Seattle Genetics Research Articles

Novel Single Agents Are Equivalent to Conventional Chemotherapy Inpatients with Relapsed and Refractory Mature T-Cell Lymphomas: A Meta-Analysis

Background: Patients with advanced peripheral and cutaneous T-cell lymphomas (PTCL and CTCL) have an unfavorable prognosis . Primary refractoriness to traditional chemotherapy and relapse is common. Few FDA-approved “novel” single agents (SA) are available but their effectiveness as salvage agents relative to traditional multiagent cytotoxic chemotherapy (CC) regimens remains unknown. Therefore, we conducted a systematic meta-analysis to compare the response rates of approved and experimental single agents to conventional chemotherapy for patients with relapsed and refractory (R/R) PTCL and CTCL.Methods: This systematic review is reported in accordance with the PRISMA guidelines. Briefly a Harvard University Librarian (PB) systematically searched the publication libraries of: MEDLINE (through Ovid SP), Embase, Web of Science Core Collection, and Cochrane's Central Register for adult patients with R/R PTCL and CTCL enrolled in phase I, II, and III clinical trials of novel single and cytotoxic drugs. Agents determined as novel included antifolates, histone deacetylase inhibitors (HDACi), antibody-drug conjugates, therapeutic antibodies, hypomethylating agents, cereblon modulators, inhibitors of PI3K/AKT/mTOR, JAK/STAT, aurora kinase, farnesyl transferase and proteosome pathways, and CD4 CAR T- cells. Conventional chemotherapy agents included ifosfamide-, gemcitabine-, anthracycline-, and platinum-based treatments.Three researchers (NS, RS and LB) independently reviewed eligible studies and extracted data for baseline demographics, histological subtype, treatment characteristics including response rates, duration of response, overall and progression free survival, toxicity, and risk of bias assessment. Primary outcome was overall response rate (ORR), defined as the best reported partial response (PR) or better. Meta-analyses were conducted for ORR and the scale of logarithm of odd using the generic inverse variance method. The random effects model was used to pool the effect sizes for each study assuming a normal distribution of the random effects. Preplanned subgroup by therapy type and histological subtypes of lymphoma were treated as fixed effects and compared using Wald test. The degree of statistical heterogeneity was evaluated by inconsistency index (I2).Results:Our literature search identified 1873 articles, which after filtering for inclusion and exclusion criteria, ruling in only papers including T-cell lymphoma specific response, was narrowed to 128 studies for data extraction. Of these 128 studies, 35 were phase I trials, 70 phase II, 13 phase III, and 10 were combination. First, we divided all studies into upfront (n=33) versus R/R (n=100) based on timing of their treatments. We specifically focused on patients with R/R TCLs and subdivided those studies into the novel SA (n=84) and conventional chemotherapy (n=16) categories. The ORR for novel agents was lower at 37% (95% confidence interval [CI]: 34, 41) in comparison with 55% (95% CI: 40, 69) for standard chemotherapy agents (p=0.02).When stratified by histological subtype, patients with PTCL-NOS (n=751) had comparable ORR to novel agents (31%; 95% CI: 27, 35) and conventional chemotherapy (40%; 95% CI: 31,50; p=0.08). Similar results were seen with patients with AITL (n=296) who achieved equivocal ORR to single agents (45%; 95% CI: 38, 52) when contrasted with conventional chemotherapy (55%; 95% CI: 27, 80; p=0.52). Similar efficacy was seen for patients with CTCL (n=612) across SA (34%, 95% CI:29, 40) and CC (44%; 95% CI: 33, 56; p=0.11).Conclusions: Our meta-analysis highlights that for particular histological subtypes of PTCL such as PTCL-NOS and AITL, single agents are non-inferior to cytotoxic chemotherapy regimens in the R/R setting. These findings warrant serious consideration in the design and development of clinical trials for patients with R/R PTCL and the need for tailored treatments. Our meta-analysis also informs clinicians and patients about the benefits of single agents in comparison with standard chemotherapy while making clinical decisions for specified histologies. DisclosuresFoss: Mallinckrodt: Honoraria; Kyowa: Honoraria; Kura: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau; Acrotech: Honoraria, Speakers Bureau; Daiichi Sankyo: Honoraria. Jain: Trillium Therapeutics, Inc: Research Funding; Acro Biotech, Inc: Research Funding; Abcuro, Inc: Research Funding.

