Faculty Bibliography

Introduction: Follicular lymphoma (FL) remains an incurable disease with a persistent risk of relapse and shorter durations of response with each subsequent line of therapy. As a result of this pattern of relapse, management of patients with FL requires multiple lines of therapy using various regimens with different mechanisms of action. To help inform FL treatment decisions among healthcare professionals (HCPs) in this complex and evolving treatment landscape, we developed an updated online treatment decision support tool that provides case-specific, individual recommendations from multiple experts in both the newly diagnosed and relapsed/refractory (R/R) disease settings. Here, we analyzed self-reported practice trends from HCPs using this tool and compared them with corresponding treatment recommendations from FL experts.
Method(s): In November 2020, 5 experts in lymphoma patient care provided therapy recommendations for 264 unique case scenarios in both newly diagnosed and R/R FL as defined by a simplified set of key patient and disease characteristics: disease stage, tumor grade, tumor burden, presence of symptoms, age, and fitness as well as previous therapy, duration of response, and EZH2 mutation status. Participating HCPs entered specific patient and disease factors using selection menus along with their intended treatment plan for each case. After case entry was completed, individual expert treatment recommendations were shown for the specific case scenario entered. Subsequently, HCPs were asked to indicate if the expert recommendations impacted their planned treatment approach.
Result(s): From March 2021 to July 2021, 205 HCPs entered 299 patient case scenarios (newly diagnosed: 154 cases; R/R: 145 cases) into the online tool. A comparison of treatment recommendations by experts and HCPs showed considerable divergence for several unique patient case scenarios (Table). For example, for patient cases with newly diagnosed, grade 1-3a, stage II-IV FL who had low tumor burden and no symptoms, 35% of HCPs recommended chemoimmunotherapy (CIT); by contrast, 100% of experts recommended observation or single-agent rituximab in this setting. For cases in the same disease setting but with high tumor burden and symptoms, 82% of HCPs chose CIT in agreement with expert consensus for CIT. However, experts exclusively recommended bendamustine-based CIT whereas 30% of HCPs selected a CHOP- or CVP-based regimen. In the setting of R/R FL, experts recommended second-line lenalidomide plus rituximab (R ²) for 78% of patient cases with relapse on frontline CIT. By contrast, only 14% of HCPs chose this regimen, with approximately two thirds of HCPs selecting either another CIT regimen or a PI3K inhibitor. In the third-line setting for symptomatic cases with high tumor burden and relapse after first-line CIT and second-line R ², experts favored tazemetostat, choosing it for 58% of cases in this setting regardless of EZH2 mutation status, while recommending CIT for 33% or a PI3K inhibitor for 9% of these cases. By contrast, HCPs favored a PI3K inhibitor (36%) over tazemetostat (18%) in this setting. For HCPs reporting on the tool's clinical impact, 63% of HCPs who initially selected another treatment option or who were uncertain indicated that they would change their intended therapy to match the experts.
Conclusion(s): Analysis of data from this tool suggests differences in clinical practice between experts and HCPs for multiple case scenarios of newly diagnosed and R/R FL, including examples of potential overtreatment. A majority of HCPs who initially selected treatment options that diverged from expert recommendations or who were uncertain about treatment choice changed their intended therapy to match the experts, suggesting that this online decision support tool may increase the number of HCPs making optimal management decisions for patients with FL. Detailed comparisons of expert recommendations and HCP responses from the online tool will be presented. [Formula presented] Disclosures: Burke: SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Kymera: Consultancy; Bristol Myers Squibb: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; MorphoSys: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; X4 Pharmaceuticals: Consultancy. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Sharman: BMS: Consultancy; TG Therapeutics: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Flowers: EMD: Research Funding; Xencor: Research Funding; Allogene: Research Funding; Iovance: Research Funding; National Cancer Institute: Research Funding; Gilead: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Guardant: Research Funding; Nektar: Research Funding; BeiGene: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Amgen: Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Denovo: Consultancy; SeaGen: Consultancy; Spectrum: Consultancy; Celgene: Consultancy, Research Funding; Biopharma: Consultancy; Epizyme, Inc.: Consultancy; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Novartis: Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Research Funding; Morphosys: Research Funding; Kite: Research Funding; 4D: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Cellectis: Research Funding; Pharmacyclics: Research Funding.
Copyright

BACKGROUND:Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. METHODS:on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. FINDINGS/RESULTS:Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. INTERPRETATION/CONCLUSIONS:Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). FUNDING/BACKGROUND:Genentech.

HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here we described the role of this HSP90 form, referred to as oncogenic HSP90, in the regulation of cytosolic metabolic pathways in proliferating B-cell lymphoma cells. Oncogenic HSP90 assisted in the organization of metabolic enzymes into non-membrane-bound functional compartments. Under experimental conditions that conserved cellular proteostasis, oncogenic HSP90 coordinated and sustained multiple metabolic pathways required for energy production and maintenance of cellular biomass as well as for secretion of extracellular metabolites. Conversely, inhibition of oncogenic HSP90, in absence of apparent client protein degradation, decreased the efficiency of MYC-driven metabolic reprogramming. This study reveals that oncogenic HSP90 supports metabolism in B-cell lymphoma cells and patients with diffuse large B-cell lymphoma, providing a novel mechanism of activity for HSP90 inhibitors. SIGNIFICANCE: The oncogenic form of HSP90 organizes and maintains functional multienzymatic metabolic hubs in cancer cells, suggesting the potential of repurposing oncogenic HSP90 selective inhibitors to disrupt metabolism in lymphoma cells.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.

Positron emission tomography-computed tomography (PET-CT) has become the primary modality for staging in diffuse large B-cell lymphoma (DLBCL), whereas the role of staging bone marrow biopsy (BMB) has become less clear. In this analysis, we included 7,005 DLBCL patients in SEER-Medicare who received either PET-CT without BMB (PET-CT w/o BMB), CT with BMB (CT w/ BMB), or both PET-CT and BMB (PET-CT w/ BMB). The proportion of patients undergoing PET-CT increased across years of diagnosis, while the proportion undergoing CT or BMB decreased. In a fully adjusted Cox proportional hazards model, PET-CT w/ BMB was associated with a marginally superior OS compared to PET-CT w/o BMB. Notably, the association between PET-CT w/ BMB and OS was strongest in patients ≤70 years, but was not present when looking at individual stage of diagnosis. Overall, these data do not provide sufficient support to eliminate staging BMB in patients who undergo PET-CT.

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m²/day for 2 days followed 14 days later by SCT. Sixteen subjects in partial remission (PR) with maximal FDG-PET SUVs ≤8 prior to bendamustine received autologous SCT, while 13 with suboptimal responses were allografted. Five subjects did not proceed to transplant. No bendamustine toxicities precluded transplantation and no detrimental effect on engraftment or early treatment-related mortality (TRM) was attributable to bendamustine. At 1 year, 75% of auto-recipients and 31% of allo-recipients were alive with CR. Two subjects in the autologous arm developed therapy-related myeloid neoplasia (t-MN). In conclusion, a bendamustine bridge to SCT can be administered without early toxicity to patients with suboptimal responses to salvage chemotherapy. However this approach may increase the risk of t-MN. (NCT02059239).Supplemental data for this article is available online at here.

This study examined distress and mental health service use in patients with newly diagnosed indolent lymphoma over the first-year post-diagnosis, as well as differences by age. Patients with indolent lymphoma completed online self-report measure of distress and whether they accessed mental health services (Yes/No) every four months for a total of four surveys. The baseline sample consisted of 74 patients; 41.9% were age 65 years and older, 24.3% endorsed elevated distress, and 16.2% accessed mental health services. Across time, less than half (36.4-46.7%) of distressed patients accessed mental health services. In patients younger than 65 years, a greater proportion of distressed than non-distressed patients accessed mental health services. However, distress was not associated with mental health service use in older adults. Future research should evaluate issues driving distress and access to mental health care in patients with indolent lymphomas, including age-based approaches.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. SIGNIFICANCE: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.This article is highlighted in the In This Issue feature, p. 1307.

PURPOSE/OBJECTIVE:Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS/METHODS:Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS). RESULTS:= .1. CONCLUSION/CONCLUSIONS:In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

Navitoclax, a novel BCL-2 and BCL-X_L inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma (n = 11, Arm A) and other relapsed/refractory lymphoid malignancies (n = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.