Vemuri, Shreya

Background: Disseminated marginal zone lymphoma (MZL) is an indolent disease often observable at diagnosis with treatment indications similar to other indolent lymphomas. First-line therapy is typically rituximab alone or in combination with chemotherapy (e.g. bendamustine). Due to the long-life expectancy, avoiding alkylating agents to reduce bone marrow damage could be beneficial. In addition, a “chemotherapy free” option could have fewer and less severe complications. Bruton tyrosine kinase inhibitors (BTKi) are active and approved or NCCN-recommended beyond first line therapy in MZL. Moreover, BTKi are approved for first line therapy in Waldenstrom's Macroglobulinemia, a disease with both diagnostic and pathophysiologic overlap with MZL. We conducted a multicenter randomized trial of rituximab induction plus ibrutinib/placebo (RI vs RP) for patients with MZL in need of first line systemic therapy. Complete response (CR) rate at 30 months was the primary endpoint and progression free survival (PFS) was secondary. The target sample size was 63 in each arm. The study was closed after 22 eligible patients enrolled due to low accrual. Methods: Patients (pts) with either nodal, splenic or extranodal MZL were eligible. Prior surgery, radiation, antibiotic or antiviral therapy for MZL were allowed if followed by disease progression requiring treatment. Documented evidence of need for treatment included, but was not limited to, threatened end-organ function, bulky disease (>5 cm), symptoms, requirement for transfusion or growth factor support, or significant need for intervention. Transformation to DLBCL was excluded prior to entry including bone marrow assessment. Randomization occurred prior to rituximab weekly x 4 to either daily placebo (RP) or ibrutinib (RI) 560 mg starting on day 1 and continued until disease progression (PD), intolerance or CR at 30 months. Those with partial response (PR) or stable disease (SD) at 30 months could continue placebo or ibrutinib. CR assessment required both a negative FDG-PET and bone marrow biopsy. RESULTS: 22 pts enrolled (Feb 2020-March 2023) with baseline characteristics including: median age 67 years (35-78) and White race 17. Stage II (3), III/IV (17). Subtype: splenic 16, nodal 4, extranodal 2. Prior therapy: splenectomy 1, radiation 0, other surgery 0, antiviral/antibiotic 0. Median maximal tumor dimension was 3.7 cm (range 1.6-23.6); with >5 cm in 9 pts. Median time from diagnosis to treatment was 32 days (5-4712 with only 3 > 1 year). 11 pts were randomized to each arm. Responses: RP: 3 CR, 4 PR, 3 SD, 1 inevaluable; RI: 7 CR, 4 PR. No patient achieved CR30, but 3 had CR at 29 months: 2 RP, 1 RI. With a median follow up of 35 months (13-50), the median PFS by Log Rank was 14 mo (RP) vs 29 (RI), though this difference was not statistically significant in the setting of small numbers. Treatment was well tolerated. Only 1 pt experienced grade 3 events at least possibly related: hypoxia and dyspnea. This was attributed to COVID-19 and occurred on the RP arm. 1 CR patient with baseline clonal hematopoiesis developed myelodysplasia. Treatment improved baseline activities in 4/5 pts (1 RP, 3 RI). Baseline pain improved in 8 pt: 4 RP, 4 RI. All pts were alive at the data cuff off. Conclusions: This study is a chemotherapy free frontline trial in MZL and the first to utilize ibrutinib in frontline MZL. All pts received rituximab induction and were randomized at entry to RP vs RI. The COVID-19 pandemic affected site activation and accrual, ultimately contributing to low accrual and early study termination. Nonetheless, the results suggest a marked difference in median PFS favoring the RI arm, although small numbers preclude a statistically significant result. Notably, our results are qualitatively similar to those of Dimopoulos (NEJM, 2018) in Waldenstrom's Macroglobulinemia, a disease with similar characteristics to MZL. In that study, the median PFS by Log Rank was 20 months (RP) vs not reached (RI); and 30-month PFS 28% (RP) vs 82% (RI). (Hazard ratio for progression or death, 0.20; P<0.001). Further, our trial supports pursing a chemotherapy free first line approach in MZL.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes, particularly given the development of more active therapies for relapsed, refractory DLBCL. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost, without clear overall survival benefit in retrospective studies (Thompson JCO 2014). A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski Lancet Oncol 2015). In this multicenter prospective study, we assessed whether a next-generation immunosequencing (IS) MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The IS MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD undetectable as no evidence of rearrangement. Results: 500 pts were enrolled and 400 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 42%. Histologies included DLBCL, NOS (88%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (3%), and other (1%). Pts received regimens including RCHOP x 6 cycles (37%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (9%), and other RCHOP variations (19%). Among the 400 evaluable pts, 44 relapses have occurred as of July 1, 2021. In 45% of pts (20/44), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation . In 10% of pts (4/44), relapse was detected by patient-reported clinical symptoms alone. In 45% of pts (20/44), relapse was detected by imaging, clinical symptoms, and/or evaluation by an oncologist. With a median follow-up of 34 months, the 2-year PFS was 88.9% (85.8, 92.1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, tumor-specific clonotypes were identified in 39 pts (4 failed quality control (QC), 1 failed calibration) and 38 pts had ≥1 sample available within 90 days of relapse. Of 356 patients in ongoing CR, tumor-specific clonotypes were identified in 279 patients (29 failed QC, 33 failed calibration, and 15 are pending sequencing). The patient-level prospective MRD results are shown in Figure 1. The overall sensitivity, specificity, positive predictive value, and negative predictive value of the IS MRD assay was 63% (24/38), 78% (218/279), 28% (24/85), and 94% (218/232), respectively. Plasma MRD detection had improved sensitivity and specificity compared with circulating cells. Among the 24 relapsed patients with a positive MRD result at or before relapse, the median anticipation of the test was 3 months (range 0 to 24 months). Conclusion: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative CR. In this multicenter prospective analysis with standardized follow up, a substantial proportion (45%) of clinical relapses are detected radiographically in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. MRD assessment using the IS MRD assay had suboptimal sensitivity and specificity in the post-treatment surveillance setting in DLBCL. Further study of the clinical context and its correlation with test performance is ongoing. Figure 1 Figure 1. Disclosures Kumar: Kite Pharmaceuticals: Other: advisory board , Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding. Westin: Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Research Funding; Morphosys: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; MorphoSys: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; 47 Inc: Research Funding. Schuster: TG Theraputics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; NCI: Research Funding; University of Miami: Current Employment; NIH grants: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria. Jacob: Adaptive Biotechnologies: Current Employment. Mullins: Adaptive Biotechnologies: Current Employment. Zelenetz: AstraZeneca: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Janssen: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; MethylGene: Research Funding; NCCN: Other; Pharmacyclics: Honoraria; Novartis: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria.

Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes with second-line curative intent therapy or novel therapies. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost. A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski, Lancet Oncol, 2015). In this multicenter prospective study, we assessed whether a next-generation sequencing (NGS)-based MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The clonoSEQ® next generation sequencing (NGS) MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD negative as no evidence of rearrangement. We also reported MRD positivity above the limit of detection (LOD) (observations required to have 95% reproducibility). Interim futility analysis was performed after approximately 50% of anticipated relapses occurred to assess the preliminary sensitivity of the assay. Progression-free survival (PFS) was defined as time from treatment start date to relapse or death. Results: 501 pts were enrolled and 401 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 40% (Table 1). Histologies included DLBCL, NOS (86%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (1%), and other (1%). Pts received regimens including RCHOP x 6 cycles (36%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (10%), and other RCHOP variations (19%). Among the 401 evaluable pts, 44 relapses have occurred as of June 1, 2020. In 47% of pts (18/38), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation. Clinical relapse was detected by clinical symptoms alone in 11% (4/28), by the evaluation of an oncologist alone in 0%, and by imaging and clinical symptoms and/or evaluation by an oncologist in 42% (16/38) (missing data in 6 pts). With a median follow-up of 2.2 yrs, the 2-yr PFS was 88.1% (84.8, 91.4) (Figure 1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, 43 pts were included in the interim analysis and tumor-specific clonotypes were identified in 39 pts (91%). In 56% (22/39), the MRD assay was positive at or before clinical relapse. In 38% (15/39), the MRD assay was positive above the limit of detection at or prior to clinical relapse, with only 10 relapses detected more than 3 mos prior to relapse, reflecting the poor clinical sensitivity of the assay. The NGS-MRD assay was more sensitive in the acellular (plasma cell-free DNA) than in the cellular (circulating leukocytes) compartment. Results: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative complete remission. In interim analysis, surveillance MRD assessment using the clonoSEQ® assay fails to consistently identify pts at risk of recurrence before clinical evidence of relapse in DLBCL. In a prospective analysis, a substantial proportion (47%) of clinical relapses are detected by imaging in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. Additional analyses are forthcoming for MRD assessment in all pts, including those in remission. Disclosures Kumar: Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Westin:Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Nowakowski:Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Lossos:Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Biotech: Honoraria; Janssen Scientific: Consultancy, Other. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Drullinsky:Roche: Research Funding; Novartis: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. von Keudell:Bayer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Matasar:Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Noy:Pharmacyclics: Research Funding; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy. Straus:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Younes:Takeda: Consultancy; HCM: Consultancy; AstraZeneca: Current Employment; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BioPath: Consultancy; Curis: Consultancy. Zelenetz:MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees.