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Non-Hodgkin lymphoma (NHL) is a disease of older adults, with a median age at diagnosis of 67 years. Treatment in older adults with NHL is challenging. The aging process is associated with a decline in functional reserve that varies among individuals, and results in an increasing risk of treatment-related toxicity and mortality. Chronological age and performance status fail to capture the multidimensional and heterogeneous nature of the aging process. A geriatric assessment (GA) screens multiple geriatric domains and provides a more accurate assessment of functional reserve. Several abbreviated GA tools have been developed for use in oncology clinics and help identify patients at high risk for chemotherapy-related toxicity and mortality. In this review, we explore GA tools validated for use in patients with NHL. We discuss the evidence behind GA–guided treatment in NHL and present a suggested approach to assessing frailty in this patient population.

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53–4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). We evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. STUDY DESIGN: In this single-arm phase II study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression free survival (PFS) and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

Patients with chronic lymphocytic leukemia (CLL) are known to be at a higher risk of developing other primary cancers (OPC). Identifying latency and risk factors associated with OPCs in CLL is of interest as select patients may potentially benefit from early treatment of CLL with targeted therapies to improve immune surveillance. In this single-center retrospective study, 16.9% of 969 patients with CLL were diagnosed with an OPC. Interestingly, 44% of OPCs were diagnosed prior to the CLL diagnosis, including 30% that were diagnosed1 year prior. This included a majority of genitourinary cancers and melanoma skin cancers. Patients with CLL and an OPC were older than pts with no OPCs but no other risk factors for developing OPCs were identified. Our data suggest that not only are patients with CLL at higher risk of developing OPCs and warrant appropriate cancer surveillance, but the risk also precedes CLL diagnosis by several years.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: “ibrutinib responders”—patients who achieved complete or partial response (CR/PR) to ibrutinib; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

The shortage of dacarbazine (DTIC) has created an acute and unprecedented crisis in the management of patients with classical Hodgkin lymphoma, with DTIC being an essential component of doxorubicin, bleomycin, vinblastine, and DTIC (ABVD) and prior attempts at omitting DTIC from ABVD leading to substantial loss of efficacy. In this review, we discuss the strategies to manage classical Hodgkin lymphoma during the DTIC shortage and propose a treatment algorithm on the basis of fitness and ability to receive anthracyclines safely.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

BackgroundThe treatment of diffuse large B-cell lymphoma (DLBCL) is limited by the development of resistance to therapy, and there is a need to develop novel therapeutic strategies for relapsed and refractory aggressive lymphoma. Metformin is an oral agent for type 2 diabetes that has been shown to decrease cancer risk and lower mortality in other types of cancer.MethodsWe performed a retrospective analysis of the RPCCC database looking at patients with DLBCL treated with front-line chemotherapy. We also performed pre-clinical studies looking at the effect of metformin on cell viability, cell number, Ki67, ATP production, apoptosis, ROS production, mitochondrial membrane potential, cell cycle, effect with chemotherapeutic agents, and rituximab. Finally, we studied mouse models to see the anti-tumor effect of metformin.ResultsAmong diabetic patients, metformin use was associated with improved progression-free survival (PFS) and overall survival (OS) compared to diabetic patients not on metformin. Our pre-clinical studies showed metformin is itself capable of anti-tumor effects and causes cell cycle arrest in the G1 phase. Metformin induces apoptosis, ROS production, and increased mitochondrial membrane permeability. Metformin exhibited additive/synergistic effects when combined with traditional chemotherapy or rituximab in vitro. In vivo, metformin in combination with rituximab showed improved survival compared with rituximab monotherapy.ConclusionsOur retrospective analysis showed that metformin with front-line chemotherapy in diabetic patients resulted in improved PFS and OS. Our pre-clinical studies demonstrate metformin has potential to re-sensitize resistant lymphoma to the chemo-immunotherapy and allow us to develop a hypothesis as to its activity in DLBCL.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients.

Background Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL. Methods This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula. Results A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative. Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD. Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3). There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure). Conclusions In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment. Disclosures Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.

Background Limited data are available on the clinical activity of venetoclax (ven) in mantle cell lymphoma (MCL). In 2 small retrospective studies of patients (pts) with MCL previously treated with BTK inhibitors (BTKi), ven resulted in overall response rates (ORRs) of 50-53% and median overall survival (OS) of 9-14 months (Eyre et al, Haematologica 2019; Zhao et al, Am J Hematol 2020). We sought to report the clinical activity of ven and identify factors associated with outcomes in a larger cohort of pts. Methods We included pts with relapsed MCL from 12 US medical centers treated with ven alone or in combination with an antiCD20 monoclonal antibody (mAb) or a BTKi. Response was determined by the local investigator. We defined OS as time from start of ven to death. Pts not experiencing an event were censored at their last known follow up. OS was determined using the Kaplan-Meier method, and univariable (UVA) and multivariable (MVA) models were developed to identify predictors of response and OS. Results Eighty-one pts were included. Pt characteristics (Table) at diagnosis (dx) were: median age 64 years (yrs) (range 38-87), male 79%, stage III/IV 95%, Ki67 >30% in 61% (available n=62), blastoid/pleomorphic histology 29% (available n=75) and ≥3 cytogenetic abnormalities 34% (available n=62). BCL2 expression was present in 93% (available n=40). Frontline treatment (tx) included intensive chemotherapy [defined as including high-dose cytarabine and/or autologous transplant (ASCT) in first remission] in 52% with ASCT in first remission in 32%. Median number of therapies prior to ven was 3 (range 1-8) including antiCD20 mAb 99%, alkylator 93%, BTKi 91%, anthracycline 58%, cytarabine 56%, and lenalidomide 37%. 55% were refractory (defined as stable (SD) or progressive disease (PD)) to last tx prior to ven. ORR to BTKi prior to ven (n=70) was 66% (complete response (CR) 20%) with median duration of tx of 6.4 months (range 0.5-69). BTKi was stopped due to PD 82% and toxicity 18%. Median time from dx to start of ven was 3.9 yrs (range 0.2-17.8). Ven was given as monotherapy in 62% (n=50) and in combination with BTKi 20% (n=16), antiCD20 mAb 14% (n=11), or other 5% (n=4). Ten pts treated with ven in combination with BTKi received prior tx with BTKi with ORR to BTKi of 40% (all PR). Ven highest dose received was 20-100 mg in 12% (n=9), 200 mg 11% (n=8), 400 mg 61% (n=46), and 800 mg 17% (n=13). Median duration of tx with ven was 2.8 months (range 0.1-30). The best response to ven was CR 18%, partial response (PR) 24%, SD 11%, and PD 47% with ORR of 42%; 19 pts (23%) did not have available data for response. ORR was not significantly different with ven monotherapy 36% (13/36) vs ven + antiCD20 mAb 56% (5/9) vs ven + BTKi 43% (6/14) (p=.559), or with ven monotherapy 36% vs combination therapy 50% (13/26) (p=.274). Ven was stopped due to PD 69%, toxicity 9%, allogeneic transplant 3% or other reasons 19%. Laboratory tumor lysis syndrome (TLS) occurred in 10 pts (12%) including 3 (3.7%) with clinical TLS. 38 pts received post-ven tx with median time from stopping ven to next tx of 0.24 months (range 0-2.2); for the 33 pts with available data, the best response to post-ven tx was CR 24%, PR 27%, SD 9% and PD 39% with ORR of 51%. For the 75 pts with available data, median OS was 12.5 months (95% CI 6-17) with 3-year OS of 13.1% (95% CI 1.4-38.0%) (Figure A). Median OS was numerically longer with ven combination (28.7 months, 95% CI 4-not reached) vs monotherapy (8.6 months, 95% CI 4.7-14.4), p=.0825 (Figure B). Median OS did not significantly differ based on response (CR/PR vs SD/PD) to prior tx with BTKi (14.4 vs 9.5 months, p=.53, Figure C) or last tx prior to ven (16.7 vs 12.4 months, p=.14, Figure D). In MVA for response, achieving CR/PR with BTKi prior to ven (vs SD/PD) was associated with response to ven (odds ratio 3.48, 95% CI 1.01-12.05, p=.049). In MVA for OS, ven combination vs monotherapy (HR 0.13, 95% CI 0.03-0.53; p=.006), longer time from dx to start of ven (>4 vs ≤4 yrs) (HR 0.08, 95% CI 0.02-0.36; p=.001), and higher dose of ven (≥400 mg vs 6 vs ≤6 months) (HR 3.47, 95% CI 1.10-10.99; p=.038) was associated with inferior OS. Conclusions In these high-risk and heavily pretreated pts with MCL, ven resulted in low response rate and poor OS. Ven may have a better role in MCL in earlier lines of therapy and when combined with other agents such as BTKi and/or antiCD20 mAbs. Disclosures Kamdar: Roche: Research Funding. Greenwell:Lymphoma Research Foundation: Research Funding; Acrotech Biopharma LLC, Kyowa Kirin: Consultancy. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Portell:Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding. Goldsmith:Wugen Inc.: Consultancy. Grover:Genentech: Research Funding; Tessa: Consultancy. Riedell:Morphosys: Research Funding; Celgene/Bristol-Myers Squibb Company: Honoraria, Research Funding; Verastem Oncology: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals/Gilead: Honoraria, Research Funding; Bayer: Honoraria; Karyopharm Therapeutics: Honoraria. Karmali:BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Kumar:AbbVie: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding. Hill:Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Kahl:AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. OffLabel Disclosure: Venetoclax is not licensed for use in mantle cell lymphoma

