) ( P = 0.06). The 2-year OS and PFS rates in the AECC and MEAM groups were 76.9% vs 68.3% ( P =0.323), and 68.2% vs 59.4% ( P =0.137), respectively. In addition, we focused er DLBCL pts whose disease status at auto-SCT was CR or PR, named as “chemotherapy-sensitive er DLBCL”. Twenty-one pts were treated with AECC and 19 pts were received MEAM. The patient characteristics between AECC and MEAM were as bellows; the median age at auto-SCT in the AECC group was younger than those in the MEAM group (53(25-65) vs 60 (47-68) years, P = 0.01), the number of pts with CR in the AECC group was higher than those in the MEAM group. (10 vs 3, P = 0.046). The OS and PFS in the AECC group were significantly higher than those in the MEAM group (2-year OS 85.4% vs 48.5% ( P = 0.019), and 2-year PFS 75.6% vs 39.0% ( P <0.01), respectively). Additionally, AECC achieved long-term survival with 8-year OS and PFS of 80.4% and 75.6% in the chemotherapy-sensitive er DLBCL, respectively. At the time of data analysis, deaths had been reported in 12 of 35 pts in the AECC and 12 of 33 in the MEAM. The most common cause of death was disease progression (10 pts in the AECC and 8 in the MEAM). Non-relapse mortality (NRM) was observed in 2 pts of the AECC (drug-induced cardiomyopathy (n = 2)), and 4 of the MEAM (liver failure (n = 2), pneumonia (n = 1), and suicide (n = 1)). It should be mentioned that grade 3 or higher heart failure was observed in the AECC group (n = 8) compared to in the MEAM group (n = 0). Treatment related mortality (TRM) within 100 days was 2 pts in the AECC group due to cardiomyopathy and 0 in the MEAM group. AECC followed by auto-SCT achieved both long-term OS and PFS compared to MEAM in chemotherapy-sensitive er DLBCL pts. Further validation for efficacy is needed due to the differences in patient's background and follow-up period in the study. However, AECC was associated with a higher incidence of cardiac toxicity and TRM within 100 days. It was suggested that auto-SCT with AECC may be a treatment option when CAR T-cell therapy was not available.

Abstract CT052: A phase 1/2 randomized study of imvotamab monotherapy and in combination with loncastuximab tesirine in relapsed/refractory non-Hodgkin lymphomas

Abstract Background: Recent advances in the treatment of non-Hodgkin lymphoma (NHL) have transformed the landscape and provided significant benefits to patients. Novel agents that target CD19 and CD20 on B cells, such as bispecific T-cell engagers and chimeric antigen receptor T-cell (CAR-T) therapy, have demonstrated benefit for patients in the relapsed and refractory setting. However, these agents can often be associated with significant toxicity and there is a need for new therapies that can provide clinical benefit with a superior safety profile. Imvotamab is a novel CD20 x CD3 bispecific antibody utilizing an IgM backbone. This allows targeting of up to 10 CD20 binding sites for every CD3 site. In preclinical models, imvotamab demonstrated encouraging antitumor activity and stimulated T-cells in a more physiologic manner than IgG-based antibodies, which may reduce adverse events typically associated with T-cell engagers and CAR-T, such as CRS and neurotoxicity. Loncastuximab tesirine is a CD19-targeting antibody-drug conjugate approved by the US FDA and EMA for relapsed DLBCL after 2 lines of systemic therapy. Loncastuximab tesirine has shown activity in both DLBCL and FL. Combining therapies such as loncastuximab tesirine, which targets CD19 and induce apoptosis of cancer cells, with imvotamab’s ability to eliminate CD20+ tumor cells by engagement with T-cells, may improve treatment outcomes among patients with NHL via synergistic mechanisms of action. Methods: This study is a Phase 1/2, multicenter, single-arm clinical trial of imvotamab as monotherapy and in combination with loncastuximab tesirine for patients with relapsed/refractory NHL. Phase 1a Dose Escalation is complete with no DLTs or neurotoxicity AEs up to 1000mg dose titration. Phase 1b Combination will evaluate imvotamab and loncastuximab tesirine in patients with R/R 2nd line or later NHL. Phase 2 monotherapy Dose Selection is currently ongoing. The Phase 2 component randomizes patients at two different dose levels (100 mg and 300 mg plateau dose) in two separate indications (R/R DLBCL and R/R FL). Patients receive weekly dosing on Day 1, 8, and 15 of each 21- day cycle. Dosing begins at 15 mg and is increased weekly for 3-4 weeks to reach the plateau dose. Patients then stay at the plateau dose until disease progression or unacceptable toxicity. Patients who achieve a response by Week 12 may switch to a less frequent dosing interval of every 3 weeks. Primary endpoints include frequency and severity of adverse events and objective response rate (ORR) based on Lugano criteria. Correlative biomarker studies will evaluate the relationship of clinical benefit with blood and tissue biomarkers. The study is currently open with patients enrolling in Phase 2 at time of submission. Phase 1b Combination is expected to begin enrollment in the first quarter of 2023. Clinical trial information: NCT04082936. Citation Format: Catherine Diefenbach, Won Seog Kim, Chan Cheah, Ajay K. Gopal, Philippe Armand, Ian Flinn, Gareth P. Gregory, Sung-Soo Yoon, Loretta Nastoupil, Jennifer Lue, Vincent Ribrag, Javier Briones, Antonio Salar-Silvestre, Anna Sureda-Balari, Matthew Ku, Hans Cruz, Paul Thaler, Ibrahim Qazi, Rachel Wei, Maya Leabman, Genevive Hernandez, Iris Sison, Elizabeth Budde. A phase 1/2 randomized study of imvotamab monotherapy and in combination with loncastuximab tesirine in relapsed/refractory non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT052.

286 - Prolonged Cytopenias after Commercial CAR T-Cell Therapy with Tisagenlecleucel and Axicabtagene Ciloleucel for Relapsed and Refractory DLBCL

286 - Prolonged Cytopenias after Commercial CAR T-Cell Therapy with Tisagenlecleucel and Axicabtagene Ciloleucel for Relapsed and Refractory DLBCL

Sequencing therapy in relapsed DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy worldwide, comprising approximately 30% of all lymphomas. Currently, 50% to 60% of patients diagnosed with DLBCL are alive at 5 years and cured with modern therapy, but about 10% to 15% of patients are refractory to first-line therapy, and an additional 20% to 30% relapse following a complete response. Patients who have relapses beyond 2 years may experience more favorable outcomes and have forms of DLBCL that can be distinguished biologically. Patients who experience early relapse or who have primary refractory disease (less than a complete response or relapse within 3 to 6 months of initial therapy) have worse outcomes. For decades, the standard of care treatment strategy for fit patients with relapsed DLBCL has been salvage therapy with non-cross-resistant combination chemoimmunotherapy regimens followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) as stem cell rescue for patients with chemosensitive disease. Recent data suggest that certain patients may benefit from chimeric antigen receptor T-cell therapy (CAR T) in the second-line setting. Additional novel therapies exist for patients who are ineligible, who are unable to access these therapies, or who fail ASCT and/or CAR T. Despite the advent of new therapies for DLBCL and improved outcomes, DLBCL remains a life-threatening illness. Thus, it is essential for clinicians to engage in serious illness conversations with their patients. Goals-of-care communication can be improved through skills-based training and has been demonstrated to have an impact on patient experiences.

Icans Prophylaxis with Simvastatin and Intrathecal Dexamethasone in Adults Receiving Axicabtagene Ciloleucel (Axi‐Cel) Treatment

BackgroundAxi-cel is approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma since 2017 and has demonstrated efficacy and durability but with significant side effects, namely cytokine release syndrome (CRS) and neurotoxicity (ICANS). In patients receiving axi-cel for aggressive lymphomas, any grade ICANS occurs at a rate of 50% and grade 3/4 occurs about 35% of the time. The mechanism underlying ICANS remains unclear. The current working hypothesis is that endothelial injury caused by the disease and lymphodepleting chemotherapy leads to breakdown of the blood-brain-barrier. Following activation of axi-cel, cytokines are trafficked into the central nervous system leading to local production of cytokines and the clinical syndrome observed. ICANS is treated with systemic steroids with good CNS penetration. Statins have been shown to stabilize the endothelium and have anti-inflammatory effects. We are currently evaluating the safety and feasibility of administering simvastatin to stabilize the endothelium in addition to dexamethasone delivered intrathecally to prevent the occurrence and decrease the severity of neurotoxicity.Methods:This is a feasibility study combining simvastatin 40 mg orally, daily, starting at least 5 days prior to apheresis in addition to dexamethasone delivered intrathecally on days -1, +6, +13 in relation to axi-cel. A schema of the trial is presented in figure 1. This is registered on Clinicaltrials.gov number (NCT04514029).Results:We have accrued 6/20 planned patients with r/r DLBCL who received axi-cel per institutional guidelines. One passed away prior to apheresis due to disease progression and was non-evaluable. Table 1 shows the patient characteristics. With a median follow up of 123 days (50-245), all patients achieved a complete response and remained alive. Table 2 summarizes the feasibility, safety, and dose-density received out of prescribed. None of the 5 patients had grade 3 or 4 ICANS and only 1 patient had grade 1 neurotoxicity (Table 3). A cytokine analysis and markers of endothelial and neuronal activation is underway.Discussion:In a preliminary analysis, simvastatin and intrathecal dexamethasone appears to be feasible to administer, safe and efficacious in a population of patients receiving axi-cel for relapsed and refractory DLBCL. There appears to be a signal in abrogating neurotoxicity without any effect on the efficacy of axi-cel. This will allow for a safer delivery of axi-cel and improve access to this treatment. This study is ongoing. [Display omitted] DisclosuresBachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Miller: Wugen: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. OffLabel Disclosure:Simvastatin is an HMG-CoA reductase inhibitor approved for hyperlipidemia and cardiovascular health.

Next-Generation Sequencing Reveals Molecular Heterogeneity in Primary Testicular DLBCL

Background:Primary testicular lymphomas (PTLs) are extra-nodal large B-cell lymphomas (LBCLs) that respond poorly to current empirical treatment options. To date, no PTL whole-exome sequencing analysis based on the Chinese population has been reported. The main objective of this study was to explore the genomic landscape of PTDLBCL, correlating the results with clinical, histological, and immunogenetic features.Methods:We retrospectively analyzed the disease characteristics in a series of 20 patients (13 paired data and 7 unpaired data). In all cases, the diagnosis of PTL was made using appropriate diagnostic criteria for the 2008 WHO classification of lymphoid tumors with combinations of histologic, immunohistochemical, flow cytometric, and genetic evaluation. Medical records were reviewed for demographic and clinical data. We performed whole-exome next-generation sequencing (NGS) and mapped the mutational landscape. Based on the differential gene results, we performed KEGG and GO enrichment analysis, and five potential new pathogenic genes for DLBCL were obtained based on the Polyphen score.Results:A total of 20 DLBCL samples were collected. All samples were subjected to whole-exome sequencing (WES). A standard bioinformatics analysis process was used to identify somatic mutations in each sample, and an average of 1200 somatic mutations was identified, involving an average of 420 mutated genes. (Figure 1.) More than 85% of the somatic mutations were found in only 1 sample, indicating that somatic mutations are highly heterogeneous. In the matched 13 cases, we validated common gene mutations that have been reported, including PIM1 53.84% (7/13), CD79B 38.46% (5/13), CDKN2A 15.38% (2/13), and MYD88 15.38% (2/13). Venn diagram shows that 25% of the mutated genes were specific to the relapsed sample. GO analysis (Figure 2) shows the functional enrichment and differences between relapsed and non-relapsed samples. Non-relapsed samples are enriched in the herpes simplex virus 1 infection pathway. (Figure 3). Focusing on relapsed/non-relapsed samples, we identified 12 mutated genes specific to relapsed samples. Mutation Polyphen scores were calculated to assess mutation deleteriousness. Five potential new pathogenic genes for DLBCL were obtained.Conclusions:Based on whole-sequencing data, we validated the previously reported common genes for PTDLBCL. In addition, we performed GO and KEGG analysis according to the relapsed and non-relapsed groups. In addition, based on the difference in enrichment results, 12 significantly enriched mutated genes in relapsed DLBCL samples are obtained, and mutation Polyphen scores are calculated to assess mutation deleteriousness. And 5 potential new pathogenic genes of DLBCL are identified. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions.

Aims:To review recent data and relevant of the role of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell non-Hodgkin lymphoma (NHL).Methods:Review and compilation of the most recent and relevant data published in full text and abstract forms of anti-CD19 CAR T-cell therapy for B-cell NHL.Results:Different anti-CD19 CAR T-cell therapy products have been tested and shown significant clinical activity across B-cell NHL patients. The objective responses in relapsed DLBCL, FL and MCL were 50–83%, 83–93% and 93%, respectively.Conclusions:Anti-CD19 CAR T-cell therapy is a viable option for poor risk refractory B-cell NHLs.

WHOLE GENOME SEQUENCING OF MATCHED PRIMARY AND RELAPSED DLBCL REVEALS DISTINCT EVOLUTIONARY DYNAMICS ASSOCIATED WITH RELAPSE TIMING

WHOLE GENOME SEQUENCING OF MATCHED PRIMARY AND RELAPSED DLBCL REVEALS DISTINCT EVOLUTIONARY DYNAMICS ASSOCIATED WITH RELAPSE TIMING

Ktx-120, a Novel Irakimid Degrader of IRAK4 and IMiD Substrates Shows Preferential Activity and Induces Regressions in MYD88-Mutant DLBCL CDX and PDX Models

An important goal of cancer therapy is to improve patient outcomes by driving to deep and durable tumor responses. The activity of single-agent targeted therapies, such as BTK inhibitors or IMiDs alone, has been modest in relapsed and refractory DLBCL, necessitating the use of combination therapy. Targeted protein degraders are heterobifunctional small molecules that co-opt the endogenous ubiquitin-proteasome system to drive the selective degradation of target proteins. Degraders of IRAK4, a key component of the myddosome complex, show potent and selective IRAK4 degradation and preferential activity in MYD88-mutant (MYD88MT) DLBCL models. Notably, the activity of IRAK4 degradation is superior to IRAK4 kinase inhibition, supporting the essential scaffolding role of IRAK4 in myddosome signaling. We have previously described IRAKIMiDs, novel IRAK4 degraders that utilize an IMiD as a pharmacologically active cereblon binder. These degraders simultaneously degrade both IRAK4 and IMiD substrates and show synergistic antitumor activity over either IRAK4 degraders or IMiDs alone, enabling a therapeutically relevant biological combination within a single small molecule. Here we describe KTX-120, a novel IRAKIMiD development candidate. KTX-120 is an equipotent degrader of both IRAK4 and the IMiD substrates Ikaros and Aiolos in lymphoma model systems with low single-digit nM DC50 for degradation of all substrates. The cell activity of KTX-120 has shown a high dependence on MYD88MT status: across a panel of MYD88MT cell lines, KTX-120 showed consistent and potent cell activity, with IC50 ranging from 7-29nM, whereas in MYD88WT lines, cell activity was poor ranging from 1800-3400nM. In the OCI-Ly10 ABC DLBCL cell line that harbors a MYD88L265P mutation, the cell activity of KTX-120 was associated with degradation of both IRAK4 and Ikaros, supporting the combined IRAK4 and IMiD targeting of this molecule as contributing to cell activity. Notably, the onset of cell death in OCI-Ly10 cells with KTX-120 treatment was rapid, with cells becoming committed to cell death within 72h of exposure, suggesting that continuous exposure to KTX-120 may not be necessary for antitumor activity. We explored the pharmacological activity of KTX-120 in several in vivo model systems. KTX-120 is orally bioavailable and shows dose-proportional exposure in several species. A single oral dose of KTX-120 (10 mg/Kg or 30 mg/Kg) showed significant degradation of both IRAK4 and Ikaros in a dose and time-dependent manner, with degradation of both substrates being sustained for >96h, further supporting the potential for intermittent dosing. To assess this, we have explored the antitumor efficacy of KTX-120 in intermittent dosing schedules. KTX-120 was well tolerated and showed potent antitumor activity in several CDX models of MYD88MT DLBCL, including OCI-Ly10, TMD8 and SUDHL2, achieving regressions in all models in as little as once every 2 weeks. As an example, in OCI-Ly10, a 30mpk dose Q2W drove >80% degradation of both IRAK4 and Ikaros and showed regressions (including CR) by D28. Similar activity and tolerability were seen with both PO and IV dosing at doses that achieve active exposure, enabling the potential for both oral and parenteral dosing. We have further explored the activity of KTX-120 in a collection of DLBCL patient derived xenograft models. KTX-120 shows robust activity (>85% TGI) in 4/5 models of MYD88MT DLBCL and shows no or modest activity in 2/2 models of MYD88WT DLBCL, supporting the preferential activity of this mechanism in patient samples harboring MYD88 activating mutations. Importantly, activity was observed in models with a variety of co-mutations that activate the NFkB pathway, including alterations in, CD79B and TNFAIP3, suggesting that KTX-120 has the potential for activity in MYD88MT lymphoma regardless of other mutations. Collectively, these data support the combined IRAK4 degradation and IMiD activity of KTX-120 has the potential to achieve robust and durable regressions in MYD88MT lymphomas with the increased convenience of an intermittently administered single agent and decreased potential for drug combination challenges. Disclosures Walker: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chen:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhaduri:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rusin:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Weiss:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

CAR T-cell therapy in diffuse large B-cell lymphoma

SummaryDiffuse large B‑cell lymphoma (DLBCL) comprises 30–40% of non-Hodgkin’s lymphoma. Clinical factors such as a high International Prognostic Index (IPI) or molecular factors as cell of origin (COO) have an influence on the clinical outcome after conventional immunochemotherapy. Patients with resistant or relapsed (r/r) DLBCL have a poor prognosis with a median overall survival of 6,3 months and low complete response rates (CR 7%) to salvage chemoimmunotherapy. Currently, therapy with autologous chimeric antigen receptor T‑cells (CAR T‑cells) provide encouraging complete responses (CR) of up to 50%. However, high costs for approved products and elaborate logistics have to be encountered.