Efficient Targeting of CD38 in Mature T-Cell Neoplasms with Daratumumab and Allogeneic NK Cells

Introduction: Mature T-cell neoplasms (MTCN) are a heterogeneous and aggressive group of lymphoid neoplasms with very limited options for precision immunotherapy. Targeted immunotherapy with antibodies directed against surface markers on tumor cells has emerged as an effective treatment for B-cell neoplasms, but the development of immunotherapy strategies for MTCN has been much slower. CD38 is expressed at low levels in a subset of normal resting T-cells. Data on the frequency and level of CD38 expression is MTCN are lacking. Our goal was to study the expression and stability of CD38 on a spectrum of neoplastic T-cell populations and assess the potential anti-tumor effect of anti-CD38 monoclonal antibodies in combination with allogeneic natural killer (NK) cells in MTCN.Methods and results: We searched the Thomas Jefferson University Hospital (TJUH) pathology records for all cases of MTCN for which immune-phenotypical characterization of the neoplastic T-cell population by multi-color flow cytometry (FC) was available. CD38 expression was evaluated in cases where an abnormal T-cell population (defined as loss of one on more pan T-cell markers and/or a skewed CD4 to CD8 ratio). A total of 103 unique patients with MTCN were identified. Of these, 51 had at least one biopsy whereby tumor cells had an abnormal immunophenotype which could then be assessed for CD38 expression. CD38 was expressed to some extent in all but 2 cases with expression levels on peripheral T-cell lymphoma-not other specified (PTCL-NOS)(% Mean±SEM = 80.84±10.26, N=11), angioimmunoblastic T-cell lymphoma (AITL) (% Mean±SEM = 80.56±7.34, N=6), nodal PTCL with T follicular-helper (T FH) phenotype (% Mean±SEM = 55.00±12.72, N=7), anaplastic large cell lymphoma (ALCL) (% Mean±SEM = 77.38±10.75, N=3), large granular lymphocytic leukemia (LGLL) (% Mean±SEM = 80.27±7.49, N=4), T-cell prolymphocytic leukemia (T-PLL) (% Mean±SEM = 88.26±4.20, N=7), cutaneous T-cell lymphoma (CTCL) (% Mean±SEM = 49.52±14.77, N=7), adult T‐cell leukemia/lymphoma (ATLL) (% Mean±SEM = 76.68±10.45, N=3), hepatosplenic T-cell lymphoma/monomorphic epitheliotropic intestinal T-cell lymphoma (HSTCL/MEITL) (% Mean±SEM = 75.00±11.37, N=3). The medians and ranges of the MFI of CD38 on CD38+ tumor cells were the following: PTCL-NOS 29.46 (3.1-115.62), AITL 13.64 (2.67-29.41), other PTCL-T FH 5.87 (0-48.67), ALCL 11.13 (3.6-11.28), LGL (13.52 (9.72-18.25), T-PLL 6.49 (3.09-18), CTCL 8.36 (0-116.75), ATLL 27.17 (3.54-60.5), HSTCL/MEITL 15.96 (6.96-167.85). We also measured surface expression of CD38 on the patient-derived MTCN cell lines HuT-78, HuT-102, Jurkat, H9, HH, and MOTN1, all of which expressed CD38, to determine which of these cell lines could be used for in vitro experiments. We next evaluated if the CD38 molecule is an effective target for antibody-mediated therapy in MTCN, by testing the ability of daratumumab (dara) to enhance antibody-dependent cellular cytotoxicity (ADCC) elicited by NK cells. For this, we purified normal NK-cells from TJUH Blood Bank leukoreduction filters and cultured with recombinant IL-15 for 48 hours prior to all experiment. T-cell lines and primary MTCN cells were treated with increasing concentrations (0.1 µg/mL - 2 µg/mL) of dara or isotype control. NK-cells were added at Effector:Target ratio of 5:1 and incubated for 4 hours at 37⁰ Celsius. Cytotoxicity was measured by LDH release assay. Dara induced significant cell lysis starting at doses as low as 0.1μg/mL in both T-cell lines and primary MTCN cells, reaching maximum cytotoxicity at 0.5-2μg/mL (mean±SEM cytotoxicity in isotype vs dara treated cells= 50.0±5.05% vs 97.5±2.5%, N=4, p-value=0.0002). The degree of ADCC induction also correlated with interferon-gamma (IFN-g) release by NK cells in vitro for both T-cell lines and primary MTCN cells.Conclusions: The majority of MTCN analyzed (N=49, 96%) showed any degree of CD38 expression by FC with a wide variation of intensity, including within the same subtype. Allogeneic NK cells efficiently elicited dara-mediated ADCC of tumor cells from all MTCN subtypes and produced abundant IFN-g. These data highlight the potential of targeting CD38 in MTCN with anti-CD38 antibodies and allogeneic NK cells. The strong CD38 expression observed in most tumor cells from ultra-rare and very aggressive subtypes of MTCL opens the door to much needed new treatment strategies. DisclosuresBrammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Chakravarti: Kiadis Pharma: Patents & Royalties. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

Smart Stop: A Phase II Study of Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Chemotherapy in Patients with Newly Diagnosed DLBCL

Smart Stop: A Phase II Study of Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Chemotherapy in Patients with Newly Diagnosed DLBCL

Droxidopa for Treatment of Refractory Orthostatic Hypotension in Patients with AL Amyloidosis: A Case Series

BackgroundOrthostatic hypotension due to autonomic dysfunction is a well-known complication of light chain (AL) amyloidosis, which can become progressively debilitating and difficult to manage. Treatment of the underlying plasma cell dyscrasia will eventually decrease further amyloid deposition. Management of orthostatic hypotension secondary to AL amyloidosis improves quality of life and facilitates delivery of plasma cell therapy. Pharmacologic interventions include fludrocortisone, sympathomimetic agents such as midodrine, droxidopa, the acetylcholinesterase inhibitor pyridostigmine or the norepinephrine transporter (NET) inhibitor atomoxetine. Fludrocortisone is often poorly tolerated in amyloid patients because it may exacerbate edema. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which increases blood pressure (BP) by inducing peripheral arterial and venous vasoconstriction.AimsTo assess the effectiveness of droxidopa in patients with AL amyloidosis with severe orthostatic hypotension refractory to midodrine. Also, to describe effective dose of droxidopa, duration of therapy, adverse effects and reasons for discontinuation.MethodsA regional retrospective study was done in patients with AL amyloidosis with severe, refractory orthostatic hypotension who received droxidopa. Retrospective data was reviewed from 2018 to 2021 at a single academic center in the United States.ResultsFive patients with AL amyloidosis were included in the study; three patients had lambda-restricted plasma cell dyscrasia and two had multiple myeloma (MM) associated AL amyloidosis (both kappa light chain restricted). Of the five patients, all had cardiac, renal, autonomic nervous system and peripheral nervous system involvement and two of the five had gastrointestinal involvement as well. Given their poor performance status and advanced organ involvement, none of the patients were eligible for high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT), and thus were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD). All patients achieved very good partial response to complete hematologic response. The main findings are summarized in table 1.All patients had severe, symptomatic orthostatic hypotension that was objectively defined as a decrease in systolic blood pressure by 20 millimeters of mercury (mmHg) or a decrease in diastolic blood pressure of 10 mmHg from supine to either sitting or standing in the clinic or at home (Freeman R consensus statement on the definition of orthostatic hypotension, 2011). Initial treatment for all patients included midodrine, ranging from 5 to 30mg TID based on individual tolerance. Three of the patients also were initially treated with fludrocortisone 0.05 to 0.2mg daily (use limited by fluid retention). Only one patient was on pyridostigmine 30mg TID (case 5). Given persistence of symptoms despite therapy, droxidopa was started at 100mg TID in all patients, and the dose was titrated as tolerated. None required the maximal approved dose of 600mg TID.The indication to start droxidopa was based on refractory, symptomatic orthostatic hypotension in all five patients. After initiation of droxidopa, all except for one patient reported improvement both in symptoms of lightheadedness as well as measurements of orthostatic blood pressure values. By the end of this study, three patients continued treatment with droxidopa (cases 1-3); one was weaned-off after resolution of symptoms (case 5) and one was discontinued due to supine hypertension (case 4).ConclusionData shows that droxidopa is an effective treatment of orthostatic hypotension refractory to midodrine in patients with AL amyloidosis. Slow titration may be important to minimize rapid changes in blood pressure. Further studies are warranted to assess droxidopa's safety and compare with other treatments for orthostatic hypotension. [Display omitted] DisclosuresHughes: Amgen: Speakers Bureau; Rigel: Other: Advisory Board, Research Funding; Abbvie: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau. Sanchorawala: Celgene: Research Funding; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria. Sloan: Nuvectis: Consultancy; Abbvie: Consultancy; Stemline: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees.

Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma Patients in Complete Metabolic Response at Time of Infusion

Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma Patients in Complete Metabolic Response at Time of Infusion

Risk Stratification for Relapsed/Refractory Classical Hodgkin Lymphoma Integrating Pretransplant Deauville Score and Residual Metabolic Tumor Volume

IntroductionPositron emission tomography (PET) positivity before autologous stem cell transplantation (ASCT) predicts poor prognosis in relapsed/refractory (rel/ref) classical Hodgkin lymphoma (cHL). However, there is limited data regarding the value of pre-ASCT residual metabolic tumor volume (rMTV) assessed by PET to predict post-ASCT outcomes. We aimed to evaluate the role of pre-ASCT Deauville score (DS) combined with rMTV in patients with rel/ref cHL who underwent salvage ASCT, and also to establish a risk model integrating pre-ASCT DS, rMTV, and other clinical risk factors.MethodsThis is a retrospective cohort study using clinical data of patients with rel/ref cHL identified from the lymphoma database and the ASCT database of the Princess Margaret Cancer Center, Toronto, Canada. Following criteria were required: (1) patients (≥18 yrs) with histologically confirmed rel/ref cHL between January 2014 to March 2019; (2) treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-equivalent regimens; (3) chemosensitive disease after salvage therapy; (4) restaging PET before ASCT clearance. Pre-ASCT PET scans were assessed using the Deauville 5-point scale, and rMTV was computed in the scans with DS 4 or 5 using the 41% maximum standardized uptake value threshold method. Receiver operating characteristics analysis was used to determine an optimal cutoff of rMTV 41% for event prediction. The primary endpoint was event-free survival (EFS), defined as time form ASCT to first documented disease progression, any new lymphoma therapy, death from any cause, or last follow-up.ResultsA total of 106 patients fulfilled the eligibility criteria and were included. Median age was 33.5 yrs (range, 18-70), and 72 (68%) were male. The cohort characteristics at time of progression were 55 (52%) patients with advanced stage, 28 (26%) with B symptoms, 39 (37%) with extranodal disease, and 39 (37%) with primary refractory disease, defined as achieving less than a complete response, disease progression during first-line therapy, or time to relapse (TTR) 3 months or less. All patients received gemcitabine, dexamethasone, cisplatin (GDP) regimen as salvage therapy. Based on the response to GDP therapy, 24 patients required second (N=20) or third (N=4) salvage regimens before ASCT (brentuximab vedotin [BV] alone or combination with bendamustine [N=16], pembrolizumab [N=9], and mini-BEAM [N=3]). 32 patients (30%) received planned pre- or post-ASCT involved field radiation for DS 4-5 lesions. 4 patients received post-ASCT BV consolidation.With a median follow-up of 26.2 months (interquartile range [IQR], 14.4-49.2), 2-year EFS and overall survival rates were 72.1% and 93.1%, respectively. Pre-ASCT DS was determined as 1-3 (N=63, 59%) and 4-5 (N=43, 41%). None of the patients with DS 5 had new lesions. Patients with pre-ASCT DS 1-3 had significantly better EFS than those with DS 4-5 (2-year; 80.8% vs 59.2%; P=0.002; Fig 1A).Median rMTV 41% of the 43 patients with DS 4-5 was 5.1 cm 3 (IQR, 2.0-24.7). The optimal cutoff of rMTV 41% was 4.4 cm 3. Patients with rMTV low (< 4.4cm 3, N=21) had better EFS than those with rMTV high (N=22; 2-year, 75.0% vs 45.4%; P=0.009), but had similar 2-year EFS when compared with patients with DS 1-3 (80.8%, P=0.280; Fig 1B)In the multivariable analysis for EFS, a combined assessment of pre-ASCT DS/rMTV 41% and rel/ref status at time of progression were independently associated with EFS (for DS 4-5/rMTV low, hazard ratio [HR] 1.58; for DS 4-5/rMTV high, HR 4.72; P<0.001: for primary refractory disease, HR 2.26; P=0.026). Based on these results, we stratified patients into 3 groups according to the post-ASCT outcomes: low-risk (relapsed disease [i.e., TTR > 3 months] and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=54), intermediate-risk (refractory disease and either pre-ASCT DS 1-3 or DS 4-5/rMTV low, N=30), and high-risk (pre-ASCT DS 4-5/rMTV high irrespective of rel/ref status, N=22) groups. The risk model was significantly associated with EFS (intermediate vs low, HR 3.26, 95%CI 1.20-8.83, P=0.020; high vs low, HR 7.61, 95% CI 2.89-20.01, P<0.001; Fig 1C).ConclusionWe propose a risk stratification model integrating a combination of DS and rMTV 41% on pre-ASCT PET and rel/ref status at time of progression, which allow discrimination of post-ASCT outcomes in patients with rel/ref cHL. The model may serve as a tool to facilitate risk-stratified treatment decisions. [Display omitted] DisclosuresMetser: POINT Biopharm Inc: Consultancy. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Crump: Roche: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees. Kuruvilla: Seattle Genetics: Honoraria; Amgen: Honoraria; Antengene: Honoraria; AbbVie: Honoraria; Janssen: Honoraria, Research Funding; BMS: Honoraria; Medison Ventures: Honoraria; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Roche: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; Pfizer: Honoraria. Kridel: Gilead Sciences: Research Funding.

Deep Phenotyping Reveals Expansion of T Follicular Regulatory Cells and Triple Positive (CTLA4, TIGIT, PD1) Exhausted Effector Memory T Cells Characterizing the Immunosuppressive Microenvironment in Follicular Lymphoma