BACKGROUND Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse

Introduction: Ibrutinib is a first-in-class small molecule inhibitor that binds irreversibly to Bruton's Tyrosine Kinase (BTK) and has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend life-long therapy with administration at a fixed daily dose of 420 mg. However, lower doses of ibrutinib have been demonstrated to adequately abrogate kinase function. Limited clinical data suggests that dose reductions are not associated with inferior outcomes. Hypothetically, judicious dose reductions to manage toxicities could result in improved tolerance and decreased discontinuation rates. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. Methods: We conducted a retrospective chart review of all CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Patients who underwent ibrutinib dose reduction were identified. Baseline characteristics and outcomes were compared between patients who underwent dose reductions vs those who did not. Reason and timing of dose reduction was also elucidated. Mann-Whitney U and Fisher's Chi Square test were used to compare groups, Kaplan Meier methods were used for time to event analysis, and Cox regression was used to obtain hazard ratios (HR). Overall survival (OS) was calculated as time from start of ibrutinib until death or last follow-up, freedom from progression (PFS) was taken as time from start of ibrutinib until progression or last follow-up. All analyses were performed in SAS v9.4 (Cary, NC). Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 21.9 months. Most patients had RR disease (n = 63) and 7 received ibrutinib as frontline therapy. All patients received a fixed dose regimen with the standard dose of 420 mg once daily. Twenty-three (31.3%) patients required dose reductions and received ibrutinib at a median dose of 140 mg . Eleven (47.8%) of these had dose reductions within 3 months of treatment initiation. There was no statistically significant difference in baseline characteristics including age, number of prior lines of treatment, WBC count, hemoglobin or LDH level in the dose reduced group (DRG) and standard dose group (SDG). Patients in the DRG had a lower median platelet count at initiation of ibrutinib than patients in the SDG (86 x 103/mm3 vs 145 x 103/mm3, p Disclosures No relevant conflicts of interest to declare.

Introduction: T-cell lymphoma (TCL) accounts for 15% of all non-Hodgkin’s lymphoma cases with most patients developing relapsed/refractory (R/R) disease. The management of R/R TCL is challenging and responses to second and beyond-line therapy are generally poor. Pre-clinical and clinical studies have identified the relevance of PI3K/AKT/mTOR signaling pathway in TCL biology. The combination of PI3K inhibitor (PI3Ki) Duvelisib and the HDACi Romidepsin improved the overall response rate (ORR) of R/R TCL to 50-55% in a phase I/II study (Horwitz et. al. ASH 2018, Lugano 2021). Evaluation of PI3Ki and HDACi combinations in TCL pre-clinical models is needed to guide the design of future clinical trials. Methods: A panel of TCL cells lines were chosen representing T-cell acute lymphoblastic leukemia, T-lymphoblastic lymphoma, cutaneous T-cell lymphoma. A panel of PI3Ki (Omipalisib, Umbralisib and Duvelisib) and HDACi (Entinostat and Romidepsin) were selected to determine which combination would be most synergistic. Entinostat, an oral HDACi, was chosen for its remarkable preclinical and clinical activity in other lymphoma subtypes. Umbralisib is a new PI3Kδ inhibitor which was recently approved for treatment of follicular lymphoma and marginal zone lymphoma. Cells were exposed to Omipalisib (3.125-100nM), Umbralisib (1-320uM), or Duvelisib (1-100uM) alone or in combination with Entinostat (0.08-10uM) or Romidepsin (0.25-6) for 24, 48 and 72 hrs. Cell viability was measured using the CellTiter-Glo viability assay. Half-maximal inhibitory concentration (IC50) at 72hrs was determined for each drug and coefficient of synergy was calculated using Calcusyn Software. Changes in cellular metabolism and cell cycle distribution after exposure to PI3Ki were determined using DiOC6 staining and Propidium Iodide staining respectively. Epigenetic changes following exposure to Entinostat or Romidepsin were investigated for possible mechanisms. Results: In vitro exposure of TCL cell lines to PI3Ki or HDACi resulted in dose-dependent cell death. The IC50 at 72 hrs was 30-500nM for Omipalisib, 9-35uM for Umbralisib, 1-35uM for Duvelisib, 0.2-2uM for Entinostat and for 1-4nM Romidepsin. All HDACi and Pi3Ki combinations demonstrated additive and/or synergistic activity. Duvelisib combined with Entinostat or Romidepsin exhibited the most synergy. Methylation profiling demonstrated genomic wide hypomethylation, specifically DNMT3A, in Romidepsin treated samples compared to Entinostat. Conclusions: PI3Ki and HDACi combinations show significant synergy in TCL preclinical models. DNMT3A hypomethylation following Romidepsin exposure is being explored as the basis of PI3Ki and HDACi synergy. If confirmed in clinical trials, these results may refine the tolerability of the regimen for patients treated with this very promising PI3Ki/HDACi combination. Citation Format: Gabrielle Hartman, Cory Mavis, Juan J. Gu, Amber White, Taylor Mandeville, Pallawi Torka, Paola Ghione, Francisco J. Hernandez-Ilizaliturri. Novel pharmacological approaches of inhibiting the PI3K/AKT/mTOR signaling pathway in T-cell lymphoma (TCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2661.

e18748 Background: Randomized-controlled trials are the gold-standard of clinical research. However, majority of patients with cancer (> 95%) are ineligible/unable to participate in these studies. Retrospective studies using real-world evidence (RWE) help fill the knowledge gap by reporting outcomes in under-represented populations such as patients with rare diseases, comorbidities or those at extremes of age. There is limited data on the pattern and quality of RWE reporting at oncology meetings or in the literature. In this study, we examine longitudinal trends in RWE reporting at ASCO annual meetings over an 11-year period. Methods: We used the search items “retrospective”, “real world” and “observational” to identify all retrospective observational studies reported between 2011 and 2021 at ASCO annual meetings. Population size, number of centers and topics represented were recorded. For studies selected as oral presentations, details about subsequent publication of the full manuscripts was also collected. The statistical significance of reporting trends was tested using the Cochran-Armitage trend test, and the Pearson chi-square test was used to study associations between categorical variables. Results: A total of 49,190 abstracts were reviewed and 6742 (13.7%) studies reporting RWE were identified. There was an increase in the relative frequency of studies reporting RWE, from 13.8% of all abstracts in 2011 to 16.2% in 2021, p < .0001. There was also an increase in the proportion of real-world studies with patient populations of ≥1000 over time (14.6% in 2011 to 19.9% in 2021, p= .0001), with fewer studies including ≤100 patients over the same period (41.4% to 32.3%, p= .0181). Overall, a majority of these studies (70.1%, 4785/6742) were accepted for publication only with a decrease in proportion of studies accepted as posters (43.9% in 2011 to 30.5% in 2021, p < .0001). There was no significant trend in proportion of studies accepted as oral presentations over the same period (.19% to 1.96%, p= .134). There was an association between number of institutions involved, population size and acceptance category (publication only vs poster or oral), p< .001). Only 27.2% of single-center studies were accepted for poster/oral presentation in comparison to 43.6% of studies involving multiple centers. Out of 54 studies that were accepted for oral presentations, 59.3% (32/54) involved ≥1000 patients ( p< .001); 28/54 were published in Pubmed-indexed journals (highest impact factor, 32.98). Conclusions: There has been a significant increase in the relative frequency of studies reporting RWE at the ASCO Annual Meetings. Involvement of multiple institutions and larger patient populations allow for collection of higher quality data, and are associated with increased acceptance as oral/poster presentations versus publication only, underscoring the importance of multi-center collaboration.

Background Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued due to progression or side effects, it is unclear how successful further therapies will be. Moreover, there is no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and methods Seventeen centers across the US and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression free survival (PFS), duration of response (DOR), and overall survival (OS). Results Eighty-one patients were included. Seventy-two percent had stage 3-4 disease, and the population was heavily pretreated with a median of 4 therapies before CBT. Most patients (65%) discontinued CBT due to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. Conclusion In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. Implications for practice Relapsed and refractory (R/R) Hodgkin lymphoma (HL) presents a clinical challenge, and better treatment strategies are greatly desired to prevent these patients from ultimately succumbing to their disease. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy usage in R/R HL may sensitize patients their subsequent treatment. This approach may potentially be used to extend the number of options patients have or to bridge them to transplant. Prospective data is warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

The role of 18F-Fluoro-2-deoxy-D-glucose positron emission tomography combined with computerized tomography (PET-CT) in evaluation of bone marrow involvement (BMI) in patients with T-cell lymphoma (TCL) is poorly understood. We investigated whether PET-CT could replace bone marrow aspiration and biopsy (BMAB) in TCL. Sixty patients with newly diagnosed TCL who underwent both diagnostic PET-CT and BMAB were identified. BMI was tissue-confirmed in 15 (25%) cases, however only 8 of these 15 showed BMI on PET-CT (sensitivity of 53.3%, specificity of 100%). BMI by BMAB was associated with lower progression-free survival (PFS) (P=0.038) and overall survival (OS) (P=0.003) while PET-CT BMI was associated only with OS (P=0.02). BMI detected by BMAB in the setting of a negative PET-CT had similar inferior prognosis as BMI identified on PET-CT. Thus, PET-CT in TCL misses BMI in almost half of the cases detected by BMAB and hence cannot substitute BMAB in evaluation of TCL.

Paraneoplastic neurological syndromes are a rare manifestation of non-Hodgkin lymphoma and can make treatment of these patients more challenging. We report the case of a 67-year-old man with high grade diffuse large B-cell lymphoma who presented with severe paraneoplastic Guillain-Barre syndrome. He was treated with intravenous immunoglobulin therapy and definitive chemoimmunotherapy, and achieved a full neurological recovery. In this report, we discuss various mechanisms of neurological dysfunction seen in lymphomas. Prompt oncologic treatment and immunotherapy for Guillain-Barre syndrome if instituted concurrently and early in the course of the disease can be associated with the best outcomes.

Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.

Background To explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20+ B-cell non-Hodgkin lymphoma (B-NHL). Patients and Methods Twenty patients with indolent B-NHL were treated with rituximab (375 mg/m2) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. Results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III-IV disease. The median number of previous therapies was 2 (range, 0-5); 90% had received previous anti-CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab-related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression-free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9-27.6 months); the median overall survival was not reached. A shorter time-to-peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). Conclusion The pegfilgrastim-rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time-to-peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-NHL.

Introduction The treatment of aggressive B-cell NHL has evolved rapidly over the last 5 years, owing to the FDA approval of 3 CD19 CAR T-cell constructs (CARTs) along with other novel targeted therapies. Real world practice data suggest that CARTs have been successfully administered in populations typically excluded from clinical trials. However, data on how to best utilize novel targeted agents as a pathway to CARTs and feasibility of CARTs in rare histologies remains limited. This retrospective multicenter study describes patient (pt) selection and practice patterns in pts treated with CD19 CARTs and provides insight on feasibility of CARTs in special populations. Methods Adult pts with R/R aggressive B-cell NHL treated with CD19 CARTs between 2015- 2020 across 12 US academic centers were identified. Data on demographic and clinical characteristics, disease and toxicity outcomes were collected. Univariate analyses (UVA) were performed to determine impact of demographic/clinical variables on survival. Survival curves were calculated using Kaplan-Meier method. Subgroup analysis was performed for pts with secondary central nervous system lymphoma (sCNSL). Results Clinical and demographic features were recorded from 400 pts (Table 1). Median age was 59 years (range 18-84). Of 271 pts with immunohistochemistry data, 79 (29%) had double-expressor lymphoma. Of 178 pts with FISH data captured, 62 (35%) had double/triple-hit lymphoma. Most common histological subtypes included 271 (68%) pts with de novo DLBCL, 81 (20%) with transformed FL, 13 (3%) with Richter's syndrome, and 8 (2%) with PMBCL. Rare histologies included 7 (2%) with transformed MZL, 5 (1%) with PTLD and 2 (0.5%) with grey zone lymphoma. 24 (6%) pts had sCNSL at time of CART apheresis. Two (0.5%) pts were HIV-positive. Median number of lines of therapy prior to CART was 2 (range 1-8); 182 (46%) pts received ≥ 3 lines. 114 (28%) pts previously had an autologous stem cell transplant. Targeted therapies used as salvage regimens at any point prior to CART are listed in Table 2: commonly used salvage targeted therapies included lenalidomide based therapy (imids, n=37, 9%), BTK inhibitors (BTKis, n=30, 8%), checkpoint inhibitors (CBIs, n=17, 4%) and polatuzumab-containing regimens (n=10, 3%). 2 (1%) pts received loncastuximab, and no pts received tafasitamab. Six (1.5%) pts proceeded to CART despite complete response to most recent pre-CART therapy. 191 (48%) pts received bridging between apheresis and CART infusion, choice of bridging noted in Table 2: the majority received chemotherapy (n=103, 54%); 28 (15%) received radiation (XRT); 25 (13%), 24 (13%) and 18 (9%) pts received imids, polatuzumab-containing regimens, or BTKis, respectively. With median follow-up of 22.4 months (mo) for the overall group, median (m) PFS was 11 mo (n=363); mOS, was 27 mo (n=397; Fig 1). Pts with sCNSL had a mPFS and mOS of 2 and 4 mo, respectively (Fig 1). On UVA, factors predicting poorer PFS and OS in the overall group included ≥3 pre-CART lines (p For outcomes according to bridging regimens: mPFS after CART for most commonly used systemic bridging therapies was 86 days (d) for platinum-based chemotherapy, 77 d for imids, 90 d for BTKis, 98 d for polatuzumab-bendamustine/rituximab, and 274 d for XRT. Median PFS for XRT bridging (274 d) was statistically better when compared to mPFS for listed systemic therapies combined (p Conclusion Survival outcomes with CARTs in our data set are consistent with those reported in clinical trial settings. CARTs are utilized in real world practice in rare subsets of aggressive R/R B-cell NHL not routinely included in clinical trials. Despite early data suggesting pts with sCNSL benefit from CART, our data suggest outcomes with CART are dismal in this group. Targeted therapies including imids, polatuzumab, BTKis and CBIs are feasible choices for salvage and/or bridging as a pathway to CARTs. Bridging with XRT resulted in improved mPFS post CART as compared to bridging with systemic therapies and suggests differences in pt selection for each with systemic therapies likely favored in those with more widespread disease burden. Minimal use of CD19-targeted agents pre-CART is attributed to later approval of these agents and concern for potential loss of CD19 antigen leading to CART resistance. Figure 1 Figure 1. Disclosures Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria. Hess: ADC Therapeutics: Consultancy; BMS: Speakers Bureau. Stephens: Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; JUNO: Research Funding; Celgene: Consultancy; CSL Behring: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ma: Loxo: Research Funding; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Juno: Research Funding; Beigene: Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Agios: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Danilov: Astra Zeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding. Shah: Umoja: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Incyte: Consultancy. Barta: Seagen: Honoraria; Daiichi Sankyo: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Karmali: Epizyme: Consultancy; BeiGene: Consultancy, Speakers Bureau; EUSA: Consultancy; Roche: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Takeda: Research Funding; BMS/Celgene/Juno: Consultancy, Research Funding; Janssen/Pharmacyclics: Consultancy; Genentech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau.

Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

INTRO: Immune profiles and immune reconstitution are increasingly studied as important contributors to the prognosis and treatment responses of hematologic malignancy patients. Data on epidemiologic factors influencing immune profiles in hematologic malignancy patients are lacking. METHODS: We performed flow cytometric analyses of immune panels including T-cell, B-cell, NK cell and dendritic cell (DC) subsets in 1,025 consecutive adult hematologic malignancy patients (N=873) and controls/donors (N=152) between 2006-2016. Immune panels were analyzed on fresh peripheral blood samples drawn during workup before autologous or allogeneic hematopoietic cell transplant (HCT). Hematologic malignancy diagnoses were AML (N=235), MM (N=228), NHL (N=197), MDS/MPN (N=85), ALL (N=60), HL (N=33) and other leukemias (N=35). Patients were 58% male, median age 58 years (range 18-77), 91% non-Hispanic white (NHW), 6% African-American (AA), 1.3% Hispanic, 1.5% other. The HCT-comorbidity index (HCT-CI) in patients showed: 63% with > 1 co-morbidity; 26% moderate pulmonary, 22% psychologic (requiring therapy/counseling), 16% severe pulmonary, 12% cardiac (CHF/CAD/MI), 11% diabetes requiring insulin, 9% obese (BMI>35mg/kg 2), 9% prior cancer. Controls were related apheresis or marrow donors of allogeneic HCT patients: 51% male, median age 49 years (range 19-73), 92% NHW, 4% AA, 1.3% Hispanic, 2.6% other. HCT-CI scoring of controls: 45% with > 1 comorbidity, 20% obese, 20% psychologic, 10% mild liver disease, 7% diabetes. Due to inter-individual cell count variability, immune cells were normalized as percent gated of lymphocytes except DC populations which were gated on mononuclear cells, both on forward and side scatter. To control for multiple comparisons, Bonferroni corrected statistically significant P was set at RESULTS: In controls, males had a significantly lower proportion of CD3+ cells/µl than females (68% vs 73%, P=0.001), NHW had a higher proportion of CD8+ central memory (CM) cells than other race/ethnicities (4.6 vs 2.7%, P=0.004) with no other significant differences by sex or race, although some of the race groups were low in our cohort. In contrast, among hematologic malignancy patients, males had significantly lower CD4+, CD4+ naïve, CD4+ recent thymic emigrants (RTEs), total T-regulatory cells (Treg), and CD19+ naïve cells but significantly higher CD8+ CM and effector memory (EM) cells than females. In addition, NHW had higher CD8+ CM than AA, Hispanic and Other races. Significant differences by age in patients and controls are shown in the Table. Across all age groups, patients had higher proportions of CD3+ cells, lower proportions of B-cells and no difference in NK or DCs than controls. As controls increased in age, CD4+ total significantly increased, while CD8+total, CD8+naive, T-γδ cells decreased, and myeloid DCs were highest at each end of the age spectrum. As patients increased in age, activated HLA-DR T-cells significantly increased, while T-γδ, CD8+naïve, and RTEs significantly decreased. The CD4:8 ratio increased while the CD4+ and CD8+ naïve:EM ratio decreased with age in both controls and patients, however patients had lower CD4:CD8 and naïve:EM ratios than controls. Immunophenotypes by patient disease are shown in the Figure. In general, patients with lymphoid diseases had lower CD3+CD4+ but higher CD3+CD8+, NK and DCs. In controls/donors, there were no significant differences in immune cell profiles by the presence or absence of comorbidities: obesity, diabetes, psychologic and mild liver disease. In patients, T-γδ were significantly lower in patients with diabetes, with no other significant differences for cardiac, psychologic, prior cancer, obesity or pulmonary co-morbidities. CONCLUSIONS: Additional analyses are ongoing to investigate the influence of prior therapies (chemotherapy, hypomethylating agents, monoclonal antibodies, etc.) and cytogenetic risk groups within each disease (AML, ALL, MDS/MPN, MM, NHL) on immune cell profiles. Studies of immunophenotyping in hematologic malignancies should include adjustment for confounders such as age, sex and race as biologic variables, as well as consideration of the diseases and treatments given. Interestingly, common co-morbidities did not broadly influence immune cell profiles in our cohort of hematologic malignancy patients. Figure 1 Figure 1. Disclosures Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Hillengass: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Griffiths: Takeda Oncology: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Apellis Pharmaceuticals: Research Funding; Abbvie: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Boston Biomedical: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. McCarthy: Bluebird: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is required to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. Figure 1 Figure 1. Disclosures Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding; Celgene/BMS: Research Funding; BeiGene: Research Funding; Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy; BeiGene: Consultancy, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Takeda: Research Funding; Genentech: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Karyopharm: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding; AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Grover: Genentech: Research Funding; Novartis: Consultancy; ADC: Other: Advisory Board; Kite: Other: Advisory Board; Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Divested equity in a private or publicly-traded company in the past 24 months; Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months; Novatis: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Divested equity in a private or publicly-traded company in the past 24 months; Morphosys: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; KITE: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Lonza: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

Introduction: There is no standard induction therapy in extranodal marginal zone lymphoma (EMZL); current guidelines borrow from follicular lymphoma, where bendamustine and rituximab (BR) is an accepted standard. The data on BR in EMZL is limited (Rummel MJ et al. Lancet 2013 & Salar A et al. Blood 2017), so we explored BR activity as part of an international consortium. Methods: This retrospective analysis involved 11 cancer centers from US and Italy. We included patients with EMZL treated with frontline BR (1/2008 to 12/2019). Expert pathology review was performed by each participating institution following the 2016 WHO classification. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier and associations with prognostic factors were assessed by log-rank test, univariable (UVA) and multivariable (MVA) Cox regression. MVA Cox models were constructed by selecting variables significant univariately. Results: 136 patients were identified; however, 18 patients with EMZL only located in bone marrow (BM) were excluded from this analysis to prevent possible inclusion of lymphoplasmacytic lymphoma. Thus, 118 patients were included in this study. Patient characteristics comprised median age of 61.5 years (range 21 to 85 years), women: 56.8%, ECOG performance status 0-1: 86%, stage III-IV: 79.7%, no B symptoms: 81.4%, normal LDH: 75.4%, BM involvement: 25.4%, and MALT-IPI score < 2: 63.6%. Most common extranodal (EN) sites were lung (22%), gastric (13.6%), ocular (11%), soft tissue (10.2%), salivary gland (10%), and gastrointestinal non-gastric (7.6%). Most patients presented with 1 or 2 EN sites (48.3% and 30.5%, respectively). Majority of patients (83.9%) had < 4 nodal sites. Paraprotein was positive in 27 of 80 (33.7%) patients with majority harboring IgM. The median number of BR cycles was 6 (range 1 to 6). Consolidation with radiation therapy was performed in 6% of the patients. Treatment response was determined by PET/CT in 70% and CT scans in the rest. The response to treatment was as follows: CR: 96 (81.4%), PR: 13 (11%), SD: 2 (1.7%), PD: 4 (3.4%), and unknown: 3 (2.5%) patients. No differences in response rate were observed by EN location. The incidence of infectious complications was 14% including herpes zoster (25%), pneumonia (18.7%) and influenza (18.7%). No treatment-related mortality was observed. Rituximab maintenance was implemented in 17% (n= 20) of the patients for a median duration of 11 (range 1 to 46) months. Biopsy-proven transformation to diffuse large B cell lymphoma occurred in 5.9% of the patients. Patients with lymphoma transformation had a higher mean SUV on diagnostic PET/CT (13.48 vs 7.77, P= 0.037, respectively). Secondary malignancies were observed in 6% of the patients with 1 case of acute myeloid leukemia. With a median follow up of 2.85 (range 0.08 to 9.45) years, the estimated 5-years PFS (Figure 1) and OS (Figure 2) were 72.3% (95%CI 59.3-81.8%) and 85.6% (95%CI 75.0-92.0%), respectively. No survival difference was observed between patients achieving CR or PR followed or not by rituximab maintenance, but the number of patients receiving maintenance was small. Similarly, no survival differences were observed in patients with gastric EMZL compared to non-gastric locations or by MALT-IPI score risk category. In both UVA and MVA analyses, variables associated with shorter survival were ECOG performance status ≥2 and failure to achieve CR (for MVA: ECOG PS ≥ 2 (HR: 6.56, P=0.006) and failure to achieve CR (HR: 5.35 P Conclusion: This study represents the largest analysis to date evaluating the activity and safety of BR in untreated EMZL. BR is a highly effective platform in upfront treatment of EMZL with majority of the patients achieving complete and durable remissions. ECOG PS ≥ 2 and failure to achieve CR were identified as prognostic factors associated with worse outcome in BR treated patients. High incidence of herpes zoster infection was observed in this study which has not been previously reported. In addition, increased median PFS and lower incidence of infectious complications was observed in this study compared to prior reports. Disclosures Alderuccio: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria; Puma Biotechnology: Other: Family member; Foundation Medicine: Other: Family member. Beaven:Tessa Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; LoxoOncology: Research Funding; MorphoSysAb: Research Funding; Roche: Research Funding. Shouse:Kite Pharma: Honoraria, Speakers Bureau. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Voorhees:AstraZeneca: Research Funding. Martin:Regeneron: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy. Kamdar:Roche: Research Funding. Herrera:AstraZeneca: Research Funding; Karyopharm: Consultancy; Immune Design: Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Friedberg:Roche: Other: Travel expenses; Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Portola Pharmaceuticals: Consultancy; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy; Astellas: Consultancy; Seattle Genetics: Research Funding. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lossos:Seattle Genetics: Consultancy, Other; Stanford University: Patents & Royalties; Janssen Scientific: Consultancy, Other; Verastem: Consultancy, Honoraria; Janssen Biotech: Honoraria; NCI: Research Funding.

