Citations

Abstract Lymphoma is the sixth most commonly diagnosed cancer in the US. Genome-wide association studies have identified common variants associated with risk of specific lymphoma subtypes, but less is known about the contribution of rare inherited variants in the genetic architecture of lymphoma risk. CHEK2 is important to DNA repair and 2 small studies have found evidence of an association between CHEK2 variants and risk of lymphoma. Here, we investigated loss of function (LoF) variants in CHEK2 with risk of lymphoma (overall and subtypes). The study population included newly diagnosed lymphoma cases from Mayo who were enrolled in the Lymphoma SPORE Molecular Epidemiology Resource (MER). Controls were from the Mayo Clinic Biobank, from which we excluded a prior hematologic malignancy. Whole exome sequencing was performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All LoF variants (nonsense, frameshift and consensus splice sites) in CHEK2 with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between CHEK2mutation status and risk of lymphoma overall, and by lymphoma subtypes that had more than 5 mutation carriers, which included diffuse large B-cell (DLBCL), follicular (FL), and T-cell lymphoma (TCL). All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. A total of 4,852 lymphoma cases and 49,724 controls were included in this analysis. Median age for both cases and controls was 62 years (range 18-99 years). Males accounted for 57.5% (n=2,789) of the cases and 40.6% (n=20,186) of the controls. The DLBCL (23.6% of cases) and FL (23.3% of cases) subtypes were the most common; 7.6% of cases had TCL. A total of 407 (0.7%) individuals had a LoF variant. The frequency of LoF variants was 1.2% in lymphoma cases and 0.7% in controls. LoF variants were associated with increased risk of lymphoma overall (OR=1.77; 95%CI: 1.32-2.33), DLBCL (OR=2.07; 95%CI: 1.20-3.13), and TCL (OR=2.78; 95%CI: 1.178-5.50), but not FL (OR=1.31; 95%CI: 0.65-2.34). CHEK2 c.1100delC was the most frequently mutated variant in this population, accounting for 76% of all LoF variants. Individuals with a c.1100delC variant had an increased risk of lymphoma overall (OR=1.90; 95%CI: 1.37-2.58), DLBCL (OR=2.06; 95%CI: 1.09-3.54), and TCL (OR=3.17; 95%CI:1.24-6.58), but not FL (OR=1.05; 95%CI: 0.41-2.15). When restricted to cases, there was no significant difference in age at diagnosis (P=0.62) or sex (P=0.53) between LoF variant carriers and non-carriers. In this large lymphoma case-control study, CHEK2 LoF variants were associated with increased risk of lymphoma, demonstrating that rare inherited variants may play an important role in the etiology of lymphoma. Additional work is needed to investigate missense variants in CHEK2 and risk of lymphoma. Citation Format: Nicholas J. Boddicker, Raphael Mwangi, Dennis P. Robinson, Allison C. Rosenthal, Thomas M. Habermann, Andrew L. Feldman, Lisa M. Rimsza, Rebecca L. King, Melissa C. Larson, Brianna J. Gysbers, Stephen M. Ansell, Jithma P. Abeykoon, Grzegorz S. Nowakowski, Thomas E. Witzig, Anne J. Novak, Susan L. Slager, James R. Cerhan. Germline CHEK2 variants and risk of lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5233.

Abstract Introduction: Cytokines are protein factors that regulate diverse cellular processes. The malignant progression of immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) to Waldenstrom macroglobulinemia (WM) is in part cytokine mediated, and we have previously shown IL-6 mediates IgM secretion in WM via the JAK/STAT pathway. Cytokine signaling can be epigenetically modulated by micro-RNAs (miRs). We aimed to identify the role of miRs in the regulation of inflammatory cytokine pathways between these diseases. Methods: Bone marrow samples of patients with IgM-MGUS (n=7) and WM (n=25) were prospectively collected and sorted for CD19+ and/or CD138+ malignant cells. Total RNA extraction and sequencing were performed, miR and mRNA profiling was conducted, and differential expression was calculated between WM and IgM-MGUS using a log2 fold change (FC)>0.5 and ←0.5, false discovery rate<0.05. Experimental differentially expressed miR-mRNA pairing was performed, and pairs were filtered for correlated expression (i.e., upregulated miR/downregulated mRNA, and vice-versa). Filtered pairs were analyzed using the Ingenuity Pathway Analysis to identify pathways between WM and IgM-MGUS with absolute activation Z-score ≥1. Results: We identified 34 differentially expressed miRs experimentally targeting 1132 mRNAs. Pathway analysis showed overall miR-based inactivation of inflammatory cytokine signaling pathways in WM compared to IgM-MGUS, especially of the interleukin (IL) family: IL-2, IL-6, IL-8, IL-9, IL-15, and IL-17. Underlying multiple pathways was upregulation of miRs-146a, 150, 194, all targets of Signal Transducer and Activator of Transcription 1 (STAT1), observed to be downregulated. Of relevance, miR-146a has been previously shown to be an inhibitor of inflammatory cytokines, including IL-6. Next, we observed upregulation of miR-142 which targets phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), observed to be downregulated. Both the STAT and PIK3 families are important cytokine signal transducers, and we have previously shown the PI3k-AKT-IkB-p65 pathway induces expression of IL-6 via a GLI2-mediated mechanism. We additionally observed granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling to be inactivated in WM. Here, miR-19b and miR-30e were upregulated, both target CSF 2 receptor subunit beta (CSF2RB), found to be downregulated. CSF2RB is the common receptor subunit of GM-CSF, IL-3, and IL-5. Conclusion: Our study identifies multiple cytokines pathways involved in inflammation and the tumor microenvironment to be potentially inactivated by differentially expressed miRs in WM compared to IgM-MGUS. Downregulation of these pathways and targeting of the STAT and PIK3 family indicates a possible miR-based negative feedback loop to down-modulate inflammatory cytokine signaling in WM. Citation Format: Karan Chohan, Jonas Paludo, Surendra Dasari, Jithma P. Abeykoon, Prashant Kapoor, Esteban Braggio, Michelle K. Manske, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher A. Chanan-Khan, Robert A. Kyle, Morie A. Gertz, Anne J. Novak, Stephen M. Ansell. Micro-RNA induced inactivation of inflammatory cytokine signaling pathways in Waldenstrom macroglobulinemia compared to IgM-MGUS. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3811.