INTRODUCTIONLymphoma cells are dependent on the tumor microenvironment (TME) for their survival and proliferation. Dissection of TME composition provides insight into lymphomagenesis, better prognostication, and enhancement of therapeutic options. Flow cytometry provides a robust approach for single-cell analysis. Nonetheless lack of well-defined comparator groups and/or a robust, reproducible approaches for analyzing the multidimensional data often limited such studies. In the current study, we analyzed the T cell background on a large reference set of follicular hyperplasia (FH) lymph node samples utilizing a robust standardized high dimensionality flow cytometry and a novel reproducible analytical pipeline. We then compared this baseline reference set with tumor infiltrating T cell subsets in follicular lymphoma (FL; in treatment naïve FL-NA and relapsed/refractory FL-RR sets).METHODSOn behalf of the imCORE Network we analyzed 44 FH and 81 FL (35 FL-NA and 44 FL-RR) with 2 standardized flow cytometry panels (23 antigen/18-color) (Table 1). We evaluated the T cell subset distribution as well as immune checkpoint expression (TIGIT, TIM3, PD-1, CD96, LAG3, CTLA4, CD73) within analytically defined T cell clusters. Analysis was performed using semiautomated multi-step analytical pipeline as outlined in Figure 1. Using standardized instrument settings and an R-based algorithms (gaussNorm) to minimize technical variations in sample acquisition we analyzed the T-cells subpopulations using a dimensionality reduction technique (UMAP), combined with an unsupervised clustering algorithm (FlowSOM). Statistical analysis was performed using non-parametric Wilcoxon test.RESULTSIn the 3 cohorts, several marked differences in the composition T cells subsets were observed. Compared to FH the FL lymph nodes were depleted for CD4 & CD8 naïve subsets (Table 2) and were characterized by an immune suppressive microenvironment enriched in specific subsets of activated T regulatory cells and exhausted memory effector cells. The pool of CD8 naïve cells was restored in FL-RR cases (Table 2).FL-NA nodes showed enrichment of T follicular regulatory cells (Tfr; Table 2) (0.9% vs 2.7%, p<0.0001) expressing FoxP3, dim to negative CD25, CD45RO, TIGIT, PD1, CTLA and CXCR5 (Table 2) and activated regulatory T cells (T-Reg) characterized by a highly suppressive phenotype CD25+, CTLA4+, TIGIT+ and PD1+ (Fig. 2B). Moreover, Tfr compartment was further expanded in relapsed/refractory FL cases (2.7% vs 4.5%, p=0.02).In association with the increase of Tfr cells, the concentration of CTLA4+, TIGIT+, PD1bright T follicular helper cells (Tfh) was reduced in FL-RR compared to FL-NA (Fig. 2C).The Tfr/Treg expansion was also associated with a marked increase in exhausted memory T cells in both CD4 and CD8 compartments (CD4 EM TP and CD8 EM DP, Table 2). In FL isolates the CD4 compartment was characterized by the expression of triple positive (CTLA4, TIGIT, PD1) phenotype in EM cells while the memory CD8 cells overexpressed TIGIT and PD1 (Fig. 2D). A smaller subpopulation of memory CD8 cells, almost undetectable in FH samples, characterized by the expression of CTLA4, PD1, TIGIT and TIM3 is expanded in FL isolates (Fig. 2D).CONCLUSIONOur data suggest that change in balance between TFH and Tfr may lead to more aggressive therapy resistant disease in FL. The interplay between TFH and Tfr, has been postulated to shape the immune response in FL with TFH promoting germinal center formation and Tfr inhibiting TFH and follicular effector T cells. While both TFH and Tfr compartments are expanded in FL, in the relapsed/ refractory FL cases, the Tfr compartment is further expanded at the expense of TFH leading to more immunosuppressive background. Furthermore our study suggests a rational way of designing immune checkpoint inhibitor studies in FL. Effector memory T-cells in FL isolates show an exhausted phenotype characterized by the expression of the inhibitory receptors CTLA4, TIGIT, PD1 in the CD4 compartment, and TIGIT, PD1 in the CD8. In addition, the noteworthy expansion of TIM3+ memory CD8 cells in FL. Targeting these most highly expressed checkpoints in FL alone or in combination may provide an avenue for rational trial design. [Display omitted] DisclosuresRoshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Dogan: Physicians' Education Resource: Honoraria; Peer View: Honoraria; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy.