Introduction Ibrutinib was FDA approved for relapsed or refractory (R/R) marginal zone lymphoma (MZL) based on a phase II clinical trial that showed an overall response rate of 48% (Noy et al, Blood 2017). However, factors associated with response to ibrutinib in R/R MZL and outcomes of patients after progression on ibrutinib are unknown. Given the poor survival in other B-cell lymphomas such as mantle cell lymphoma (MCL) after progression on ibrutinib (Martin P et al, Blood 2016), we sought to evaluate clinicopathologic characteristics predictive of ibrutinib failure in R/R MZL, and describe outcomes of patients who experienced progression on ibrutinib therapy. Methods We performed a multicenter retrospective study of MZL patients treated at 19 US medical centers. Eligible patients were ≥ 18 years diagnosed with MZL from 2010-2019, who received ibrutinib for R/R MZL. Patients achieving a complete response (CR) or partial response (PR) with ibrutinib were considered ibrutinib responders, while those who had stable disease (SD) or progression of disease (PD) were classified as non-responders. The primary endpoint was to evaluate factors predictive of primary progression (PD) on ibrutinib. Secondary endpoints include evaluation of predictors of overall survival (OS) and progression-free survival (PFS) following ibrutinib therapy, assessment of outcomes based on the sequencing of ibrutinib therapy, and evaluation of outcomes following ibrutinib failure. PFS was defined as time from the start of ibrutinib therapy until lymphoma relapse/progression or death from any cause, censoring at last clinical assessment if no progression or death. OS was defined as time from the start of ibrutinib treatment until death or last follow-up. A multivariable Poisson regression analysis was performed to model ibrutinib progression on the clinicopathologic factors (see Table). To identify significant predictors for OS and PFS, we used a multivariable Cox model. Results 101 patients with R/R MZL received ibrutinib, of whom 99 had sufficient data for inclusion in the analysis. Among these patients, 63% (n=62) had CR/PR to ibrutinib (ibrutinib responders, CR=17, PR=45) and 37% (n=37) had no response (ibrutinib non-responders, SD=25, PD=12). The median duration of follow-up was 1.8 years (range=0.1-5.4 years) and 2 years (range=0.2-6.3 years) for ibrutinib responders and non-responders, respectively. Baseline characteristics of the R/R MZL patients stratified by ibrutinib response are shown in the Table. Among all the baseline factors examined for association with ibrutinib progression, only primary refractory disease (refractory to frontline therapy, RR=3.78, 95%CI=1.36-10.45, p=0.01) was predictive of a higher probability of primary progression on ibrutinib on multivariable analysis. The median OS was significantly better for responders (NR [not reached], 95%CI=3.2-NR) compared to non-responders (3.4 years, 95%CI=1.4-NR) (Figure 1A). Achieving CR/PR with ibrutinib (HR=0.22, 95%CI=0.09-0.52) and lack of complex cytogenetics (HR=0.22, 95%CI=0.08-0.59) were predictors of superior PFS. Similarly, ibrutinib response (HR=0.13, 95%CI=0.03-0.53) and lack of complex cytogenetics (HR=0.19, 95%CI=0.04-0.87) were predictors of better OS. There was no difference in PFS or OS based on the timing of ibrutinib administration (second vs third vs fourth line and beyond, Figure 1B and 1C). The median post ibrutinib relapse/progression OS (PROS) for patients who initially responded then progressed on ibrutinib (secondary progression, n=19) was 4 years (Figure 1D). The median PROS for patients who had no response to ibrutinib were stratified according to SD vs PD. The median PROS for those who had SD was NR and those with PD was 0.1 year (Figure 1E). Conclusion This is the largest series of R/R MZL patients treated with ibrutinib. A history of primary refractory disease was predictive of primary progression on ibrutinib, while the presence of complex cytogenetics was associated with inferior PFS and OS. In contrast to MCL, the outcomes of patients who progress on ibrutinib in R/R MZL are not poor except for the primary progression cohort (those with PD as the best response to ibrutinib). Improving therapeutic options for patients who experience PD with ibrutinib treatment represents an urgent unmet need and these patients should be prioritized for evaluation of novel therapeutic approaches. Figure Disclosures Epperla: Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Reddy:Genentech, BMS: Research Funding; KITE Pharma, Abbvie, BMS, Celgene: Consultancy. Caimi:Genentech: Research Funding; Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding. Greenwell:Lymphoma Research Foundation: Research Funding; Acrotech Biopharma LLC, Kyowa Kirin: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Olszewski:Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Awan:Genentech: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Consultancy; Celgene: Consultancy; Blueprint medicines: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy. Barta:Monsanto: Consultancy; Atara: Honoraria; Seattle Genetics: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria. Grover:Genentech: Research Funding; Tessa: Consultancy. Bartlett:Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed Therapeutics: Research Funding; Acerta: Consultancy; BTG: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Merck: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding. Christian:Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Herrera:Pharmacyclics: Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy.

BMT CTN 1401 is an academically led randomized study of a personalized cancer vaccine in which the combination of DC/MM fusion vaccine and lenalidomide maintenance after autoHCT is compared with maintenance alone as upfront treatment of MM (NCT#02728102). Assessment of the percentage of patients achieving CR and therapy-induced changes in MM-specific immunity are the primary clinical and immunologic endpoints, respectively. The protocol represents a transformative open source approach to cell therapy in MM and required collection of tumor cells prior to treatment initiation and vaccine production at day 60 after autoHCT. The process featured a multi-step approach of procedural standardization, training, and centralized verification of manufactured product/release criteria. Here we present initial analysis of accrual and vaccine manufacturing. Enrollment of 203 patients completed within 26 months with 140 patients randomized. Drop-out rate from enrollment to randomization was 31% (expected 30%). Sixty-eight patients were randomized to the DC/MM fusion vaccine arm, with 63 having products successfully manufactured and approved for release at 14 manufacturing sites. Vaccine products for 5 patients were not approved for release for the following reasons: final TC/DC viability did not meet release criteria (n = 3), product failed to meet sterility release criteria (n = 1), and disease progression prior to manufacture (n = 1). Among 63 participants who received vaccine, mean DC viability and CD86 expression was 79.3% (Standard Deviation = 11.3) and 80.6% (SD = 12.9), respectively. Mean viability and percent cells co-expressing DC and tumor antigens was 78.6% (SD = 13.0) and 47.9% (SD = 11.4), respectively. The process devised for BMT CTN 1401 led to rapid patient accrual and successful point-of-care DC/MM fusion vaccine generation. Feasibility of serial sample collection and performance of immunologic correlates were demonstrated. This multi-center collaboration highlights the development of a personalized tumor vaccine platform that serves as a model for future immunotherapy trials in MM.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies. See related commentary by Rogers, p. 3501

Passive immunotherapy with therapeutic monoclonal antibodies (mAbs) has revolutionized the treatment of cancer, especially hematological malignancies over the last 20 years. While use of mAbs has improved outcomes, development of resistance is inevitable in most cases, hindering the long-term survival of cancer patients. This review focuses on the available data on mechanisms of resistance to rituximab and includes some additional information for other mAbs currently in use in hematological malignancies. Mechanisms of resistance have been identified that target all described mechanisms of mAb activity including altered antigen expression or binding, impaired complement-mediated cytotoxicity (CMC) or antibody-dependent cellular cytotoxicity (ADCC), altered intracellular signaling effects, and inhibition of direct induction of cell death. Numerous approaches to circumvent identified mechanisms of resistance continue to be investigated, but a thorough understanding of which resistance mechanisms are most clinically relevant is still elusive. In recent years, a deeper understanding of the tumor microenvironment and targeting the apoptotic pathway has led to promising breakthroughs. Resistance may be driven by unique patient-, disease-, and antibody-related factors. Understanding the mechanisms of resistance to mAbs will guide the development of strategies to overcome resistance and re-sensitize cancer cells to these biological agents.