Changes in Tumor Immune Micro-Environment in Diffuse Large B-Cell Lymphoma (DLBCL): A Comparative Study of Relapsed Versus Diagnostic DLBCL

Introduction The tumor immune microenvironment (TiME) of DLBCL at diagnosis bears many biomarkers known to predict sensitivity to checkpoint blockade therapy (CBT). Approximately 25% of DLBCL, harboring PDL1 gene alteration, exhibit an immune inflamed phenotype. However, CBT studies in relapsed DLBCL show very low response rates. The immune landscape of DLBCL in the setting of relapse has not yet been characterized. We hypothesized that the TiME can be influenced by the therapy, explaining the CBT lack of efficacy. We explored the TiME evolution by comparing the tumor infiltrating lymphocytes (TIL) and the immune evasion signature by protein and gene expression (GE) in paired biopsies of DLBCL at diagnosis and at relapse. Method This study included patients with DLBCL treated with first-line R-CHOP-like regimen, in which we had access to nodal biopsies obtained pre-treatment and at relapse. Assessment of TIL and PDL1+ cell content was carried out by CD3, CD4, CD8 immunostaining and with PDL1 (Ventana, SP263) and PAX5 double staining. These were performed on formalin-fixed, paraffin-embedded (FFPE) tissue sections cut at 4µm. The proportion of each cell-type was expressed in relation to total nucleated cells. PDL1+ cell proportion was expressed for both total cells and tumor cells. The paired non-parametric Wilcoxon test, double-sided with p=0.05, was used for comparison. GE using a panel of 760 cancer immune genes was performed with the digital hybridization NanoString platform on paired FFPE specimens. NSolver software was used for normalization on housekeeping genes, differential expression (DE) and cell-type profiling. The correlation between IHC and GE variation were computed using the Spearman test. Analysis of enriched pathways on combined patient data were performed with GSEA software, using two gene sets for T-cell activation and immune evasion validated in B-cell lymphoma, and Ingenuity Pathway Analysis (IPA) for the 339 highest changed genes. The pathway enrichment analysis was reported for false discovery rate (FDR) <0.05. Results Twenty DLBCL patients with paired diagnostic and relapse biopsies were studied. IHC was performed on 19 patients (necrotic tissue for one patient) and GE by NanoString on 6 patients. The median number of treatments received prior to obtaining the relapsed biopsy was 3 (1-6). Three patients had prior exposure to CBT, none from the patients in whom GE was performed. Our population was composed of 2/3 germinal center B-cell (GCB) DLBCL. Six patients had transformed DLBCL. At relapse, CD4 and CD8 cells density was significantly reduced compared to diagnosis. The median percentages of CD3, CD4 and CD8 were 15%, 7.5% and 5% at diagnosis and 7.5%, 2.5% and 2.5% at relapse, respectively (Figure 1A). The median proportion of PDL1+ cells (n=15) did not differ at relapse compared to pre-treatment (5.25% and 5%, respectively) (Figure 1B). At diagnosis, 87% of biopsies were found to be positive for PDL1 (≥1% of positive cells) and 73% at relapse. The PDL1 positive cells were mostly immune cells; only 3 samples had tumor cells expressing PDL1 at pre-treatment and 4 at relapse with <1% of positive tumor cells in all cases. The GE profile detected 63 genes that were significantly different in relapse vs pre-treatment samples (p<0.005), including 8 up-regulated and 55 down-regulated. The correlation for T-cell abundance variation between IHC and GE was high (r=0.94, p=0.017). For the subset of 6 patients in whom GE was performed, the T-cells were not significantly reduced as measured by both IHC and GE. However, the GSEA for immune escape genes and T-cell activation signatures were both down-regulated (FDR=0.033 and 0.010, respectively) (Figure 2). IPA predicted decreased activation of leukocytes (z-score=-6.317) and Th2 activation pathway (z-score=-3.182). Conclusion At relapse, a proportion of DLBCL have a significant reduction in T cell infiltration. As well, they acquire a non-T cell-inflamed TiME. The T-cell inhibition seems to be independent of local T-cell immunoregulatory mechanisms as the immune escape signature is also reduced. This non immunogenic, "cold" condition could explain the lack of efficacy of CBT in the relapsed setting. Prior exposure to steroid containing therapy might be a trigger for intra-tumor T-cell desertion and downregulation. This observation must be confirmed on a larger population. Further analyses will be presented. Disclosures Johnson: BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Seattle Genetics: Honoraria; Merck: Consultancy, Honoraria; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria.

Radiotherapy in Combination with Chimeric Antigen Receptor T Cell Therapy Is a Safe and Promising Approach in Relapsed/Refractory Diffuse Large B Cell Lymphoma Patients with High Tumor Burden

Radiation therapy (RT) for localized-refractory or relapsed (R/R) DLBCL after chemotherapy is a standard therapy. Chimeric antigen receptor T cells (CAR-T) therapy is demonstrated as a novel immunotherapy modality with impressive efficacy in R/R B-cell malignancies including DLBCL. However, CAR-T therapy is also associated with potentially fatal toxicities, including cytokine release syndrome (CRS) and neurological toxicities. Whether radiotherapy in combination with CAR-T is a better approach to enhancing efficacy and decreasing toxicity of CAR-T therapy in R/R DLBCL patients with high tumor burden remains unknown. Human CD3+T cells were separated from peripheral blood mononuclear cells (PBMS) of patients or donors by degradable anti-CD3 magnetic microbeads followed by 24h stimulation with CD3 and CD28 monoclonal antibody (5ug/ml). Then CD3+T cells were transduced with humanized CAR construct targeting CD19, CD20 and CD22 and further expanded for 7 to 10 days in vitro. 14 patients with high tumor burden R/R DLBCL were enrolled in the study. Patients from 39 to 66 years of age had received two to four prior lines of therapy. 7 patients received intensive second-line chemotherapy (median age, 46 years) and 7 received radiotherapy (median age, 63 years) to debulking tumor after leukapheresis and during CAR-T cells preparation. Intensive combined chemotherapy or radiation (40 Gy in 20 fractions) were carried out for debulking condition after sequential FC regimen (cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 X 3d) for lymphodepletion chemotherapy. Two days after FC regimen, CAR-T cells targeting CD19 and CD20 or CD22 at average dose of 1-2×107 cells for each target per kilogram (kg) were infused within 3 days. Severe CRS (grade 3/4/5) was reported in all patients of chemotherapy cohort and mild CRS (grade 1/2) was reported in all patients of radiation cohort. 4 patients (57.1%) in chemotherapy cohort showed neurological toxicity while no patient in radiation cohort showed neurological toxicity. Comparable hematological/non-hematological toxicity and non-neurological toxicity were observed in both two groups. In chemotherapy cohort, four of seven (57.1%) patients achieved an objective response after CAR-T infusion with three of seven (42.9%) achieving a CR. In radiation cohort, seven of seven (100%) achieved an objective response after CAR-T therapy with four of seven (57.1%) achieving a CR. Our results indicate that compared to intensive second-line chemotherapy, radiation is a better approach with enhanced efficacy and decreased toxicity of CAR-T therapy in R/R DLBCL patients with high tumor burden. Radiotherapy in combination with CAR-T cell infusion may be the optimal alternative treatment model of R/R DLBCL with high tumor burden.

Surveillance PET 100 Days after Autologous Hematopoietic Cell Transplantation Identifies Diffuse Large B Cell Lymphoma Patients with Extremely Poor Survival

Introduction The utility of surveillance imaging following auto-HCT in relapsed/refractory DLBCL remains unclear. Imaging is costly and exposes patients to radiation. Novel interventions are now available for patients relapsing after auto-HCT making early disease recognition crucial to intervene prior to clinical progression. We analyzed a cohort of auto-HCT recipients who were uniformly monitored with surveillance (18)F-FDG-PET CT at day 100 (Interquartile range (IQR): 97-103 days) post-HCT. Objectives We explored the PET parameters including Deauville (D) and total metabolic tumor volume (TMTV) as predictors of relapse and survival after auto-HCT. In addition, we assessed outcomes of patients with clinically versus radiographically detected relapsed DLBCL after auto-HCT. Methods/Results We included 131 DLBCL patients (median age 56 years) with available day 100 PET scan treated with auto-HCT between 2006-2016. Median follow-up was 3.3 years. Five-year cumulative incidence of relapse after auto-HCT was 50%, (95%CI 39 to 59) and overall survival (OS) was 51% (95% CI 41 to 63). Twelve (9%) relapsed prior to day 100 and 91 patients underwent surveillance PET/CT imaging at day 100. At time of surveillance re-staging most patients' scores were D1 (22%) or D2 (55%) and 21 (23%) had a D≥3. Patients with D5 (n=12) had higher TMTV (137 cm3) compared to D4 (n=9, TMTV 12.5 cm3). 5-year OS in post-HCT D4 and D5 were only 37% (95%CI=14 to 100) and 25% (95%CI=43 to 89), respectively, whereas those with post-transplant D1 and D2 both had 5-year OS of 62%. Median survival in years for D1, D2, D4 and D5 were 6.0, 6.8, 4.7, and 1.2, respectively. Risk of death was 4 times higher in D5 patients relative to D1 (HR 4.10, 95%CI =1.56 to 10.77; p ≤ 0.01). The hazard ratio for death following relapse was 2-fold higher (HR 1.8 [95% CI 0.9 to 3.4]; p=0.08) if relapse was detected clinically versus only radiographically over a median follow-up time period of 3.3 years. Conclusion In patients with relapsed/refractory DLBCL, PET scan D5 in day 100 post-HCT PET is associated with extremely poor survival ∼ 1 year. Identifying this high-risk cohort can potentially highlight patients that might benefit from cell therapy or other rescue treatment strategies.

Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation (allo-HCT) Provides Durable Progression-Free Survival (PFS) in a Subset of Diffuse Large B-Cell Lymphoma (DLBCL) Patients Relapsing after Autologous (auto-) HCT

▪Background: DLBCL relapsing after an auto-HCT has a poor prognosis. Unfortunately this is a common clinical dilemma, since ~50% of auto-HCTs for DLBCL ultimately fail. Allo-HCT is often considered following failure of an auto-HCT; however, limited information is available regarding prognostic factors identifying DLBCL patients likely to benefit from a subsequent allo-HCT.Methods: Adult (≥18 years) DLBCL patients undergoing an alloHCT between 2000-2012, after experiencing disease progression/relapse (P/R) following a prior autoHCT and reported to the CIBMTR were included. Patients undergoing tandem auto-allo HCT and those receiving allo-HCT for indications other than relapsed DLBCL were excluded. Primary outcomes were non-relapse mortality (NRM), P/R, PFS, and overall survival (OS). Cox regression method was used to develop a prognostic model of PFS and OS.Results: Characteristics of 503 patients included in this analysis are shown in Table 1. The 3-yr univariate probabilities of NRM, P/R, PFS and OS were 30%, 38%, 31% and 37% respectively. Factors associated with higher NRM on multivariate analysis (MVA) included chemoresistance disease prior to allo-HCT (RR=1.86; p=0.003), myeloablative conditioning (MAC) (RR=1.99; p=0.0006; within 1st 10months following alloHCT) and unrelated donors (URD) grafts (RR=1.44; p=0.03). Factors associated with P/R on MVA included chemoresistance (RR= 2.25, p<0.0001), Karnofsky performance status (KPS) <80 (RR 1.81, p=0.006), and interval between auto-HCT and allo-HCT of <1 yr (RR=2.28, p<0.0001). Factors associated with inferior PFS on MVA included KPS <80 (RR=1.79, p=0.0005), chemoresistance (RR=2.04, p<0.0001), auto-HCT to allo-HCT interval <1 yr (RR=1.32, p=0.01), and MAC (RR 1.29, p=0.03). Factors associated with worse OS on MVA included KPS <80 (RR1.86, p=0.0003), chemoresistance (RR=1.94, p<0.0001), MAC (RR=1.39, p=0.008). Three adverse prognostic factors were used to construct a prognostic model for PFS, including; (i) KPS <80 (2 points) (ii) Interval between auto-HCT & allo-HCT of <1yr (1 point) and (iii) chemoresistant disease at allo-HCT (2 points). This CIBMTR prognostic model classified patients into three prognostic groups: low risk (0-1 points), intermediate risk (2-3 points), or high risk (4-5 points), predicting 3-yr PFS probabilities of 38% (95% CI=32-44), 19% (95% CI=11-27) and 10% (95% CI=0-22), respectively (Fig 1). The 3-yr OS probabilities in similar order were 43%, 25% and 14% respectively.Conclusion: The CIBMTR prognostic model identifies a subgroup of DLBCL patients relapsing from an auto-HCT who can experience long-term PFS following an allo-HCT. Reduced-intensity conditioning is preferred in this setting. TableN=503 (%)Median age at alloHCT, years52 (range 19-72)Male gender305 (61)KPS ≥80393 (78)Stage III-IV at diagnosis54%Rituximab prior to HCT72%Median lines of therapy4 (range 1-7)High LDH at HCT34%Time from auto-HCT to allo-HCT, months15 (range 1-198)Disease status at transplantCR175 (35)PR197 (39)Chemorefractory106 (21)Untreated12 (2)Missing13 (3)Type of donorSibling253 (50)URD250 (50)Myeloablative conditioning127 (25)PB graft456 (91)TBI in conditioning133 (26)Median follow up, months55 (range 1-149) [Display omitted] DisclosuresSmith:Celgene: Consultancy; Pharmacyclics: Consultancy. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

A Phase 2 Trial of AZD1152 in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) and has an aggressive natural history. R-CHOP has improved patient (pt) survival and established a standard of first line care. In the rituximab era the prognosis for relapsed DLBCL is poor, with salvage chemotherapy and autologous stem cell transplantation (ASCT) only curing a small proportion (<25% of all relapses) of those with adequate performance status. Relapsed DLBCL in those unfit for ASCT or post-ASCT is rarely curable, and remains an unmet clinical need.AZD1152 (barasertib) is a highly selective and potent Aurora B kinase inhibitor. Aurora B kinase has an important function at the spindle assembly check-point in mitosis. The kinase is overexpressed in 48% of DLBCL. Exposure of high grade lymphoma B cells to AZD1152-HQPA in vitropotently induced growth arrest and apoptosis via caspase-dependent and independent mechanisms.AZD1152 was well tolerated in a phase I study in relapsed/refractory acute myeloid leukaemia. We performed a phase II single arm open-label trial to determine the efficacy and tolerability of AZD1152 in relapsed/refractory DLBCL pts who had failed or were ineligible for salvage/high dose chemotherapy and had received at least one line of potentially curative immunochemotherapy.MethodsPts with relapsed/refractory (de novoor transformed indolent NHL) DLBCL with measurable disease (at least a non-irradiated single lesion (>1.5cm)) were treated with up to six cycles of 96-hour continuous intravenous (iv) infusions of AZD1152 as an inpt every 3 weeks.Due to concerns over possible precipitation of drug in the line, regular 4 hourly saline flushes were required via each lumen to maintain patency. Prophylactic G-CSF was permissible per ASCO guidelines. Ongoing cycles were commenced when neutrophils recovered to ≥1.0x109/L and platelets to ≥50x109/L.The primary endpoint was overall response rate (ORR). Secondary end-points were progression-free survival (PFS) at one year, % change in tumour size, and safety measured by the incidence and severity of adverse events (AEs). Response assessment using FDG-PET was completed at day 15 of cycle 2. Pts with stable disease (SD), minimal, partial (PR) or complete response (CR) according to Cheson criteria remained on protocol, but those with progressive disease (PD) were taken off study.As data that suggests MYC overexpression may enhance responses to aurora B kinase inhibition, MYC by IHC and FISH for c-MYC translocation was performed. All diagnostic specimens were reviewed by specialist haemato-pathologists.ResultsFifteen pts were enrolled in 20 months, and received 1-6 cycles. Overall, 42 cycles were administered (41 at full dose). One pt completed all six planned cycles. The cohort included 8 males and 7 females, with a median age of 65 (35-74 years). 13% had a low International Prognostic Index (IPI) (0-1), 53% an intermediate IPI (2-3) and 33% a high IPI (4-5). The best ORR was 20% (see Fig 1 for tumour percentage reduction) with no cases of CR and 3 PR. 33% obtained SD for between 2-6 cycles. The median PFS was 60 days (95% CI 36-84 days) (see Fig 2). IPI (p=0.584) (See Fig 3), gender (p=0.113), disease bulk at diagnosis (p= 0.654) or c-MYC dysregulation (p=0.331) did not predict PFS. Early discontinuation occurred in 14 pts from PD.SafetyMost AEs were grade 1-2. 18 episodes of neutropenic fever occurred, including one grade 4 bacteraemia. There were no fatal SAEs and each episode resolved with iv antibiotics and G-CSF. All other toxicities were transient, manageable and expected. 13% of pts developed a total of 2 episodes of mucositis following 42 total doses. Neutropenia (grade 3-4), diarrhoea and nausea were common but manageable and expected. No Suspected Unexpected Serious Adverse Reactions occurred.ConclusionsThree-weekly AZD1152 was safely administered to pts with relapsed DLBCL. Responses were seen, providing a proof of concept that Aurora B kinase is a valid target in DLBCL. However, efficacy was modest. The infusate delivery was cumbersome. Dose intensity was maintained during treatment. Important but manageable AEs included neutropenic fever and mucositis. Aurora B kinase is a rational target for further investigation. NCT01354392. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety Of Treatments For Relapsed Or Refractory DLBCL: Results Of a Systematic Literature Review

BackgroundDiffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of non-Hodgkin's lymphoma (NHL) cases in Western countries. Although two-thirds of patients may be cured with combination chemotherapy, in the event of treatment failure and for those who are refractory to treatment, survival is usually measured in months. Several therapeutic modalities have been utilized for patients with relapsed or refractory disease, but among patients who are not eligible for high-dose chemotherapy with stem cell transplant, a comprehensive assessment of efficacy and safety is lacking. This systematic literature review (SLR) was designed to exhaustively collect and review information on the clinical efficacy and safety of the different interventions used in the treatment of refractory or relapsed DLBCL, and if possible to perform a meta-analysis. MethodsElectronic databases (PubMed, Cochrane Library, Embase) were searched for relevant studies published from 1997 to August 2, 2012. In addition, conference abstracts, bibliographic reference lists of included articles and recent reviews, and the Clinicaltrials.gov database were searched for phase 2, 3, or 4 studies displaying results, potentially unpublished in peer-reviewed journals. Main efficacy outcomes included objective response rate (ORR), complete response, partial response, duration of response, progression-free survival (PFS), and overall survival (OS). Safety endpoints focused on grade 3/4 toxicities and treatment discontinuation due to toxicity. Studies had to report on relapsed or refractory DLBCL after at least one standard treatment and patients who were not eligible to receive high-dose chemotherapy or stem cell transplant (autologous or allogeneic). Mixed type NHL studies were required to report DLBCL outcomes separately for inclusion. ResultsA total of 3,308 publications were identified in the first pass of a broad SLR on NHL; of these, 57 provided relevant data for DLBCL representing 54 unique studies. Of the 54 studies, there was 1 phase 3 study, 33 phase 2 studies, and 4 phase 1/2 studies (15 studies did not report the study phase and 1 was an observational study). Six studies were comparative (3 randomized trials; 3 nonrandomized trials) with two treatment arms; 48 studies were single arm. Of the 48 regimens evaluated, few regimens were represented more than once. Overall survival and PFS were often not reported or not reported separately for the patients with DLBCL in studies that enrolled patients with any of the multiple lymphoma histologies. Refractory and relapsed criteria were often not defined, and definitions were heterogeneous when available.The ORR from the few comparative studies ranged from 27% to 100%, with most estimates between 40% and 70%. PFS with low and high doses of obintuzumab was 2 months and 3 months, respectively in one study, and OS was 4 months with MEP and 7 months with C-MEP in another study. There was a common regimen in two of the randomized controlled trials, but the patient populations in these studies differed too greatly to allow a valid meta-analysis to be performed. In the single-arm studies, ORR ranged from 11% to 100%, with the estimates evenly distributed across that range. Progression-free survival was approximately 1 to 10 months. Reported median OS ranged from 1 to 13 months. Main safety concerns included thrombocytopenia, leukopenia, and neutropenia. ConclusionsThere is a high unmet need for effective therapies for patients with relapsed or refractory DLBCL who are ineligible for stem cell transplant. Although numerous regimens have been evaluated in single-arm trials and a handful in comparative studies, there is no clearly superior regimen for patients with relapsed or refractory DLBCL, especially in third- and later lines of therapy.FA is supported by a Clinical Career Development Award from the Lymphoma Research Foundation Disclosures:Colosia:RTI Health Solutions: Employment. Trask: Sanofi: Employment. Olivares: Sanofi: Employment. Khan: RTI Health Solutions: Employment. Abbe: Sanofi: Employment. Police: RTI Health Solutions: Employment. Njue: RTI Health Solutions: Employment. Wang: RTI Health Solutions: Employment. Sherrill: RTI Health Solutions: Employment. Ruiz-Soto: Sanofi: Employment. Kaye: RTI Health Solutions: Employment. Awan: Lymphoma Research Foundation (Career Development Award): Research Funding.

Lenalidomide In Combination With R-ESHAP (LR-ESHAP) In Patients With Relapsed Or Refractory Diffuse Large B-Cell Lymphoma Candidates To Autologous Stem-Cell Transplantation: A Phase 1b Study From Spanish Group Geltamo

BackgroundDiffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing first-line therapy have a poor outcome with the current salvage regimens. Consequently, new drugs designed to increase the response rate of salvage regimens should be explored (Gisselbrecht et al, J Clin Oncol 2010, 28: 4184-90). We conducted a phase Ib trial (3+3 design) to establish the safety, tolerability and determination of the maximum-tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were also collected as secondary objective. Patients and MethodsEligible patients must be refractory to, or have relapsed following, first-line treatment with rituximab in combination with an anthracycline-containing regimen, and be eligible for autologous stem-cell transplantation (ASCT). Subjects received three cycles of lenalidomide (5, 10 or 15 mg) given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP salvage chemotherapy at standard doses (rituximab 375 mg/m2 day 1, etoposide 40 mg/m2 days 1-4, cisplatine 25 mg/m2 days 1-4; citarabine 2000 mg/m2 day 5, and methilprednisolone 500 mg days 1-5). Responding patients received BEAM followed by ASCT. ResultsDuring the escalating phase, 3 patients had dose-limiting toxicity in the 15 mg cohort: 1 grade 3 angioedema, and 2 mobilization failures. The MTD was therefore established at 10 mg of lenalidomide and this cohort was expanded to further explore the safety and efficacy of LR-ESHAP. A total of 20 patients (3, 13, and 4 in the 5, 10, and 15 mg lenalidomide cohorts, respectively) were enrolled (18 with DLBCL-NOS, and 2 with Burkitt-like lymphoma): 60% male, median age 58 (23–70) years. First-line treatment consisted of R-CHOP or similar in 18 patients and Burkitt's lymphoma protocols in 2. Disease status at LR-ESHAP was: primary refractory disease in 13 patients (partial response [PR], n=7; and<PR, n=6), and relapsed disease in 7 (3 early and 4 late relapses). IPI was 0-1 in 35%, 2-3 in 40%, and 4-5 in 25%. To date, 16 serious adverse events (SAEs) have been reported, including 5 episodes of febrile neutropenia, 2 pneumonia, 2 sepsis, 1 ionic imbalance, 1 renal toxicity, 1 facial angioedema, 2 thrombosis, and 1 hepatic toxicity, all of them recovered, and there were no treatment-related deaths. Seventeen patients (85%) completed the planned three cycles of treatment (3 without lenalidomide in the third cycle due to significant toxicity) and 1 patient two cycles (due to persistent neutropenia and thrombocytopenia after the second cycle). Two patients discontinued treatment during the first cycle (1 due to angioedema and 1 due to hepatic toxicity). Of the 18 patients with at least one post-baseline tumor assessment, the overall response rate to LR-ESHAP was 77.8% (44.4% complete remission). All 18 patients were successfully mobilized after one (13 patients) or two (5 patients) mobilization procedures, and 14 (70% of the overall series) underwent ASCT according to protocol. Reasons for not performing the transplant were: early progression of lymphoma (n=4), clinical trial discontinuation due to toxicity (n=2). At the time of this analysis, 8 patients had disease progression and 5 patients have died (all of them from lymphoma). With a median follow-up of 7.4 (2.9 to 27.6) months, the estimated 1-year progression-free survival and overall survival were 52% and 72%, respectively. ConclusionsLR-ESHAP shows an acceptable safety profile and encouraging activity in rituximab-pretreated relapsed or refractory DLBCL patients. Further investigation with this regimen is warranted. Disclosures:No relevant conflicts of interest to declare.

Allogenic Transplantation in Lymphomas: A Focused Analysis On Aggressive Lymphomas and Factors Predictive of Outcome in a Series of 179 Pts Treated At John Theurer Cancer Center.

AbstractAbstract 3120▪▪This icon denotes a clinically relevant abstract Introduction:Chemo-immunotherapy (i.e. rituximab combinations) has clearly had a significant impact on the outcome of all B-cell NHL both in terms of PFS and OS. However in the relapse/refractory setting a large proportion of pts still do very poorly especially in aggressive subtypes including DLBCL and MCL. Salvage therapy followed by HDT-ASCT in relapsed DLBCL remains the standard, though pts with early failures (<1y) and/or prior exposure to rituximab still show dismal results (CORAL data). In MCL the use of HDT-ASCT in the relapse setting is debated given the frequency of chemo-resistance leading to poor results even in second CR. The use of allogeneic transplantation was developed based on observations c/w with a clear GVL effect in NHL as illustrated by pts going into remission after DLI injections. The development of non-myeloablative approaches has allowed expansion of use of allogeneic BMT in relapsed/refractory NHL. We report here one of the largest series (179 consecutive pts) with relapsed/refractory lymphoma focusing on overall survival and outcome predictors. Methods:Utilizing Kaplan-Meier survival and Cox regression methods, we report on the outcome of 179 consecutive pts with relapsed/refractory lymphoma who underwent allogeneic stem cell transplantation at the John Theurer Cancer Center between 1995–2012. The primary study endpoint was overall survival (OS) assessed by chart and SSDI database review. Secondary study endpoints included examination of the association between overall survival and allogeneic stem cell source, donor source, development of GVHD, pre-transplant chemo-sensitivity and prior failure to HDT-ASCT (second transplant). The proportional hazards assumption was met for this analysis. Results:Survival data on 179 pts (median age 48, range 20–71) were analyzed, representing 86 deaths and 5720 total months at risk (median follow up=12.3 months). Baseline characteristics included: ECOG PS (med 1, range 0–2), diagnosis (25% DLBCL, 21% HD, 20% MCL, 13% FCL, 13% PTCL, 8% other), donor source (50% matched SIB, 31% MUD, 19% mismatched MUD), stem cell source (73% PB, 23% BM, 6% Cord) and prior autologous SCT (38%). The median OS for the entire cohort was 31.2 months. OS KM curves by selected aggressive NHL subtypes are represented in Figure 1. We performed COX regression analyses to address outlined secondary endpoints. In univariate analyses statistically significant inferior outcomes were associated with the use of mismatched unrelated donor (HR 1.4, p=.01, Figure 2), bone marrow donor stem cells vs. PBSCT (HR=1.7 p=.04), pre-transplant stable/refractory disease (HR 1.8, p=.03), absence of cGVHD (HR=4.7, p<.001) and presence of acute GVHD (HR 2.8, p=.001). No difference in OS was detected whether pts had undergone allogeneic SCT as a second transplant (med time between auto/allo=20.9 months) following relapse after auto SCT (HR 1.14, CI .75–1.73, p=.5). Conclusions:This series represents a large cohort of poor risk, relapsed/refractory lymphoma pts treated consecutively with allogeneic stem cell transplantation over a > 10-year period at our institution with the following observations: 1.These data clearly demonstrate that a sizable subset of pts with either HL or aggressive NHL (MCL, DLBCL, PTCL) can enjoy long disease-free survival following allo SCT (beyond the expectation of standard salvage chemotherapy).2.Relapse following autologous SCT should not preclude consideration of allo SCT as second salvage.3.New strategies to improve outcome include our ongoing TH2 study which led to reduced GVH incidence and promising outcome.4.Our ongoing study looking at expanded donor derived T-cells is showing promising results in reducing GVH incidence and improving outcome, including in aggressive NHL, and will be presented on a separate presentation. [Display omitted] [Display omitted] Disclosures:Mato:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Goldberg:Eisai: Speakers Bureau. Feldman:Allos: Speakers Bureau; celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau; Merck: Speakers Bureau. Goy:Milennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; J & J: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees.

Radioimmunotherapy efficiency and safety in consolidation and relapse treatment of aggressive B-cell non-Hodgkin lymphoma: An updated analysis of 230 patients of the international RIT-network.

8052 Background: In aggressive lymphoma, few reliable clinical data about the use of radioimmunotherapy exist. Pts. with DLBCL registered in the international RIT-Network (RIT-NT) were analyzed with regard to Indication, line of therapy and outcome. Methods: The RIT-NT recruited 1111 pts. between Dec. 2006 and 2010. It is a web-based registry that collects observational data from RIT-treated patients with malignant lymphoma. 232 pts. with DLBCL registered in the database were evaluated in the analysis. Results: 232 pts with DLBCL are registered, 17 pts were excluded. Histologic subtypes: 190 DLBCL, 15 primary mediastinal, 9 large cell anaplastic, 1 intravascular. Median age was 62 years (range 17-88), 27% of pts &gt;70 years old. Stage I 16pts, II 54 pts, III 60 pts, IV 68 pts; 6 extranodal involvement, for 11 pts. stage is not documented. 187 pts had 1-3 previous chemotherapies (Ctx), 21 pts 4-6 previous Ctx, 1 pts had 7 previous Ctx, for 6 pts. previous Ctx is not documented. 15 pts. had previous RIT and 24 pts a stem cell transplantation prior to RIT. 6 pts had bone marrow infiltration prior to RIT, 3 with more than 25%. 87 pts had RIT as first line (8 pts. conditioning, 68 pts consolidation, 1 primary therapy, 10 other), and 84 pts received RIT in relapse (2d to 8 th. line therapy) (2 pts. conditioning, 31 pts consolidation, 26 recurrence, 19 therapy refractory, 6 other). Grade IV° hematotoxicity occured for neutrophils and platelets, grade III° for hemoglobin after RIT. Median time to recovery of blood count was 81 days (range 0-600 days). ORR was 63,3 %; CR 54,4%; PR 8,8%, SD 0,9%, PD 23,7%, N.D. 12%. CR rate first line was 76,3 %, for relapse 44,3%. Mean overall survival (OS) in first line was 26,5 months 14,3 months for pts. treated in relapse or refractory disease. Conclusions: Most pts. with DLBCL in the RIT-N received RIT as consolidation after first line therapy with excellent CR rates and OS compared to published data from risk groups . In relapsed DLBCL RIT is a safe and feasible treatment leading to satisfactory response rates with low toxicity. A prospective randomized phase III trial in front line DLBCL is currently planned (ZEST).