Clinical Characteristics and Responses of Patients with Relapsed or Refractory High-Grade B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Clinical Trial

Clinical Characteristics and Responses of Patients with Relapsed or Refractory High-Grade B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Clinical Trial

Change in Patients' Perceived Cognition Among Chimeric Antigen Receptor T-Cell Therapy Recipients at Day 360

Change in Patients' Perceived Cognition Among Chimeric Antigen Receptor T-Cell Therapy Recipients at Day 360

Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma

Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma

Efficacy Comparison of Tisagenlecleucel Versus Standard of Care in Patients with Relapsed or Refractory Follicular Lymphoma

Efficacy Comparison of Tisagenlecleucel Versus Standard of Care in Patients with Relapsed or Refractory Follicular Lymphoma

Clinical Outcomes in Patients (Pts) with Dose Reduction of Selinexor in Combination with Bortezomib, and Dexamethasone (XVd) in Previously Treated Multiple Myeloma from the Boston Study

Clinical Outcomes in Patients (Pts) with Dose Reduction of Selinexor in Combination with Bortezomib, and Dexamethasone (XVd) in Previously Treated Multiple Myeloma from the Boston Study

Enrollment Characteristics and Outcomes of Hispanic and Black AYA ALL Patients Enrolled on a U.S. Intergroup Clinical Trial: A Comparison of the CALGB 10403 (Alliance) Cohort with U.S. Population-Level Data

Enrollment Characteristics and Outcomes of Hispanic and Black AYA ALL Patients Enrolled on a U.S. Intergroup Clinical Trial: A Comparison of the CALGB 10403 (Alliance) Cohort with U.S. Population-Level Data

Pacific: A Phase II Study of Brentuximab Vedotin and Nivolumab Alone and then Combined with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone for Patients with Untreated Primary Mediastinal Large B-Cell Lymphoma

Pacific: A Phase II Study of Brentuximab Vedotin and Nivolumab Alone and then Combined with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone for Patients with Untreated Primary Mediastinal Large B-Cell Lymphoma

Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, Dexamethasone (Dara-CVRd), V-Augmented Autologous Stem Cell Transplant (V-ASCT) and Dara-Vrd Consolidation in Ultra-High Risk (UHiR) Newly Diagnosed Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL) Compared with Myeloma XI/XI+ Trial Treatment for Uhir MM: The UK Optimum/Muknine Trial

▪Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a ‘digital comparator arm’ trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the ‘MyXI prior’. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior.Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life.Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare (<5%) for all categories, consistent with previously presented data on induction. We previously reported high MRD-negativity rates of 61% at day +100 post V-ASCT for OPTIMUM, with a lower rate of 40% of patients showing both complete response (CR) and MRD-neg. With further follow-up, CR rate increased to 68.2% (95% CI: 58.5-76.9) at end of Cons1, including virtually all patients with MRD-neg finding post V-ASCT.Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. [Display omitted] DisclosuresKaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.

Metabolic PET/CT Analysis of Aggressive Non-Hodgkin Lymphoma Prior to Axicabtagene Ciloleucel CAR-T Infusion: Predictors of Progressive Disease, Survival, and Toxicity

Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion.Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use.Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD.Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each).While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2).Additional patients and follow-up will be presented.Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. [Display omitted] DisclosuresBennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

Targeting Control of Cell Cycle Enhances the Activity of Conventional Chemotherapy in Chemotherapy-Resistant Acute Myeloid Leukemia