1533 Background: FDA-approved chimeric antigen receptor T-cell (CAR-T) and bispecific T cell engager (TCE) therapy are most commonly managed inpatient. Here we report our experience with hospital-based outpatient (HBO) management of patients (pts) receiving FDA-approved CAR-T or TCE and a predictive model for increased risk of early hospitalization (≤3 days post CAR-T). Methods: We reviewed the outcomes of pts who received FDA-approved CAR-T (axi-cel, brexu-cel, ide-cel, cilta-cel) or TCE (teclistamab) in the HBO unit between 3/2021 and 1/2023 at Mayo Clinic, Rochester. Results: HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. CAR-T and TCE are given on HBO followed by monitoring per REMS and as clinically needed until admission criteria is met. Remote patient monitoring (RPM) tools were used as part of outpatient monitoring. Out of 169 CAR-T pts, 87 (51%) were dosed with new indication/products (follicular lymphoma, mantle cell lymphoma, myeloma). Among those, 80 (92%) pts were dosed outpatient, among whom 21 (27%) were never hospitalized. CRS and ICANS incidences were comparable to that reported in registration studies. Median time to first admission from CAR-T infusion was 1 day (range, 0-9), with 31% (n=18/59) of admissions after day 3 post infusion. The most common cause of hospitalization was fever (n=40, 59%). Median length of hospital stay was 4 days (range, 1-49). Median time to tocilizumab (n=45, 80%), steroid (n=1, 2%), escalation of oxygen support (n=7, 12%), vasopressor (n=2, 3%), ventilator (n=1, 2%), hemodialysis (n=1, 2%) and ICU transfer (n=3, 5%) was 1 day (range, 0-31) after first admission. Use of bridging therapy, elevated CRP and LDH were predictive of early admission (ROC AUC 0.62). Four pts received teclistamab on HBO and enrolled in RPM. Data from more pts will be reported at ASCO. Conclusions: Our expanded study in CAR-T and TCE confirms that HBO is feasible and that CAR-T and TCE can be safely dosed outpatient. Approximately 31% of pts were admitted after 3 days from CAR-T infusion, and 27% of our pts were never admitted. Variables associated with aggressive disease can predict early hospitalization in pts receiving FDA-approved CAR-T. Extension of HBO practice to TCE is feasible.[Table: see text]

Abstract Non‐follicular low‐grade B‐cell lymphomas (LGBCL) are biologically diverse entities that share clinical and histologic features that make definitive pathologic categorization challenging. While most patients with LGBCL have an indolent course, some experience aggressive disease, highlighting additional heterogeneity across these subtypes. To investigate the potential for shared biology across subtypes, we performed RNA sequencing and applied machine learning approaches that identified five clusters of patients that grouped independently of subtype. One cluster was characterized by inferior outcome, upregulation of cell cycle genes, and increased tumor immune cell content. Integration of whole exome sequencing identified novel LGBCL mutations and enrichment of TNFAIP3 and BCL2 alterations in the poor survival cluster. Building on this, we further refined a transcriptomic signature associated with early clinical failure in two independent cohorts. Taken together, this study identifies unique clusters of LGBCL defined by novel gene expression signatures and immune profiles associated with outcome across diagnostic subtypes.

SummaryThere remains no one standard induction for nodal‐based peripheral T‐cell lymphoma (PTCL). We conducted a phase II study of lenalidomide plus CHOEP as a novel induction strategy. Patients received CHOEP at standard doses in combination with 10 mg of lenalidomide on days 1–10 of a 21‐day cycle for six cycles of therapy followed by observation, high‐dose therapy with autologous stem cell rescue, or maintenance lenalidomide per provider preference. Among 39 patients evaluable for efficacy, the objective response rate after six cycles was 69%, with complete response in 49%, partial response in 21%, stable disease in 0% and progressive disease in 13%. Thirty‐two patients (82%) completed full induction, and seven patients (18%) discontinued for toxicity, primarily hematologic. Any grade hematologic toxicity occurred in over 50% of patients, with grade 3 or 4 febrile neutropenia occurring in 35% of patients despite mandated growth factors. With a median followup of surviving patients of 21.3 months, the estimated 2‐year progression‐free and overall survival were 55% (95% CI 37%–70%) and 78% (95% CI 59%–89%), respectively. In sum, six cycles of lenalidomide plus CHOEP resulted in a modest response rate primarily due to hematologic toxicity, which prevented all patients from completing planned induction.

Abstract Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory immune checkpoint receptor expressed on subsets of T-cells and natural killer (NK) cells. TIGIT inhibits T and NK cell function by binding to CD155 and CD112. SEA-TGT is an investigational human, nonfucosylated monoclonal antibody directed against TIGIT, blocking TIGIT's interaction with CD155 and CD112. SGNTGT-001 (NCT04254107) is a phase 1, open-label, multicenter study of SEA-TGT in patients (pts) with advanced malignancies (solid tumors and lymphomas). In this abstract, we present data from the dose-escalation phase (Part A). Methods: Pts received SEA-TGT ranging from 0.01 to 6.0 mg/kg of body weight intravenously every 3 weeks (Q3W). The primary objectives were to evaluate the safety and tolerability of SEA-TGT and identify the maximum tolerated dose (MTD) or the recommended dose and schedule of SEA-TGT. The optimal biological dose was defined using the Clinical Utility Index. Secondary objectives included the evaluation of antitumor activity, pharmacokinetics (PK) and immunogenicity. Antitumor activity was based on Response Evaluation Criteria in Solid Tumors version 1.1 or the Lugano classification criteria with Lymphoma Response to Immunomodulatory Therapy Criteria. Results: From June 12, 2020, to October 5, 2022, 41 pts were enrolled (2, 4, 5, 11, 12, and 7 pts in the 0.01, 0.1, 0.3, 1, 3, and 6 mg/kg cohorts, respectively). Among the 39 pts who were treated 23 pts had solid tumors and 16 had lymphomas. The median number of prior therapies across all cohorts was 5. Treatment emergent adverse events of any grade were reported in 100% of pts, and treatment-related adverse events (TRAEs) of any grade were reported in 69.2%. TRAEs seen in ≥10% of the pts were infusion-related reaction (38.5%), chills (25.6%), pyrexia (17.9%), fatigue (12.8%), maculopapular rash (12.8%), and rash (10.3%). Seven pts (17.9%) reported TRAEs grade ≥3, and rash (5.1%) was the most frequently reported. No grade 4 or 5 TRAEs were reported. One dose-limiting toxicity, pruritic rash, was observed in 1 pt in the 6 mg/kg cohort, and MTD was not exceeded. Based on the PK and pharmacodynamic data, 1 mg/kg Q3W was selected as the optimal biological dose for the expansion cohorts. One partial response was observed in a pt with gastric cancer, and 2 partial metabolic responses were seen in a pt with Hodgkin’s lymphoma and a pt with diffuse large B-cell lymphoma. Conclusions: Overall, clinical data for SEA-TGT from the SGNTGT-001 trial suggest a manageable and tolerable safety profile. Preliminary antitumor activity warrants further clinical evaluation of SEA-TGT. SGNTGT-001 is ongoing and evaluating monotherapy and combination therapies. Citation Format: Elena Garralda Cabanas, Elisa Fontana, Honey Kumar Oberoi, Nataliya V. Uboha, Ecaterina E. Dumbrava, Emiliano Calvo, Giuseppe Curigliano, Diwakar Davar, Bridget K. Keenan, Vincent K. Lam, Sudhir Manda, Amitkuma Mehta, Anna Minchom, Alison Moskowitz, Ravi Paluri, Vincent Ribrag, Donald Richards, Lillian Siu, Paul Swiecicki, Trisha Wise-Draper, Jasmine Zain, Andres Forero-Torres, Ping Xu, Stephen Ansell. Phase 1 dose-escalation study of SGN-TGT monotherapy in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT265.

Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1–12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (P = 0.006) and OS was NR versus 7.60 versus 3.08 versus 3.51 versus 3.17 years (P = 0.28) in patients first treated with ICIs versus BV versus investigational agents versus chemotherapy versus radiation therapy (RT). First-line treatment with novel agents (ie, ICIs and BV) was associated with superior outcomes compared with investigational agents and chemotherapy/RT with a median PFS of 1.65 versus 0.50 versus 0.79 years (P = 0.003) and a median OS of 7.60 versus 3.08 versus 3.32 years (P = 0.08). Regardless of lines of therapy, the treatment with ICIs had the most favorable outcome with a median PFS and OS of 3.98 and NR years, respectively. Allogeneic stem cell transplant (allo-SCT) was done in 23 patients (20%), and the median post-allo-SCT PFS and OS were 1.31 and 2.35 years, respectively. In conclusion, survival following post-ASCT relapse improves significantly when patients receive novel agents.