12043 Background: Oral targeted therapies (OTT) have transformed the treatment landscape of Non-Hodgkin lymphoma (NHL). However, measuring, defining and optimizing adherence to OTT remains a challenge. Prior studies have reported variable adherence rates (12-100%) to OTT in cancer patients (pts), with suboptimal adherence associated with inferior outcomes. In older adults (OA), geriatric syndromes (GS) such as polypharmacy and cognitive impairment can impact adherence. While geriatric assessment (GA) can predict chemotherapy-related toxicity in OA, its utility in NHL pts on OTT is unknown. In this pilot study, we evaluate the role of GA in predicting adherence and outcomes in NHL pts on OTT. We also report the feasibility of using MEMS Cap, an electronic event monitoring system, to measure adherence in this population. Methods: Pts ≥70 years (yrs) with NHL, initiating/receiving OTT were included. A GA was performed at baseline; pt, disease, and OTT characteristics were recorded. Pts were followed monthly for the first 3 months (mos), then every 3 mos for 1 year. Primary endpoint was treatment adherence rate, measured using both subjective [brief adherence rating scale (BARS)] and objective (pill counts and MEMS cap) methods. Progression free survival (PFS) was measured from time of therapy initiation to disease progression or death. Results: Of the 54 pts screened, 25 were enrolled. Median age was 77 yrs (71-93 yrs), 21 pts had chronic lymphocytic leukemia, 3 had mantle cell lymphoma and 1 had marginal zone lymphoma. Most frequently used OTT were ibrutinib (n = 17) and venetoclax (n = 5). Most pts (72%) were on OTT at study entry. Median time on therapy was 16.4 mos (1.9-44.6 mos). GS included cognitive impairment (28%), depression (24%), polypharmacy (92%) and recent falls (12%); 48% pts had ≥2 GS. Nine pts (36%) had impaired 4-meter gait speed and/or timed-up-and-go; 20 pts (80%) had an adjusted CIRS-G score of ≥6. So far, pts have completed a median follow up of 3.3 mos. BARS was the most consistent measure of adherence used (63/63 visits, 100%). MEMS Cap and pill counts were used at 13% and 8% visits respectively. Only 5 pts used the MEMS Cap, mostly due to packaging incompatibility (44%-pill box, 32%-blister packs). Median adherence was 100% (range, 70%-100%) with no pts missing > 7 days of prescribed doses. Five pts (20%) required dose interruptions, mostly due to adverse events. Six pts discontinued therapy and 2 pts died of unrelated causes. Median PFS was not reached. Chronological age and presence of a GS were not associated with adherence rate or outcomes. Conclusions: Despite presence of ≥2 geriatric syndromes in 48% of older adults with NHL on OTT, self-reported adherence remains high ( > 99%) in this group. The MEMS Cap device has poor applicability in measuring adherence to OTT due to pill package incompatibility and increasing use of virtual/tele visits.

Purpose: In patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), resistance to rituximab confers chemotherapy-resistance and poor response to salvage regimens. MDM2 is an E3 ligase which regulates the degradation of multiple cellular protein targets, but is known best as the major negative regulator of the tumor suppressor, p53. Recently, we demonstrated that MX69, a MDM2 inhibitor, re-sensitized resistant DLBCL cell lines to chemotherapy agents or small inhibitors (i.e. Venetoclax) in vitro by blocking the MDM2 protein-XIAP RNA interaction, led to both MDM2 and XIAP degradation, thus establishing the feasibility of this approach for overcoming rituximab and chemotherapy resistance in DLBCL. We now report the activity of Idasanutlin, an investigational Nutlin-family MDM2 antagonist, in pre-clinical models of R-chemo resistant B-cell lymphoma. Methods: We used a panel of rituximab sensitive and R-chemo resistant B-cell lymphoma cell lines representing activated B-cell-like (ABC) DLBCL (TMD8, U2932); germinal center B-cell like (GCB) DLBCL (RL, RL 4RH, OCILy2); double hit DLBCL (DHL4, DHL6, DOHH2, VAL, ROS50), and Burkitt's lymphoma (Raji and Raji 4RH). Cells were exposed to escalating doses of Idasanutlin as single agent and in combination with various chemotherapeutic agents and small molecule inhibitors for 24, 48 and 72 hrs. Differences in cell viability were evaluated by PrestoBlue. IC50 was calculated by GraphPad and Coefficient of synergy was calculated using CalcuSyn. Low mitochondrial potential was detected by staining cell with DiOC6 followed by flow cytometric analysis. Western blot was used to detect changes in MDM2, XIAP and PUMA expression. Results: In vitro exposure to Idasanutlin demonstrated dose- and time-dependent cell death in DLBCL cell lines, IC50 ranged from 0.7uM to 63.07uM at 48h. Idasanutlin at the dose of 1uM was able to disrupt mitochondria and lowered the mitochondrial membrane potential in both ABC and GCB cell lines at 48 h. Idasanutlin reduced the expression of MDM2 in TMD8, U2932, VAL, OCILy2 DHL4 and ROS50 cell lines. XIAP expression was reduced in VAL and DHL4. PUMA, the downstream product of p53 activation, was increased after idasanutlin exposure in all cell lines. Idasanutlin demonstrated significant synergy with chemotherapeutic reagents (etoposide and vincristine), proteasome inhibitors (carfilzomib and ixazomib), Bcl-2 inhibitor venetoclax and Bruton tyrosine kinase inhibitor ibrutinib. Conclusion: Idasanutlin showed promising cell-of-origin agnostic anti-tumor activity as a single agent and in combination with several small molecule inhibitors in pre-clinical models of DLBCL. It decreased MDM2 and XIAP protein level and induced PUMA expression. Its unique mechanism of action through p53 modulation makes it an attractive partner for use in a variety of clinical settings in B-cell lymphomas. Citation Format: Juan J. Gu, Samuel Thompson, Cory Mavis, Pallawi Torka, Francisco Hernandez-Ilizaliturri. MDM2 inhibitor Idasanutlin potentiate therapeutic agents in Diffuse Large B-Cell Lymphoma by targeting MDM2 and XIAP [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2404.

Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-Hodgkin's lymphomas. NK/T-cell lymphomas are predominantly extranodal and most of these are nasal type, often localized to the upper aerodigestive tract. Because extranodal NK/T-cell lymphomas (ENKL) are rare malignancies, randomized trials comparing different regimens have not been conducted to date and standard therapy has not yet been established for these patients. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with ENKL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Background: Although first-line chemo-immunotherapy cures a significant number of diffuse large B-cell lymphoma (DLBCL) patients, long term survival is only observed in 30% or 41% of patients treated with second-line therapy followed with high dose chemotherapy and autologous stem cell support (HDC-ASCS) or chimeric antigen receptor anti-CD19 T-cell therapy (CART-19) respectively. The use of third-line therapy with chemotherapy drugs or current available small molecule inhibitors for relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) is associated with a poor response rate and a median survival of 6.3 months, stressing the need to identify druggable biomarkers associated with therapy resistance and poor clinical outcomes. Methods: To this end, we identified patients with rel/ref DLBCL that failed at least 2 prior lines of therapy treated at our Institute. Demographic, clinical and pathological characteristics were identified. Archived pathological material from the biopsy performed at the second relapse/progression was obtained for each patient. Using the Nanostring nCounter Analysis System (Nanostring Technologies, Seattle, WA), gene expression profiling (GEP) was performed for each sample as previously described using a custom designed code set containing 770 genes. Analysis and normalization of the raw Nanostring data was performed using nSolver Analysis Software v1.1. Raw counts were normalized to internal levels of 7 reference genes: CNOT2, GAPDH, HPRT1, PHGDH, SUMO2, SYS1 and WDR45L. A background count level was estimated using the average count of the 8 negative control probes in every reaction plus 2 standard deviations. Correlation between clinical outcomes (response rate to third line therapy, progression free-survival [PFS] and overall survival [OS]) and IPI score, clinical characteristics and GEP. Subsequently and based on the GEP results, we evaluated the expression of Bcl-XL and other Bcl-2 family proteins in a panel of DLBCL cell lines. Immuno-precipitation (IP) studies were conducted to determine protein-protein interaction between Bcl-XL and other Bcl-2 related proteins. In addition, cell lines were exposed to A1331852, a novel Bcl-XL inhibitor at different doses alone or in combination with chemotherapy drugs. Cell viability was evaluated using Presto Blue assay and IC50 values were calculated using the GraphPad Prism6 software. Results: A total of 53 rel/ref DLBCL were identified that received third line therapy at our Institute. The median age was 59yrs. The median PFS and OS was 23 months and 21 months respectively. Over-expression of BCL-XL RNA levels was associated with a shorter OS (P=0.015, HR=1.17). Pre-clinically higher levels of Bcl-XL as determined by western blotting were found in lymphoma cell lines resistant to chemotherapy agents in vitro. IP studies demonstrated a strong interaction between Bcl-XL and BIM in chemotherapy resistant cell lines. In vitro exposure of DLBCL cell lines to A1331852 resulted in dose- and time-dependent cell death. Moreover, synergistic activity was observed when A1331852 was combined with chemotherapy drugs (doxorubicin, vincristine and etoposide). Conclusion: Our data suggests that high expression level of BCLxL was associated with inferior prognosis in the refractory and/or relapsed DLBCL patients. Inhibition of Bcl-XL results in cell death of rituximab-chemotherapy resistant lymphoma cell lines and potentiates the anti-tumor activity of chemotherapy agents. Selective targeting of Bcl-XL may be a novel therapeutic strategy for rel/ref aggressive B-cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Objectives: T-cell lymphomas (TCL) pose a significant therapeutic challenge due to their aggressive behavior and poor response to treatment. Significant controversy exists regarding the benefit of intensification of therapy in the frontline and relapse settings due the lack of randomized studies in this rare and heterogenous population. We performed a retrospective analysis of survival outcomes in our cohort of TCL patients (pts) to assess the impact of intensification of therapy and other baseline disease, treatment and response characteristics. Methods: Adult pts with TCL diagnosed between January 2001 to December 2018 at Roswell Park Comprehensive Cancer Center were included in this single institution, retrospective chart review. Pts were classified according to the 2008 WHO classification of lymphomas. Demographics, pathology and treatment data were collected across all subtypes. Survival outcomes were summarized by treatment type using standard Kaplan-Meier methods. Comparisons were made using the log-rank test. All other statistics were descriptive. Results: Eighty-seven pts were included in our study. Histological subtypes of TCL included: 27 (31%) peripheral TCL-unspecified (PTCL-U), 15 (17%) Angioimmunoblastic TCL (AITL), 30 (34.5%) anaplastic large cell lymphoma (ALCL), out of which 10/30(33%) were ALK+ ALCL, 11(12.6%) NK TCL, 4(4.6%) enteropathy associated TCL (EATCL). Median age at diagnosis was 62 yrs (range, 20-92), 39 pts (68%) had stage IV disease, 11 pts (12.6%) had ECOG performance status >2, 21 (24%) with IPI risk of 3-4. Fourteen pts (18.6%) received Hyper-CVAD, 54 pts (72%) received CHOP and 7 pts (9.3%) received CHOEP. Others were treated with either less intensive chemotherapy (n=10), SMILE (n=1) or CMED (n=1). With a median follow up of 94 months (mo), the median OS for the entire cohort was 79 mo (95% CI 45.9-127.4). Complete remission (CR) on interim PET (after 2 cycles of therapy) was seen in 29 pts (53.7%) and this was associated with significantly higher CR rates at the end of treatment as well as improved PFS and OS (NR vs 6.7 mo; p=0.001; NR vs 48 mo; p=0.003) (Figure 1). Impact of frontline therapy was assessed in PTCL pts excluding NK TCL and EATCL (Total n=67). Pts treated with Hyper CVAD or those with CHOP/CHOEP followed by high dose chemotherapy and autologous stem cell transplant (HDC-ASCT) were grouped into the Intensive upfront therapy (IUT) group and compared with less intensive upfront therapy (LIUT) that included CHOP/CHOEP or other chemotherapy (Table 1). IUT (n=17; 25.4%) as compared to LIUT (n=50; 74.6%) had improved PFS (5yr PFS 64 mo vs 33 mo, p=0.037), although OS did not reach statistical significance (5yr OS 70 mo vs 48 mo, p=0.24). (Figure 2). A total of 48 pts (55%) in the entire cohort had relapse/progression(R/P). Pts with early relapse (ER) 12 mo were associated with a significantly lower 5 yr OS (18%; 95% CI 7-33; vs 53%; 95 % CI 29-72). For pts with ER, median OS after progression was only 2.4 mo, as compared to those with LR (14.2 mo). Notably, among pts who received IUT, 4 pts had ER (23.5%); whereas 23 pts (46%) with LIUT had ER. While, this did not meet statistical significance, our cohort may be underpowered to find a true effect. At R/P, 20 pts (41.7%) received multiagent salvage (mostly ICE/CHOP or cytarabine based), 18 pts (37.5%) received single agent therapy (mostly romidepsin), while 10 pts (20.8%) were placed on hospice. As compared to single agent therapy, multiagent salvage was associated with improved median PFS2 and OS2 (calculated from time of R/P to second progression or death) [mPFS 10.4 vs 3.4 mo; p= 0.01; mOS 14.2 vs 5.8 mo; p= 0.004] (Figure 3). Conclusions: While the ideal front-line therapy for TCL continues to be a subject of debate, the use of intensified front-line chemotherapy and/or early HDC-ASCT appears to be associated with better PFS in our cohort of TCL. Attaining an early CR by functional imaging was associated with improved survival. Pts with early relapse of disease or refractoriness to frontline therapy had a dismal overall survival. Use of multiagent intensive salvage therapy over single agent therapy at the time of relapse may improve outcomes. Further analysis on factors influencing choice of salvage treatment strategy at relapse would be important to study. Disclosures No relevant conflicts of interest to declare.

Background: Minimal residual disease (MRD) status is an independent prognostic marker for response duration in patients with mantle cell lymphoma (MCL). Rituximab-based therapy led to a molecular remission (MR) in 48% young MCL patients treated with intense chemo-immunotherapy. More recently, 4 courses of R-DHAP were reported to yield a 66% MRD negativity rate prior to high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Ofatumumab is a humanized type 1 anti-CD20 mAb that binds to a unique, more membrane-proximal epitope on the CD20 antigen. Pre-clinical studies have demonstrated that ofatumumab (O) is more active than rituximab in eliciting complement-mediated cytotoxicity (CMC) in MCL cell lines, primary tumor cells and murine lymphoma xenograft models. Hence, we evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL (NCT01527149). Study design: This was a single-arm, open-label, multi-center (2 centers), prospective, phase 2 clinical trial. Thirty-seven transplant-eligible patients with newly diagnosed MCL were enrolled. Ofatumumab (1000mg) was given every 3 weeks on day 1, followed by standard doses of alternating HyperCVAD and MA starting on day 3. A total of 6 cycles were given at 3-week intervals followed by HDC-ASCT. Maintenance rituximab 375 mg/m2 every 2 months for 3 years post-ASCT was added after protocol amendment following publication of the LyMa study. Primary objectives were to determine the overall response rate (ORR) and CR rate (CRR) at the end of therapy. Secondary objectives included MRD negativity, progression free survival (PFS), overall survival (OS), feasibility of successful mobilization of autologous stem cells and safety assessment. MRD assessment was performed in peripheral blood (PB) and bone marrow (BM) using high sensitivity multiparametric flowcytometry at baseline, after 2 cycles, after 4 cycles, pre-ASCT, post-ASCT and 6 months post-ASCT. Exploratory endpoints included correlation of MRD with survival, correlation of surface CD20 levels with response and to compare differences in ORR according to Cheson and modified Cheson (MC) criteria. Results: Median age was 60yrs; 73% of patients were male, 92% had an ECOG PS 0-1, majority (81%) had stage 4 disease with 86% having bone marrow involvement; 22% had low risk, 43% had intermediate risk and 35% had high risk MIPI score; 11% had blastoid and 11% had pleiomorphic variants of MCL; 25% harbored p53 deletion. MRD was assessed in 28 of 37 patients; 9 patients from partner site were excluded due to time lag in sample delivery for flowcytometry. MRD positivity was noted in 75% patients in PB and 71.4% patients in BM at baseline. Subsequent samples showed an MRD negativity rate of 82.1% and 64.3% after 2 cycles and 76% and 96% pre-ASCT in PB and BM respectively. Post-ASCT, MRD in BM and PB was found negative in 58% and 90%, respectively. Attainment of early MRD negativity (after 2 cycles) was associated with improved PFS (p=0.04) and OS (p=0.03). Since majority of patients were MRD negative pre-ASCT, we could not demonstrate correlation between pre-ASCT MRD and survival outcomes. The ORR and CRR were 95% and 62% by Cheson and 97% and 84% respectively by modified Cheson criteria. At the end of induction therapy, ORR was 86% and CRR was 62% by Cheson criteria. 73% pts underwent HDC-ASCT. Only one patient failed stem cell collection. The median PFS and OS were 45.5 months and 56 months respectively. There were 3 deaths while on therapy- 2 from sepsis and one from acute myeloid leukemia. Grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients, most of them were hematological AEs related to the chemotherapy regimen. Correlation of surface CD20 expression using mean fluorescent intensity (MFI) and response rates is currently under analysis and will be reported at the meeting. Conclusion: The addition of ofatumumab to HyperCVAD/MA led to high rates of MRD negativity by flowcytometry in patients with newly diagnosed MCL. Early MRD negativity (after 2 cycles) was associated with better PFS and OS. Despite higher ORR, CR and MRD negativity rates, survival outcomes were similar to historical cohorts using rituximab-HypeCVAD/MA. This may be in part due to increased number of patients with high-risk disease in our study. Disclosures Reddy: KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Sait:Celgene: Consultancy. OffLabel Disclosure: Ofatumumab was investigated in combination with chemotherapy in newly diagnosed mantle cell lymphoma in this clinical trial.

Background: X-linked inhibitor of apoptosis protein (XIAP) has been implicated in development of resistance to chemotherapy via its direct inhibition of caspases 3,7 and 9. It is overexpressed in several lymphoma cell lines including rituximab-resistant cell lines (RRCL), Raji4RH and RL4RH, produced by our group. We have previously demonstrated that XIAP is critical for chemotherapy-resistance and survival in RRCL by knocking down XIAP using siRNA interference which demonstrated that XIAP is critical for chemotherapy-sensitivity and survival in RRCL. MDM2 inhibition activates p53 transcription and inhibits translation of XIAP, thus promoting apoptosis of cancer cells. Here, we targeted XIAP at a translational level by inhibiting it with MX69, a dual inhibitor of MDM2 and XIAP. Materials and Methods: Cell lines representing Burkitt’s lymphoma (BL), activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL, germinal center B-cell like DLBCL (GCB-DLBCL), mantle cell lymphoma (MCL) and B-cell lymphoblastic leukemia were exposed to MX69 as a single agent (0-80 uM) over 24, 48 and 72 hrs and IC50 concentrations were calculated. Subsequently, Raji, Raji4RH, RL, RL4RH, HBL-2, TMD-8, Daudi and Reh cell lines were exposed to MX69 (0-80 uM), in combination with doxorubicin (0-1 uM), cytarabine (0-50 uM), vincristine (0-10 nM), etoposide (0-50 uM), carboplatin (0-10 uM), ixazomib (0-1.5 uM), ibrutinib (0-10 uM) and venetoclax (0-10 uM) for 48 hours. Cell viability was determined by Cell Titer-Glo. Coefficient of synergy was calculated using CalcuSyn. Induction of apoptosis was evaluated by flow cytometry (Annexin V/PI stain). MDM2, p53, XIAP and PARP protein expression was determined by Western blotting. Results: MX69 induced cell death in a dose- and time-dependent manner in all cell lines. Annexin/PI staining showed caspase-dependent apoptosis with MX69 in all cell lines. Western blotting confirmed significant inhibition of MDM2, XIAP and changes in p53 and PARP following exposure to MX69. MX69 demonstrated significant synergistic activity when combined with doxorubicin, ixazomib, ibrutinib or venetoclax; synergy was strongest for the MX69- venetoclax combination. Conclusion: Our data suggests that in vitro exposure to MX69 resulted in anti-tumor activity in a wide variety of B-cell lymphoma cells lines (including BL, DLBCL, MCL). Perhaps related to its anti-tumor effects, MX69 inhibited XIAP levels. These findings are similar to prior siRNA XIAP knockdown experiments. Strong synergistic activity was observed when XIAP was combined with various chemotherapy agents and small molecules inhibitors (such as venetoclax, ixazomib or ibrutinib). Ex vivo experiments using primary tumor cells isolated from lymphoma patients and lymphoma mouse models have been planned. Targeting MDM2 and XIAP can be an attractive therapeutic strategy in patients with rituximab-sensitive or -resistant B-cell lymphoma. Citation Format: Sumera Khan, Cory Mavis, Ahmad Hanif, Juan Gu, Pallawi Torka, Francisco Hernandez-Ilizaliturri. MX69 induces apoptosis by inhibiting XIAP in both rituximab sensitive and resistant lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 723.

Background: Upregulation of the anti-apoptotic protein Mcl-1 has been implicated in chemotherapy resistance and poor clinical outcomes in activated B-cell like (ABC)-DLBCL. We hypothesized that singular inhibition of Mcl-1 by AMG-176 and/or dual inhibition of MCL-1 and Bcl-2 by combining AMG-176 with venetoclax could be an effective strategy for inducing cell death in DLBCL pre-clinical models. Materials and Methods: Using a panel of DLBCL cell lines, we conducted pre-clinical targeting of Mcl-1 with AMG-176. Cells were exposed to AMG-176 as a single agent (0-20uM) over 24, 48, 72 hrs and IC50 concentrations were calculated for each cell line. Subsequently, DOHH-2, OCI-LY1, DHL4, DHL6, TMD8, and VAL cells were exposed to AMG-176 (0-20 uM) in combination with Doxorubicin (0-1uM), Cisplatin (0-10uM), Cytarabine (0-10uM), Vincristine (0-10uM), Ixazomib (0-100nM), Carfilzomib (0-12.5nM), and Venetoclax (0-10uM) for 72 hours. Cell viability was determined by Cell Titerglo. Coefficient of synergy was calculated using CalcuSyn. In addition, induction of apoptosis was evaluated by flow cytometry (Annexin V/PI staining) as well as changes in cell cycle (PI staining). Bcl-2 family member protein expression was determined by Western blotting. Primary tumor cells isolated from a patient with a composite lymphoma: angioimmunoblastic T-cell lymphoma (AITL) and EBV-driven DLBCL were exposed ex vivo to AMG-176 +/- venetoclax. By immune-phenotype, the primary tumor cells isolated and expanded were ABC-DLBCL. Results: In vitro, AMG-176 single agent exposure induced cell death in a dose- and time-dependent manner in all DLBCL cell lines tested. AMG-176 IC50 values varied from 0.03 to 11.42 uM for OCI-LY1 and ROS-50 respectively. Western blotting studies confirmed changes in Bcl-2 family members, specifically in Bok, Bcl-XL, Mcl-1 and Bcl-2 following in vitro exposure to AMG-176. The combination of AMG-176 with Doxorubicin, Cisplatin, Cytarabine, Vincristine, Ixazomib, Carfilzomib, or Venetoclax resulted in significant synergistic activity for each combination. The strongest coefficient of synergy was observed when AMG-176 was combined with venetoclax. Similar synergy results were noted in primary tumor cells isolated from the lymphoma patient. Annexin/PI staining with AMG-176 demonstrated caspase dependent apoptosis. No significant changes in cell cycle were observed with AMG-176 exposure. Conclusion: Our data suggests that AMG-176 exhibits strong synergistic activity with various chemotherapy agents and small molecule inhibitors especially venetoclax. In vivo experiments are planned. Combination therapy targeting Mcl-1 and Bcl-2 may provide an alternative therapeutic approach in DLBCL. Citation Format: Cory Mavis, Juan Gu, Matthew Barth, Sumera Khan, Pallawi Torka, Francisco Hernandez-Ilizaliturri. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in diffuse large B-cell lymphoma (DLBCL) pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2501.

Background: The spectrum of FL varies from an indolent disease course spanning decades to early transformation and death. Longitudinal studies have identified a subset of high risk patients (pts) who progress within 24 months of frontline therapy. It is still unclear how best to treat these patients and as yet, there is no standard 2nd line therapy for FL. Given the multitude of treatments available and the heterogenous disease course, it is challenging to compare outcomes of 2nd line therapy. It is unclear if the efficacy of second-line therapy in FL is influenced by the type of therapy, disease biology (early vs. late progression) or both. We conducted a single institute, retrospective study to determine the clinical benefit of 2nd line therapy in FL and to evaluate if any particular type of therapy was associated with improved outcomes in FL patients with early progression (EP). Methods: All patients with relapsed/refractory FL treated at our Institute between 1990 and 2014 were included. Patients were included if they received anti-CD20 monoclonal antibody (mAb)-based therapy in the first-line setting and completed both, first-line and second-line therapy at our Institution. Demographic, clinical, pathological and outcomes data was collected by retrospective chart review. Clinical endpoints included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). Treatments were divided in two groups for comparison: immunotherapy alone (anti-CD20 mAb) (IT) or chemo-immunotherapy (CIT). Differences in clinical outcomes were analyzed between FL patients with early progression after 1st line therapy (EP, i.e. progression ≤ 2yrs) vs. FL with late relapse (LP, i.e. progression > 2yrs). Comparisons were made using the Mann-Whitney U and Person chi-square tests as appropriate. Survival outcomes were assessed using standard Kaplan-Meier methods. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: A total of 537 newly diagnosed FL pts were identified of which 291 pts received 1st line therapy at our Institute. IT or CIT was given to 19.6% and 80.4% pts respectively. IT treated pts were older (median age: 61y vs 57y, p=0.033) and had lower FLIPI scores (1.5 vs 2.1, p Conclusion: FL pts with LR have excellent outcomes to 2nd line therapy and treatment selection could be determined by the agent(s) toxicity profile. In contrast, EP predicts poor clinical outcomes with short duration of response to standard IT or CIT. Therapeutic approaches incorporating clinically available targeted agents (i.e. immunomodulatory agents of B-cell receptor signaling inhibitors) or novel agents in the context of clinical trials, may provide a more effective disease control in this subgroup. Disclosures No relevant conflicts of interest to declare.