Chemotherapy-resistant acute myeloid leukemia (AML) manifesting as primary refractory or relapsed disease carries a dismal prognosis and is often driven by clonal evolution. We have performed a genome-wide CRISPR knockout screen investigating resistance to conventional AML therapy, cytarabine and doxorubicin (AraC/Dox), in 2 independent human AML cell lines. Chemoresistant populations were enriched with gRNAs disrupting cell cycle arrest genes, including cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53. Here, we validate the direct contribution of these genes to chemoresistance and demonstrate that rationally designed therapeutic regimens targeting cell cycle enhances chemotherapy response in AML.Using CRISPR-mediated gene editing, we individually inactivated CDKN2A and CHEK2 in Cas9-expressing OCI-AML3 and MV4-11 cells. CDKN2A- and CHEK2-deficient cells demonstrated proliferative advantage in the presence of AraC/Dox in co-culture competition assays, confirming direct contribution of these gene knockouts to chemoresistance. Nil to modest reductions in apoptosis were seen in CDKN2A- and CHEK2-deficient cells treated with AraC/Dox for 72 hours compared to unedited controls. However, failure of accumulation of cells in the non-cycling G 0/G 1 proportion was seen in these edited cells after chemotherapy, corresponding with maintained DNA synthesis, as measured by BrdU incorporation, and a failure to downregulate phospho-Rb protein expression, indicating ongoing active cell cycling in spite of chemotherapy. These results confirm failure of cell cycle arrest as the major mechanism of resistance with inactivation of CDKN2A or CHEK2.To assess relevance of these genes in chemotherapy response in human AML, we analysed the effect of CDKN2A expression on prognosis. Reduced expression of CDKN2A conferred inferior overall survival in 3 independent clinical cohorts. Additionally, downregulation of CDKN2A and an increase in downstream cell cycling effector, cyclin-dependent kinase 6 (CDK6) was seen at relapse in paired diagnosis-relapse AML samples (Li et al. 2016, Nature Medicine). Further, CHEK2 mutations in clonal hematopoiesis are enriched in patients with solid organ cancers following chemo- or radiotherapy, functionally demonstrating chemoresistance over non-mutated cells. These data suggest CDKN2A and CHEK2 loss-of-function is relevant in promoting chemoresistance in human hematopoiesis.We therefore investigated whether therapeutically targeting cell cycle control pathways that converge on the G 1/S restriction point could synergise with cytotoxic chemotherapy, potentially circumventing chemoresistance. The addition of MDM2 inhibitor, nutlin-3a with AraC/Dox achieved striking synergism in TP53-competent cell lines in reducing viability and promoting apoptosis. Inhibition of CDK4/6 with palbociclib alone induced cell cycle arrest without apoptosis, however combination therapy with AraC/Dox significantly potentiated apoptosis. To functionally validate the role of CDKN2A itself, we examined the inhibitor of histone acetyltransferase KAT6A, WM-1119 (Baell et al. 2018, Nature), which transcriptionally upregulates CDKN2A. WM-1119 had anti-leukemic activity across multiple cell lines, corresponding with down regulation of cell cycling and upregulation of senescence signatures. The anti-leukemic activity was prevented by CDKN2A inactivation, indicating that CDKN2A upregulation is essential for WM-1119's anti-leukemic effect. WM-1119 enhanced activity of AraC/Dox in multiple cell contexts, mediated by cooperative induction of CDKN2A. Its efficacy and synergy with AraC/Dox was further demonstrated in MLL-AF9 primary murine AML ex vivo, demonstrating broader applicability of the approach.Our findings reveal defects in cell cycle arrest pathways as clinically relevant contributors to chemoresistance in AML. Combining agents to target cell cycle components improved in vitro anti-leukemic activity of chemotherapy and warrants further exploration of their translational potential. DisclosuresBullinger: Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Menarini: Consultancy; Hexal: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Consultancy, Honoraria; Astellas: Honoraria; Gilead: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Honoraria; Abbvie: Consultancy, Honoraria. Lane: BMS: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Novartis: Consultancy; Geron: Consultancy.

Clinical and Genomic Characterization of Secondary Acute Myeloid Leukemia with Mixed Phenotype

Clinical and Genomic Characterization of Secondary Acute Myeloid Leukemia with Mixed Phenotype

Quality of Life and Caregiver Burden in Patients and Their Caregivers Undergoing Outpatient Autologous Stem Cell Transplantation Compared to Inpatient Transplantation

Quality of Life and Caregiver Burden in Patients and Their Caregivers Undergoing Outpatient Autologous Stem Cell Transplantation Compared to Inpatient Transplantation

Completed Induction Phase Analysis of Magnify: Phase 3b Study of Lenalidomide + Rituximab (R 2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Completed Induction Phase Analysis of Magnify: Phase 3b Study of Lenalidomide + Rituximab (R 2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma