Bulky Disease Research Articles

Depth of metabolic response at interim PET and survival outcomes among patients with primary refractory and early relapsing diffuse large B-cell lymphoma (DLBCL).

7543 Background: Total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) may improve upon standard 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT)-based assessment of advanced DLBCL during treatment. We report the association of TMTV and SUVmax changes at interim PET-CT (PET2) on survival outcomes in patients with primary refractory DLBCL (prDLBCL) and early relapsing DLBCL (erDLBCL). Methods: Adult patients with prDLBCL (less than a complete response (CR) or progression by the end of treatment (EOT)) or erDLBCL (CR at EOT with relapse within 12 months) between 2005 and 2019 at Mayo Clinic Rochester were included. The % change (Δ) from baseline to PET2 (after 2 cycles of 1L therapy) of TMTV and SUVmax were measured. A PET segmentation threshold of 1.5 liver mean SUV + two standard deviations with a minimum volume constraint of 0.5 mL was utilized (MIM Software, Inc., Cleveland OH, USA) with manual input as needed. Functional splines analysis determined SUVmax and TMTV threshold for analysis. Results: 131 patients had complete PET-CT data (N=79 prDLBCL, N=52 erDLBCL). Baseline median TMTV and SUVmax were 767.4 cm3 (range 0.9-6840.4) and 20.5 (2.0-52.6), respectively. At a median follow up of 77.6 months, 81 patients had died. 2-year OS rate was 53% (95% CI: 42-67) for patients with a PET2 ΔSUVmax decline ≥65% compared to 15% (95% CI: 7-29) for patients with a PET2 ΔSUVmax decline <65%(p<0.001). PrDLBCL had a 2-year OS rate of 48% (95% CI: 31-74) for a ΔSUVmax ≥65% compared to 7% (95% CI: 2-21) for a ΔSUVmax <65%(p<0.001), which captured 58% of prDLBCL patients (N=46). Two-year OS rate was 43% (95% CI: 34-54) for patients with a ΔTMTV ≥75% compared to 5% (95% CI: 1-35) for patients with ΔTMTV <75% (p<0.001). All patients with a ΔTMTV <75% had prDLBCL. PrDLBCL had a 2-year OS rate of 28% (95% CI: 18-44) for a ΔTMTV ≥75%. The outcomes for ΔSUVmax <65% and ΔTMTV <75% at PET2 remained significant in a cox regression model adjusted for IPI and bulky disease (>10cm)(Table). Conclusions: A ΔTMTV decline <75% or a ΔSUVmax decline <65% at PET2 identified an ultra-high-risk subgroup of DLBCL with particularly poor outcomes, that captured a high percentage of prDLBCL patients, and was significant after adjusting for IPI and bulky baseline disease. These patients may benefit from clinical trials evaluating alternative PET-adapted treatment strategies, but further evaluation among all patients with DLBCL is needed. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Aim to find the efficacy treatment strategy for refractory/relapsed(r/r) patients with pediatric mature B-cell lymphoma (MBL) by summarizing the treatment outcome of 46 patients from Chinese Children's Lymphoma Multi-center Cooperation Group (CNCL). Methods: The MBL children treated from 1 May 2017 to 31 December 2022 were enrolled. The modified LMB89/96 protocol was adopted for the initial treatment. Clinical characteristics and risk factors were analyzed with r/r patients. Two treatment groups after r/r: salvage chemotherapy (ICE protocol), chimeric antigen receptor T-cell (CAR-T) group. OS and EFS were both analyzed. Results: Total of 861 newly diagnosed children with MBL ≤ 18 years old were enrolled in this study, of which 46(5.3%) cases were relapsed or refractory(R/R). Baseline characteristics of 46 patients: the median age was9 (1∼16) years old, 38/46 males, 8/46 females. Stage I-II was 0/46, Stage III–IV was 19/46 and 27/46 according to St. Jude's stage, of which 11/46 (23%) had a leukemia stage, and 14 (30.4%) had CNS invasion. Risk grouping: group B: 3 cases (%), group C1: 28/46 cases group C2: 14/46 cases. Pathological types: 34/46 cases of Burkitt's lymphoma, 5/46 cases of diffuse large B-cell lymphoma, 5/46 cases of high grade B-cell lymphoma, and 2/46 cases of other types. There were 17/46 with bulky disease, 26/46 cases with LDH > 1000 U/L. Univariate analysis showed that LDH > 1000, Bulky disease, leukemia stage and CNS invasion before initial chemotherapy was significantly related to poor survival. Treatment result: the median follow-up time was 12.49 months (95% CI: 12.86, 23.99), (0.3∼59.6) months, 46 patients with r/r. Salvage treatment: 24 patients received second-line chemotherapy: 6 patients got a CR2, 6 patients quit to treatment due to SD/PD, 4 patients got a treatment related death, 8 patients died of PD/SD. The median survival time was 4.3 months (0.3∼45.9), 2-year OS was 33.33 ± 15.90%. Discussion and conclusion: The outcomes with r/r patients treated with salvage chemotherapy is poor, CART therapy can significantly improve the outcomes of r/r patients, and is expected to be an effective treatment strategy for children with r/r MBL. Keywords: chemotherapy, immunotherapy, non-Hodgkin (pediatric, adolescent, and young adult) No conflicts of interests pertinent to the abstract.

Matching‐adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL)

Introduction: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n = 66, NCT03846427; BGB-3111-AU-003, n = 20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n = 60 [Noy et al. Blood 2017; Noy et al. Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU versus IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model (PSM) was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. Number of prior lines of therapy, MZL subtype, response to prior therapy, and age were identified as key prognostic factors and included in the base case PSM. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [>5 cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs). Results: After applying weights estimated from the base case PSM, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU significantly reduced the risk of progression (HR 0.38; 95% CI: 0.21, 0.69; p = 0.001) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13, 4.96; p = 0.022). OS was comparable for ZANU and IBRU, which is consistent with expected survival for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the 2 treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU versus IBRU in R/R MZL. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: Indolent non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. C. Thieblemont Honoraria: AbbVie, Bayer, Celgene, Gilead Sciences, Incyte, Janssen, Novartis, and Roche Research funding: Roche Educational grants: AbbVie, Janssen-Cilag, Kite/Gilead, Novartis, and Roche S. Keeping Employment or leadership position: PRECISIONheor Research funding: BeiGene I. Zhang Employment or leadership position: PRECISIONheor Research funding: BeiGene K. Yang Employment or leadership position: BeiGene Stock ownership: BeiGene Research funding: BeiGene Educational grants: BeiGene B. Tang Employment or leadership position: BeiGene Stock ownership: BeiGene Other remuneration: BeiGene L. Mohseninejad Employment or leadership position: BeiGene Consultant or advisory role: BeiGene Research funding: BeiGene

Matching-adjusted indirect comparison (MAIC) of zanubrutinib (ZANU) versus ibrutinib (IBRU) in relapsed/refractory marginal zone lymphoma (R/R MZL).

e19527 Background: ZANU is a Bruton tyrosine kinase inhibitor (BTKi) that has been evaluated for the treatment of R/R MZL in two phase 2, single-arm trials (MAGNOLIA, n=66, NCT03846427; BGB-3111-AU-003, n=20, NCT02343120). At 28 and 35 months of study follow-up in MAGNOLIA and BGB-3111-AU-003, respectively, median progression-free survival (PFS) and overall survival (OS) were not reached. IBRU, a first-generation BTKi, has also been evaluated for R/R MZL in a phase 2, single-arm trial (PCYC-1121, n=60 [Noy et al., Blood 2017; Noy et al., Blood Adv 2020]). Here, we conducted an unanchored MAIC to estimate the comparative efficacy of ZANU vs IBRU in R/R MZL. Methods: The MAIC utilized study-level data from PCYC-1121 and pooled individual patient-level data from MAGNOLIA and BGB-3111-AU-003. A logistic propensity score model was used to estimate weights for patients in the ZANU trials so that weighted mean baseline characteristics matched those in PCYC-1121. The following characteristics were identified as key prognostic factors and included in the base case propensity score model: number of prior lines of therapy, MZL subtype, response to prior therapy, and age. A sensitivity analysis was conducted including additional characteristics (B symptoms, time since last therapy, prior anti-CD20 therapy, bulky disease [>5cm], and lactate dehydrogenase above normal). Comparisons were conducted for OS, PFS, and objective response rate (ORR) by independent review committee using weighted statistical models with relative treatment effects presented as hazard ratios (HRs), odds ratios (ORs), and 95% CIs. Results: After applying weights estimated from the base case propensity score model, the effective sample size (ESS) for ZANU was 68 (Table). Compared with IBRU, ZANU reduced the risk of progression (HR 0.38; 95% CI 0.21–0.69) and was associated with a higher ORR (OR 2.37; 95% CI: 1.13–4.96). OS was comparable for ZANU and IBRU, which is consistent with expectations for indolent lymphomas. The sensitivity analysis accounting for additional prognostic factors suggested the two treatments were comparable across all outcomes, owing in part to the low ESS (24) for ZANU associated with the expanded model. A leave-one-out analysis showed improved PFS (HR 0.33–0.45) for ZANU when excluding B symptoms, time since last therapy, or bulky disease from the expanded model. Conclusions: This MAIC demonstrated ORR and PFS benefits for ZANU vs IBRU in R/R MZL. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Ibr is a standard therapy for CLL with demonstrated efficacy in first-line and R/R settings. Within R/R CLL, single-agent Ibr was evaluated in 3 randomized phase 3 trials: RESONATE (vs. ofatumumab), ALPINE (vs. zanubrutinib), and ELEVATE-RR (vs acalabrutinib in pts with del(11q) or del(17p)). This analysis evaluated outcomes of Bruton’s tyrosine kinase inhibitor (BTKi) treatment in pts with R/R CLL by comparing the efficacy of Ibr in RESONATE to ALPINE and ELEVATE-RR using a matching-adjusted indirect comparison analysis. Methods: Individual patient data (IPD) of Ibr-treated pts from RESONATE (NCT01578707) were separately match-adjusted to Ibr-treated arms of 1) ALPINE (NCT03734016) and 2) ELEVATE-RR (NCT02477696) for key baseline characteristics: age ≥75 y, bulky disease, ≥3 or ≥4 prior treatments, b2 microglobulin >3.5 mg/L, and del(11q) or del(17p). For comparison with ELEVATE-RR, only pts with del(17p) or del(11q) from RESONATE were included. After matching, adjusted ORR (CR + CRi + nPR + PR) and PFS from RESONATE were compared with published outcomes from ALPINE and ELEVATE-RR; for PFS, IPD for ALPINE and ELEVATE-RR were extracted from published Kaplan-Meier curves. Hazard ratios (HRs) were calculated using a weighted Cox model. Results: The analysis comprised 785 Ibr-treated pts across RESONATE (n = 195), ALPINE (n = 325), and ELEVATE-RR (n = 265). After omission of pts with missing values and the adjustment procedure, the effective RESONATE sample size was 95 pts (vs ALPINE) and 69 pts (vs ELEVATE-RR). Median follow-up was 36.0 versus 29.6 mo (RESONATE adjusted vs. ALPINE published) and 36.1 versus 40.9 mo (RESONATE adjusted vs. ELEVATE-RR published). 2-y PFS (95% CI) for Ibr-treated pts in RESONATE adjusted sample and ALPINE was 81% (74–90) and 66% (60–71), respectively; median PFS was 40.7 and 34.2 mo, with an HR (95% CI) of 0.57 (0.39–0.84) favoring RESONATE, P = 0.0048 (Figure). ORR (95% CI) was 90% (86–94) and 74% (69–79), respectively (P < 0.0001). Compared with the ELEVATE-RR Ibr arm, which included more pts with high-risk genetic features than ALPINE, the RESONATE adjusted sample had greater 2-y PFS (79% [69–89] vs. 69% [64–75], not statistically significant). Median PFS was 41.2 vs. 44.1 mo (HR [95% CI] 0.85 [0.55–1.31], P = 0.46), respectively; ORR was 89% (83–95) and 80% (75–85) (P = 0.0381). Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by Pharmacyclics LLC, an AbbVie Company. Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Honoraria: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Research funding: AbbVie, AstraZeneca, and Janssen T. Munir Consultant or advisory role: Morphosys and Sunesis Honoraria: AbbVie, AstraZeneca, Gilead, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AbbVie, Gilead, or Janssen J. Burger Consultant or advisory role: BeiGene, Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Honoraria: Gilead, Janssen, Novartis, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Other remuneration: travel/accommodation expenses from Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics J. F. Seymour Research funding: AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd. Other remuneration: speakers’ bureau with AbbVie, Celgene, and F. Hoffmann-La Roche Ltd.; patents, royalties, or other intellectual property with AbbVie; and expert testimony for F. Hoffmann-La Roche Ltd. K. Rogers Consultant or advisory role: Acerta Pharma, AstraZeneca, Beigene, Genentech, Innate Pharma, and Pharmacyclics, LLC, an AbbVie company Research funding: AbbVie, Genentech, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AstraZeneca H. Huang Employment or leadership position: Everest Clinical Research and AbbVie Consultant or advisory role: Everest Clinical Research and AbbVie Research funding: Everest Clinical Research and AbbVie C. Moreno Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, and Janssen Research funding: AbbVie and Janssen Other remuneration: speakers’ bureau for Janssen L. Neumayr Employment or leadership position: AbbVie Consultant or advisory role: ApoPharma Stock ownership: AbbVie Honoraria: Novartis Research funding: Pfizer and Sancilio Other remuneration: travel accommodations from Forma Therapeutics C. Abbazio Employment or leadership position: AbbVie Stock ownership: AbbVie and Bristol Myers Squibb J. Sharman Consultant or advisory role: AbbVie, AstraZeneca, and BeiGene Honoraria: AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Genentech, Lilly, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics

Unfavorable early-stage Hodgkin lymphoma: assessment of patient characteristics in a real-world setting.

Aim: Unfavorable prognostic factors among classical Hodgkin lymphoma (cHL) patients in the real-world setting have yet to be fully characterized. Methods: In this retrospective study using the ConcertAI Oncology Dataset, patient characteristics, unfavorable prognostic factorsand treatment patterns were evaluated among patients diagnosed with cHL. Results: Among 324 adult cHL patients diagnosed 2016-2021, 16.1% were classified as early favorable, 32.7% early unfavorableand 51.2% advanced disease. Early unfavorable patients were younger and had a larger nodal mass. The prognostic factor B symptoms was most frequently documented in early unfavorable patients (59.4%), followed by bulky disease (46.2%), >3 involved lymph node regions (31.1%), and erythrocyte sedimentation rate ≥50 (25.5%). Conclusion: In this analysis of real-world data, we found that nearly a third of newly diagnosed cHL patients had early unfavorable disease. Our analysis also showed differences in the proportion of patients for each unfavorable factor among patients with early-stage unfavorable cHL.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Next-generation Bruton tyrosine kinase inhibitors (BTKis) acalabrutinib (acala) and zanubrutinib (zanu) were compared with the standard of care BTKi ibrutinib in relapsed/refractory chronic lymphocytic leukemia (RR CLL) in the head-to-head randomized clinical trials (RCTs) ELEVATE-RR and ALPINE, respectively. However, differences in these RCT’s populations prevent comparison of acala and zanu. ASCEND, another RCT assessing acala, had a similar population to ALPINE but a different comparator. Thus, we used unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala vs zanu using individual patient data (IPD) from ASCEND and published aggregate data from ALPINE. Methods: Acala IPD from ASCEND were weighted to match zanu baseline data from ALPINE. This reduced differences in variables that were prognostic/effect-modifying of progression-free survival (PFS) in an exploratory multivariate cox regression analysis of ASCEND. These included sex, ECOG PS, bulky disease, prior chemoimmunotherapy, del(11q), del(17p), TP53 without del(17p), IGHV status, region, age, prior lines of therapy and Rai stage. An efficacy analysis assessed investigator-assessed PFS (INV PFS) in randomized patients with baseline data (acala, n = 149; zanu, n = 327). Pseudo IPD for INV PFS for zanu were obtained from Kaplan-Meier curves. A safety analysis assessed odds ratios (ORs) of adverse events (AEs) in treated patients with baseline data (acala, n = 148; zanu, n = 324). To compare the incidence of AEs, an artificial data cut-off (Feb 21, 2020) was imposed for acala to match the zanu median treatment exposure (both 28.4 months). Results: After matching, the effective sample size of acala was 99 (66.6%; 65% male; median age 66 years). 12- and 24-month INV PFS are shown in Table 1. The MAIC hazard ratio (HR) for INV PFS is similar for acala vs zanu: HR 0.90, 95% confidence interval (CI) 0.60–1.36. The risk of having grade ≥3 AE (OR 0.66, 95% CI 0.41–1.05), atrial fibrillation (AF; OR 1.32, 95% CI 0.56–3.08), grade ≥3 AF/atrial flutter (OR 0.60, 95% CI 0.12–2.89), grade ≥3 hemorrhage (OR 0.61, 95% CI 0.19–2.03) or an AE leading to discontinuation (OR 1.14, 95% CI 0.61–2.13) was similar with acala vs zanu. The risk of having a serious AE (OR 0.61, 95% CI 0.39–0.97), hypertension (any grade: OR 0.18, 95% CI 0.09–0.37; grade ≥3: OR 0.22, 95% CI 0.09–0.54), any grade hemorrhage (OR 0.54, 95% CI 0.34–0.87) or an AE leading to dose reduction (OR 0.30, 95% CI 0.14–0.67) favored acala vs zanu. Conclusions: Acala and zanu have a similar efficacy in RR CLL, while acala has a lower risk of grade ≥3 hemorrhage, any grade and grade ≥3 hypertension and dose reduction due to AEs vs zanu. Limitations of MAICs mean results should be viewed as hypothesis-generating. Encore Abstract—previously submitted to ASCO 2023, EHA 2023 The research was funded by: AstraZeneca Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract P. Ghia Consultant or advisory role AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Research funding: AbbVie, AstraZeneca, Janssen, Roche A. Skarbnik Consultant or advisory role AstraZeneca, Abbvie, Genentech, Genmab, Novartis, Kite Pharma, Epizyme, Janssen, Morphosys, Pharmacyclcics, SeaGen, TG Therapeutics, Lilly (LOXO) Other remuneration: Speakers' Bureau: AstraZeneca, Abbvie, Beigene, Celgene, Genentech, Janssen, Kite Pharma, Pharmacyclics, SeaGen, TG Therapeutics M. Miranda Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca A. S. Yong Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Roos Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca Other remuneration: Patient/Royalties/Other Intellectual Property: CalciMedica R. Hettle Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Palazuelos-Munoz Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca V. Shetty Employment or leadership position: AstraZeneca Stock ownership: Verona Pharma A. Kittai Consultant or advisory role Abbvie, AstraZeneca, Beigene, BMS, Eli Lilly, Janssen, KITE Research funding: AstraZeneca Other remuneration: Speaker's bureau: Beigene

BONE MARROW VOLUME IRRADIATED AND RISK OF CYTOPENIAS IN AGGRESSIVE B‐CELL LYMPHOMA PATIENTS BRIDGED WITH RADIATION THERAPY FOR CART CELL THERAPY

Introduction: Patients (pts) with aggressive B cell lymphomas undergoing anti-CD19-directed chimeric antigen receptor T cell therapy (CART) can benefit from bridging radiation therapy (bRT) as immune priming. Previously, by measuring the bone marrow (BM) volume irradiated in multiple myeloma pts, we established that RT does not adversely affect stem cell collection.1 Here, we examined the impact of irradiated BM distribution on the risk of acute cytopenias after bRT prior to CART. Methods: We retrospectively reviewed adults with DLBCL between 2017 and 2022 who received bRT prior to CART, which included axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel. Clinical characteristics, labs, and response were extracted. RT plans were reviewed; % BM irradiated was calculated as described previously with published estimates of skeletal BM distribution.2 Progression free survival (PFS), disease specific survival (DSS) and overall survival (OS) were modeled using the Kaplan-Meier method. Binary logistic regression and Mann-Whitney U correlated RT distribution with cytopenias (anemia, thrombocytopenia, and neutropenia per CTCAE v4.03). Results: Fifty-one pts received bRT, of which 13 (25.5%) had bulky disease (≥10 cm). Majority received bRT alone; 16 (31.4%) were additionally bridged with systemic therapy. The median bRT was 30 Gy (range: 4–48 Gy) and 26 pts (51%) pts received ≥30 Gy. Thirty-one pts (61%) received bRT comprehensively to all disease sites. The incidence of ≥Grade 3 cytopenias in timepoints following bRT are shown below. The median cumulative % of BM irradiated was 5.05% (range: 0%–50%). Nine pts (18%) received bRT encompassing ≥15% of the BM, for whom there was no increased incidence of ≥Grade 3 cytopenias overall (as well as specifically anemia, thrombocytopenia, and neutropenia) at any timepoint (all p > 0.2). Receipt of RT comprehensively to all disease sites, or bridging with both RT + systemic therapy, or delivery of ≥30 Gy bRT did not correlate with the incidence of ≥Grade 3 cytopenias at any timepoint. Regarding outcomes, 26 pts (51%) had CR at 30 days post-CART. Sixteen had PR (31.4%), and 9 pts (17.6%) had PD or SD. The OS/PFS were 84% (71–92)/78% (64–87) at 1 year, and 59% (44–71)/57% (42–70) at 2 years. Twenty-seven pts (52.9%) remain alive at last follow-up, 19 (70.4%) of whom have no evidence of disease. Conclusions: bRT is not associated with increased incidence of cytopenias, even for doses ≥30 Gy, when encompassing ≥15% of the BM, or when pts are treated comprehensively to all disease sites. While bRT can be delivered safely, we still urge careful field design to ensure minimum BM is treated to incorporate into pre-CART regimens. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, radiation therapy Conflicts of interests pertinent to the abstract R. E. Steiner Research funding from Seagen, BMS, GSK and Rafael pharmaceuticals.

Safety and efficacy of ABR in pts with TN or R/R MCL: Ph Ib trial.

7546 Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Bendamustine (B) + rituximab (R) is used for treatment-naive (TN) and R/R MCL. We present updated data on safety and efficacy of ABR in patients (pts) with TN or R/R MCL. Methods: Eligible adults received ABR in this phase 1b study (NCT02717624) as follows: ABR for 6 28-d cycles, maintenance A+R for up to 2 y (TN cohort responders), then oral A continuously until progressive disease (PD) or treatment discontinuation due to toxicity (both cohorts). The primary endpoint was safety. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), all per Lugano. Results: Overall, 38 pts were enrolled (TN, n=18; R/R, n=20) with median age 66 y (range, 47–86). Baseline characteristics were (TN and R/R cohorts, respectively): stage IV disease in 88.9% and 95.0%, high-risk simplified MIPI score in 11.1% and 15.0%, bulky disease &gt;5 cm in 16.7% and 30.0% or ≥10 cm in 5.6% and 10.0%, and blastoid morphology in 5.6% and 15.0%; R/R pts had a median of 2 prior lines of therapy. As of the data cutoff date (6/15/22), 6 (33.3%) TN pts and 4 (20.0%) R/R pts were receiving A monotherapy (Table). Most common any-grade AEs were nausea (n=14, 77.8%; TN) and neutropenia (n=11, 55.0%; R/R). Grade 3–4 AEs occurred in 13 (72.2%) TN pts and 17 (85.0%) R/R pts, most commonly neutropenia in both cohorts (n=7, 38.9% [TN]; n=10, 50.0% [R/R]). Serious AEs occurred in 11 (61.1%) TN pts and 13 (65.0%) R/R pts. There were no reports of ventricular tachyarrhythmia. Grade 3 atrial fibrillation occurred in 1 pt outside the safety reporting period and was not related to study treatment. Grade ≥3 major hemorrhage was reported in 2 (11.1%) TN pts and 3 (15.0%) R/R pts. Grade ≥3 hypertension was reported in 3 (16.7%) TN pts and 2 (10.0%) R/R pts. Five TN pts died (AE: pneumonitis, n=1; unknown, n=4) and 6 R/R pts died (AE: COVID and cerebrospinal meningitis, n=2; PD, n=2; unknown, n=2). ORR was 94.4% (n=17) in the TN cohort and 85.0% (n=17) in the R/R cohort, with CR rates of 77.8% (n=14) and 70.0% (n=14), respectively. Median DOR was not estimable (NE) in the TN cohort and 43.5 mo in the R/R cohort. Median PFS and overall survival were NE in the TN cohort (median follow-up 47.6 mo) and 28.6 mo and NE, respectively, in the R/R cohort (median follow-up 20.4 mo). Conclusions: Triple-combination ABR was tolerable and effective in pts with TN or R/R MCL. Clinical trial information: NCT02717624 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Patients (pts) with cHL with slow early response (SER) to initial chemotherapy (chemo) have a high risk of relapse. Current treatments such as chemo dose intensification and radiotherapy (RT) can increase the risk of secondary malignancies and cause long-term toxicity. KEYNOTE-667 (NCT03407144) is an open-label, phase 2 study being conducted to evaluate pembrolizumab (pembro) plus chemo in pts with cHL and SER to front-line chemo. We present results of an interim analysis of pts with high-risk cHL and SER (group 2). Methods: Pts eligible for group 2 were aged 3–17 (children) or 18–25 y (young adults) with newly diagnosed high-risk (stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB) cHL. Pts in group 2 received induction therapy with 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Response was then assessed by PET/MRI/CT. Pts with rapid early response to OEPA received nonstudy therapy and pts with SER to OEPA (Deauville score, 4/5) received consolidation with 4 cycles of cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV Q3W (3–17 y) or 200 mg IV Q3W (18–25 y). After consolidation, pts with PET positivity (Deauville score, 4/5 at late response assessment [LRA]) received involved-site RT (28.8 Gy) to late PET-positive residua. RT was omitted in pts with PET negativity. All pts with SER continued to receive pembro Q3W for 17 doses. The primary end point was ORR in pts with SER by blinded independent central review (BICR) per Cheson 2007 International Working Group criteria. Secondary end points included PET negativity at LRA and safety. Results: 49 pts with high-risk cHL with SER to OEPA were included in group 2. The median age was 15 y (range, 6–22), 24 pts (49%) had bulky disease, and 31 (63%) had Ann Arbor stage IV disease. At data cutoff (2 September 2022), the median follow-up was 15.3 mo (range, 3.2–30.5); 22 pts (45%) had completed treatment and 24 (49%) were ongoing on consolidation/maintenance. Median time on pembrolizumab was 10.4 mo (range, 0.5–11.8). 42 pts (86%) had an LRA, of whom 27 (64%) were PET negative by BICR (30 pts [71%] were PET negative by investigator review). Adverse events (AEs) occurred in 42 pts (86%), with grade 3/4 AEs in 13 pts (27%). Serious AEs were reported in 7 pts (14%). No pts died because of an AE. Treatment-related AEs occurred in 30 pts (61%), with grade 3/4 treatment-related AEs in 6 pts (12%). 4 pts (8%) had immune-mediated AEs: 2 grade 1 hypothyroidism and 2 grade 2 hypothyroidism. Conclusions: The results showed that pembro plus COPDAC-28 consolidation had manageable safety and promising efficacy in children and young adults with high-risk cHL and SER to front-line chemo. 64% of pts with a LRA had a PET-negative response and were spared RT. These findings suggest that adding pembro to COPDAC-28 consolidation may augment responses in this high-risk cHL population. Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA Keywords: Hodgkin lymphoma, immunotherapy Conflicts of interests pertinent to the abstract L. Vinti Consultant or advisory role: Amgen, Clinigen Research funding: Merck, Sharp & Dohme Educational grants: Takeda, Neon Other remuneration: Amgen, Takeda F. Fagioli Employment or leadership position: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Consultant Or Advisory Role: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Honoraria: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Educational Grants: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi Other Remuneration: Takeda, Novartis, Jazz Pharmaceuticals, Sanofi D. Plaza Lopez de Sabando Research funding: MERCK J. Landman-Parker Research funding: BMS, MSD J. Shen Employment or leadership position: Merck P. Pillai Employment or leadership position: Merck Stock ownership: Merck P. Marinello Employment or leadership position: Merck Stock ownership: Merck C. Mauz-Koerholz Consultant or advisory role: MSD Research funding: MSD

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) may improve upon standard 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT)-based assessment during treatment. We report the association of TMTV and SUVmax response by interim PET (PET2) on survival outcomes in patients with primary refractory DLBCL (prDLBCL) and early relapsing DLBCL (erDLBCL). Methods: Adult patients with prDLBCL (less than a complete response at EOT or progression during treatment) or erDLBCL (CR at EOT with a relapse within 12 months) between 2005 and 2019 and seen at Mayo Clinic Rochester were included. The % change (Δ) from baseline to PET2 (after 2 cycles of 1L immunochemotherapy) of TMTV and maximum SUV uptake (SUVmax) were measured. A PET segmentation threshold of 1.5 liver mean SUV + two standard deviations with a minimum volume constraint of 0.5 mL was utilized (MIM Software, Inc., Cleveland OH, USA) with manual input as needed. Functional spline analysis showed a ΔSUVmax decline ≥65% and a ΔTMTV decline ≥75% at PET2 were associated with improved OS and determined threshold for further analysis. Results: 131 patients with prDLBCL or erDLBCL, 131 had complete PET-CT data available (N = 79 prDLBCL, N = 52 erDLBCL). Median baseline TMTV was 939.5 cm3 (range 13.1–6840.4) in prDLBCL and 670.4 cm3 (0.9–5464.5) in erDLBCL (p = 0.01). Baseline median SUVmax was 22.2 (3.1–52.6) in prDLBCL and 19.1 (2.0–49.7) in erDLBCL (p = 0.02). The 2-year estimated OS rate was 21% (95% CI: 13–34) for prDLBCL and 58% (95% CI: 45–75) for erDLBCL. At a median follow up of 77.6 months, 81 patients had died. Among all patients, Two-year OS rate was 53% (95% CI: 42–67) for patients with a PET2 ΔSUVmax decline ≥65% compared to 15% (95% CI: 7–29) for patients with a PET2 ΔSUVmax decline <65% (p < 0.001) (Figure A). PrDLBCL had a 2-year OS rate of 48% (95% CI: 31–74) for a ΔSUVmax ≥65% compared to 7% (95% CI: 2–21) for patients with a ΔSUVmax <65% (p < 0.001)(Figure B), which captured 58% of prDLBCL patients (N = 46). Among all patients, 2-year OS rate was 43% (95% CI: 34–54) for patients with a ΔTMTV ≥75% compared to 5% (95% CI: 1–35) for patients with a ΔTMTV <75% (p < 0.001) (Figure C). All patients with a ΔTMTV <75% had prDLBCL. PrDLBCL had a 2-year OS rate of 28% (95% CI: 18–44) for a ΔTMTV ≥ 75% (Figure D). The outcomes for ΔSUVmax <65% and ΔTMTV <75% at PET2 remained significant in a cox regression model when adjusted for IPI and bulky disease (>10 cm). Encore Abstract - previously submitted to ASCO 2023 Keywords: Aggressive B-cell non-Hodgkin lymphoma, PET-CT Conflicts of interests pertinent to the abstract. M. J. Maurer Employment or leadership position: Exact Sciences - immediate family member Consultant or advisory role: Genmab; Adaptive Biotechnologies Stock ownership: Exact Sciences Research funding: Morphosys; Bristol-Myers-Squibb; Roche/Genentech; Genmab J. Paludo Consultant or advisory role: Abbvie Research funding: Karyopharm; Biofourmis J. R. Cerhan Consultant or advisory role: Bristol-Myers Squibb/Celgene; Protagonist Therapeutics Research funding: NanoString Technologies; Celgene; Genentech; Genmab Other remuneration: Uncompensated relationship: Regeneron T. E. Witzig Consultant or advisory role: Tornado Therapeutics; Salarius Pharmaceuticals Honoraria: Curio Science Research funding: Celgene; Acerta Pharma; Kura Oncology; Acrotech Biopharma; Karyopharm Therapeutics T. M. Habermann Consultant or advisory role: Celgene; Kite/Gilead; MorphoSys; BeiGene; Loxo Oncology Research funding: Genentech; Sorrento; Celgene Other remuneration: Data Monitoring Committee: Tess Therapeutics; SeaGen, Eli Lilly and Co Y. Wang Employment or leadership position: Merck - immediate family member Consultant or advisory role: Loxo; Incyte; Innocare; TG Therapeutics; Kite, A gilead company; Lilly; Janssen; BeiGene Stock ownership: Merck - immediate family member Honoraria: Kite, A Gilead Company Research funding: InnoCare; Incyte; Novartis; Genentech; Loxo; MorphoSys; Genmab G. S. Nowakowski Consultant or advisory role: Celgene; MorphoSys; Genentech; Selvita; Debiopharm Group; Kite/Gilead; TG Therapeutics; Kymera; Karyopharm Therapeutics; Ryvu Therapeutics; Bantham Research funding: Celgene; NanoString Technologies; MorphoSys

Results of MOLTO, a multicenter, open label, phase II clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in Richter syndrome.

7502 Background: Chemoimmunotherapy is the standard first line of patients (pts) with diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). Response rate and duration are unsatisfactory. The biology of RS (high rate of DNA damage response pathway defects, high tumor mutation burden coupled with the expression of the PD1/PDL1 axis) prompts investigation of non-chemo combinations leveraging agents that circumvent TP53 abnormalities and trigger anti tumor immune response. MOLTO is a multicenter international ph 2 study (NCT04082897) evaluating activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in untreated DLBCL-RS. Methods: Treatment consisted of 35 cycles with obinutuzumab (1000 mg C1-8), atezolizumab (1200 mg C1-18) and venetoclax (400 mg/d C1-35), q21. Primary endpoint was ORR ≥67% at C6. RS diagnosis was centrally revised. RS mutation profile was tested on pre-treatment cell free DNA. Minimal residual disease (MRD) was tested by 12 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: 28 planned pts were enrolled from Oct 2019 to Oct 2022 (Table). Three were not evaluable for primary endpoint due to G5 infection (n=1) or early withdrawn (n=2). As per intention-to-treat ORR was 67.9% (19/28) thus meeting primary endpoint. CR rate was 28.6%. No clinical characteristics influenced C6-ORR. After a median follow-up of 11.6 mo, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS) among them, 6 for ≥24 mo. Of the remaining 8 pts, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response, PFS and OS were 11.7, 16.2 and 31.6 mo, respectively. Out of the 13 patients who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 mo. Bulky disease and ECOG PS &gt;1 affected PFS. Rate of unmeasurable MRD, impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. Overall 43 G3-4 adverse events (AE) were recorded in 17 pts (60.7%), mostly hematological (51.2%). Any grade immune-related AEs were reported in 6 pts (G3-4 in 2), none led to discontinuation. No tumor lysis syndrome observed. Infections ≥G3 occurred in 6 pts, including 2 G5. One pt developed MDS. Conclusions: Atezolizumab, obinutuzumab and venetoclax combination is active in pts with untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 yrs in one third of responders. Clinical trial information: NCT04082897 . [Table: see text]

A matching-adjusted indirect comparison (MAIC) of the efficacy and safety of acalabrutinib (acala) versus zanubrutinib (zanu) in relapsed or refractory chronic lymphocytic leukemia (RR CLL).

7540 Background: The BTKi ibrutinib is the standard of care in RR CLL and was compared in head-to-head randomized clinical trials (RCTs) with second-generation BTKis: acala in ELEVATE-RR and zanu in ALPINE. However, major differences in these RCT's populations prevents comparison of acala and zanu. Acala was also assessed in the ASCEND RCT, which had a similar population to ALPINE but a different comparator. Thus, we used unanchored MAIC to compare the efficacy and safety of acala vs zanu using individual patient data (IPD) from ASCEND and published aggregate data from ALPINE. Methods: In the unanchored MAIC, acala IPD from ASCEND were weighted to match zanu baseline data from ALPINE. This reduced between-study differences in variables that were prognostic/effect-modifying of progression-free survival (PFS) in an exploratory multivariate cox regression analysis of ASCEND. These included sex, ECOG PS, bulky disease, prior chemoimmunotherapy, del(11q), del(17p), TP53 without del(17p), IGHV status, region, age, prior lines of therapy and Rai stage. An efficacy analysis assessed investigator-assessed PFS (INV PFS) in randomized patients with baseline data (acala, n = 149; zanu, n = 327). Pseudo IPD for INV PFS for zanu were obtained from Kaplan-Meier curves. A safety analysis assessed odds ratios (ORs) of AEs in treated patients with baseline data (acala, n = 148; zanu, n = 324). To allow comparison of the incidence of AEs, an artificial data cut-off (Feb 21, 2020) was imposed for acala to match the zanu median treatment exposure (both 28.4 months). Results: After matching, the effective sample size of acala was 99 (66.6%; 65% male; median age 66 years). 12- and 24-month INV PFS are shown below. The MAIC hazard ratio (HR) for INV PFS is similar for acala vs zanu (HR 0.90, 95% CI 0.60–1.36). The risk of having grade ≥ 3 AE (OR 0.66, 95% CI 0.41–1.05), atrial fibrillation (AF; OR 1.32, 95% CI 0.56–3.08), grade ≥ 3 AF/atrial flutter (OR 0.60, 95% CI 0.12–2.89), grade ≥ 3 hemorrhage (OR 0.61, 95% CI 0.19–2.03) or an AE leading to discontinuation (OR 1.14, 95% CI 0.61–2.13) was similar with acala vs zanu. The risk of having a serious AE (OR 0.61, 95% CI 0.39–0.97), hypertension (any grade: OR 0.18, 95% CI 0.09–0.37; grade ≥ 3: OR 0.22, 95% CI 0.09–0.54), any grade hemorrhage (OR 0.54, 95% CI 0.34–0.87) or an AE leading to dose reduction (OR 0.30, 95% CI 0.14–0.67) was lower with acala vs zanu. Conclusions: Acala and zanu have a similar efficacy in patients with RR CLL, while acala has a lower risk of grade ≥ 3 hemorrhage, any grade and grade ≥ 3 hypertension and dose reduction due to AEs vs zanu. Limitations of MAIC analyses mean the results should be viewed as hypothesis-generating. [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Chemoimmunotherapy is the standard first line treatment of diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). However, response rate and duration are unsatisfactory. The biology of RS (high rate of DNA damage response pathway defects, high tumor mutation burden coupled with the expression of the PD1/PDL1 axis) prompts investigation of non-chemo combinations leveraging agents that circumvent TP53 abnormalities and trigger anti-tumor immune response. MOLTO is a multicenter international phase 2 study (NCT04082897) evaluating activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in untreated DLBCL-RS. Methods: Treatment consisted of 35 q21 cycles with obinutuzumab (1000 mg C1–8), atezolizumab (1200 mg C1–18) and venetoclax (400 mg/d C1–35). Primary endpoint was ORR ≥67% at C6. RS diagnosis was centrally revised. RS mutation profile was tested on pre-treatment cell free DNA. Minimal residual disease (MRD) was tested by 8 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: Overall 28 planned pts were enrolled from October 2019 to October 2022 (Table 1). Three were not evaluable for primary endpoint due to G5 infection (n = 1) or early withdrawn (n = 2). As per intention-to-treatment ORR was 67.9% (19/28) thus meeting primary endpoint. CR rate was 28.6% (8/28). No clinical characteristics influenced ORR at C6. After a median follow-up of 11.6 months, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS), among them 6 for ≥24 months. Of the remaining 8 pts, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response was 11.7 months, median PFS was 16.2 months and median OS 31.6 months. Out of the 13 pts who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 months. Bulky disease and ECOG PS >1 affected PFS. Rate of unmeasurable MRD and impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. A total of 43 G3–4 adverse events (AE) occurred in 17 pts (60.7%), mostly hematological (51.2%). Any grade immune-related AEs was reported in 6 pts (G3–4 in 2), none led to discontinuation. No tumor lysis was observed. Infections ≥G3 occurred in 6 pts, including 2 G5. One pt developed MDS. Conclusions: Atezolizumab, obinutuzumab and venetoclax combination is active in pts with untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 years in one third of responders. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Roche Keywords: combination therapies, immunotherapy, molecular targeted therapies Conflicts of interests pertinent to the abstract A. M. Frustaci Other remuneration: Abbvie, AstraZeneca, Janssen, Beigene; advisory boards, travel grants, speaker invitations

CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Cytosolic DNA of exogenous or endogenous origin triggers activation of cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, that activates innate immune responses through activation of the adaptor protein STING. The latter, in turn, activates TBK1 and IKK kinases that, in turn, activate IRF3 and NF-κB transcription factors, which induce expression of interferons (IFNs), chemokines and cytokines involved in anti-tumor immune responses. The expression patterns of STING in Hodgkin and Reed-Sternberg (HRS) cells and the potential role of cGAS-STING pathway in anti-tumor immune responses in classical Hodgkin lymphoma (cHL) remain unknown to date. Methods: In this prospective study, STING expression was immunohistochemically analysed in a cohort of 52 previously untreated patients with cHL and available tissue for flow cytometry (FC) analysis and histology as well as available peripheral blood samples for FC. An arbitrary 10% cutoff was used for positivity in HRS. The in vitro system included 6 cHL cell lines (MDAV, L1236, L428, L540, HDLM2, KMH2). Gene (mRNA level) and protein expression/activation of cGAS-STING components at baseline and experimental conditions were analysed by quantitative RT-PCR (RT-qPCR) and Western blot, respectively. The cHL cell lines were treated with a STING agonist or were subjected to silencing of STING gene using transient transfection with specific STING siRNA construct. The gene expression of cGAS-STING-associated IFNs and cytokines, including IFN-β, CXCL10, IFN-γ, STING, and a control gene (GAPDH), was analysed with RT-qPCR. Results: STING was positive in HRS cells of cHL in 22 of 52 (42%) patients. STING positivity in HRS significantly correlated with lower numbers of STING+ T-lymphocytes (p < 0.0001) and CD3+ T-lymphocytes (p = 0.04) but higher numbers of CD20+ B-cells assessed by FC in the tissues. In peripheral blood samples assessed by FC at presentation, STING expression by HRS correlated with higher numbers of CD3+ T-cells (p = 0.005) but lower numbers of NK-cells (p = 0.02). STING expression did not correlate with clinical features at presentation, including age, gender, Ann Arbor stage, B-symptoms, tumor burden, bulky disease, anemia, or other hematologic values. STING expression at the mRNA and protein level was substantially higher in L1236, L428 and HDLM2 compared to other cHL cell lines. Treatment with STING agonists stimulated gene expression of IFN-β and/or CXCL10 at a variable level indicating functional cGAS-STING pathway in HRS. Knocking down STING gene resulted in dramatic increase in CXCL10 gene expression in cHL cells. Conclusions: STING is expressed by HRS in a subset of cHL and significantly correlates with the lymphocytic populations in the tumor microenvironment and peripheral blood. The cGAS-STING pathway is functional in HRS suggesting that STING agonists may have therapeutic implications in patients with cHL. Keywords: Diagnostic and Prognostic Biomarkers, Hodgkin lymphoma, Microenvironment No conflicts of interests pertinent to the abstract.

Circulating tumor DNA (ctDNA) status and clinical outcomes in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) in the POLARIX study.

7523 Background: the POLARIX study, pts with previously untreated DLBCL were randomized to Pola-R-CHP or R-CHOP (NCT03274492; Tilly et al. 2022). We previously validated the prognostic value of ctDNA at baseline and after one cycle of therapy in POLARIX (Herrera et al. 2022); here, we evaluate the relationship between ctDNA clearance and PFS and OS. Methods: Pts were included if baseline and longitudinal ctDNA results were available. Plasma ctDNA was measured at baseline, Cycle (C) 5 Day (D) 1, and end of treatment (EOT), with the AVENIO NHL CAPP-Seq assay (Stokowski et al. 2022). ctDNA clearance was determined as previously described (Herrera et al. 2022). PFS and OS according to ctDNA status were reported as landmarked hazard ratios (HR) and 3-yr rates. HRs were adjusted for IPI score (&gt;2), region, bulky disease (&gt;7.5cm), age (&gt;60 years), and cell of origin. Results: At baseline, 654 pts had ctDNA results; 494 (76%) and 519 (79%) pts were evaluable at C5D1 and EOT, respectively. Undetectable ctDNA (ctDNA−) was achieved by 57% (152/265) of Pola-R-CHP-treated pts and 59% (135/229) of R-CHOP-treated pts at C5D1 (p=0.79), and by 66% (172/262) of Pola-R-CHP-treated pts and 67% (172/257) of R-CHOP-treated pts at EOT (p=0.83). Achieving ctDNA− was prognostic for PFS and OS in each treatment arm at C5D1 and EOT (Table). Pts in the Pola-R-CHP arm who had complete response (CR) with PET-CT and ctDNA− at EOT had superior PFS and OS compared with pts with CR and detectable ctDNA (ctDNA+) at EOT (PFS HR 0.30, 95% confidence interval [CI]: 0.14–0.66; OS HR 0.20, 95% CI: 0.07–0.60). This was not observed with R-CHOP (PFS HR 0.74, 95% CI: 0.34–1.63; OS HR 1.11, 95% CI: 0.30–4.16). Among pts with CR and ctDNA− at EOT, pts treated with Pola-R-CHP had superior PFS vs R-CHOP (HR 0.41, 95% CI: 0.21–0.82); this was not observed with OS (HR 0.41, 95% CI: 0.14–1.18). There was no statistically significant difference in PFS between treatment arms in pts with CR and ctDNA+ at EOT (PFS HR 1.20, 95% CI: 0.49–2.83). Conclusions: Achieving ctDNA− at C5D1 and EOT was prognostic for longer survival. Although no difference was observed in the number of pts with ctDNA− at EOT between arms, pts achieving CR and ctDNA− at EOT had superior PFS in the Pola-R-CHP vs the R-CHOP arm, suggesting deeper molecular responses in pts treated with Pola-R-CHP beyond the detection sensitivity of the assay used in this analysis. Clinical trial information: NCT03274492 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Classical Hodgkin Lymphoma (cHL) is one of the most manageable human cancers. The early identification of patients who experience relapse after completion of front-line therapy, regardless of their initial stage currently represent an unsolved need. It is likely that disease progression reflects some innate features that escape the current prognostic criteria but that can be revealed by a deep analysis of the molecular assets of the lesions. We employed a deep gene expression analysis searching for molecular determinants that could anticipate the risk of relapse among patients who achieve a complete metabolic response after 2 ABVD courses (iPET-). Patients and methods: We conducted a retrospective search of our local clinical archives to include patients with the following characteristics: confirmed cHL histology, age >18, iPET negative after 2 ABVD course (Deauville score 1–3). We retrieved the baseline diagnostic biopsy to conduct a gene expression analysis by nCounter Nanostring Technology using the PanCancer Immune-panel. Genomic data were correlated with clinical and laboratory data and with patients’ outcomes. Primary endpoint of this analysis was Progression Free Survival (PFS). Results: Out of 215 cHL patients seen in our institution from 2004 to 2019, 148 achieved a negative iPET after 2 ABVD course. FFPE material was available for 120 iPET- cases which constitute the study population. Forty percent of patients were older than 45 years, 38% had stage III-IV, and 15% had Bulky disease. With a median follow up of 63 months (range, 7–139 months) we recorded 31 events for PFS. The resulting 4 year PFS rate was 77% (95% CI: 71.1–84.9). Analysis performed by Cox Proportional Hazard model identified 54 genes whose expression was significantly associated with PFS (p ≤ 0.05). Of these, 43 were positively associated with improved PFS indicating a potential protective role of these factors. Vice versa, only 11 genes were significantly associated with reduced survival probability. Gene Ontology analysis showed that protective genes were enriched in B-cells related pathways and response to cytokines, pointing to a shielding function of the microenvironment with respect to disease aggressiveness. Unsupervised clustering analysis using the 43 genes protective signature identify two separate clusters of patients (Figure 1A). Kaplan Meyer curve analysis showed that Cluster 2 patients had a significative reduced PFS as compared to Cluster 1 (p = 0.00043), supporting the prognostic relevance of these genes (Figure 1B). The research was funded by: AIRC-IG2021-25802 Keywords: Genomics, Epigenomics, and Other -Omics, PET-CT, Tumor Biology and Heterogeneity No conflicts of interests pertinent to the abstract.

Efficacy and safety of pembrolizumab (pembro) in children and young adults with newly diagnosed classical Hodgkin lymphoma (cHL) with slow early response (SER) to front-line chemotherapy (chemo) in the phase 2, open-label, KEYNOTE-667 study.

10027 Background: Patients (pts) with cHL with SER to initial chemo are at higher risk of relapse, and chemo dose intensification and radiotherapy (RT) can increase the burden of late organ toxicities. The open-label, phase 2 KEYNOTE-667 study (NCT03407144) is evaluating pembro plus chemo in pts with cHL and SER to front-line chemo. Results of an interim analysis in pts with high-risk cHL (group 2) and SER are presented. Methods: Pts were aged 3-17 (children) or 18-25 y (young adults) with newly diagnosed stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL. Pts received induction with 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA). Response was assessed after induction (early) and consolidation (late) therapy by PET/MRI/CT. After induction, pts with rapid early response at the early response assessment (ERA) received nonstudy therapy and pts with SER at ERA received consolidation with 4 cycles cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28) plus pembro 2 mg/kg up to 200 mg IV every 3 weeks (Q3W; aged 3-17 y) or 200 mg IV Q3W (aged 18-25 y). Pts with PET positivity (Deauville score 4-5) after consolidation (late response assessment [LRA]), received involved-site RT (28.8 Gy) to late PET-positive residua; RT was omitted in pts with PET negativity. All pts with SER received maintenance pembro Q3W for a total of 17 doses. Primary end point was ORR by blinded independent central review (BICR) per Cheson 2007 International Working Group criteria in pts with SER. Secondary end points included PET negativity after consolidation and safety. Results: At data cutoff (Sep 02, 2022), median follow-up was 15.3 mo (range, 3.2-30.5); 49 pts with high-risk cHL with SER were included. Median age was 15 y (range, 6-22), 24 (49%) pts had bulky disease, and 31 (63%) had Ann Arbor stage IV disease. 22 (45%) pts completed treatment and 24 (49%) were ongoing on consolidation/maintenance treatment. Median time on pembrolizumab was 10.4 mo (range, 0.5-11.8). 42 (86%) of 49 pts had a LRA, of whom 27 (64%) were PET negative by BICR (30 [71%] PET negative by investigator). All-cause adverse events (AEs) occurred in 42 (86%) pts, with 30 (61%) having a treatment-related AE. Grade ≥3 AEs occurred in 13 (27%) pts, with 7 (14%) having a serious AE. Grade ≥3 treatment-related AEs occurred in 6 (12%) pts. 4 (8%) pts had immune-mediated AEs (2 grade 1 hypothyroidism; 2 grade 2 hypothyroidism). Conclusions: In pediatric pts with high-risk cHL and SER to standard OEPA induction, pembro plus COPDAC-28 consolidation had manageable safety and resulted in 64% of pts having a PET-negative response at end of chemo and being spared RT. These results suggest adding pembro to COPDAC-28 consolidation may augment responses in this high-risk population. Clinical trial information: NCT03407144 .

SINGLE AGENT BRENTUXIMAB VEDOTIN AS BRIDGE TO ALLOGENEIC STEM CELL TRANSPLANT IN ADOLESCENTS WITH RELAPSED ANAPLASTIC LARGE CELL LYMPHOMA (ALCL): THE UCLH EXPERIENCE

Introduction: Optimal treatment for relapsed ALCL in children and adolescents is still subject of debate. We present here the results of our salvage strategy in the TYA Unit at UCLH, using single agent brentuximab vedotin (BV) as bridge to allogeneic stem cell transplant (alloHSCT). Methods: Between 2011 and 2021 we treated 7 patients with relapsed ALCL; all patients had received first line treatment according to ALCL99 guidelines. All relapses were biopsy proven and centrally reviewed if not performed at UCLH. Brentuximab Vedotin was given at the standard dose of 1.8mg/kg intravenously every 3 weeks. Results: All 7 patients were male; median age at diagnosis was 16 (range 13–19). Baseline characteristics were as follows: 7/7 were CD30+, 3/7 were CD3+, 6/7 biopsies were ALK positive, and 3/7 presented with a small cell/lymphohistiocitic (SC/LH) pattern. Six/7 patients had stage IV disease, 4/7 had skin involvement, bone marrow involvement was seen in 3/7 cases (infiltrate between 2 and 10%); 1/7 patients had bulky disease. Of the 7 patients, 3 had primary progressive disease, while 4/7 patients initially achieved a complete metabolic response (CMR), but had a very early relapse, between 2 and 3 months after completion of treatment. 6/7 patients received BV as first line of salvage treatment, 1 as second salvage, after failing ICM (ifosfamide, carboplatin, mitoxantrone), which was still our standard of care in 2011. Median number of doses of BV received was 3 (range 2–5); 6/7 (86%) patients obtained a complete metabolic remission, after a median of 3 doses (range 3–5). One patient progressed on BV; after failing crizotinib he achieved CMR with vinblastine-dexamethasone, then proceeded to transplant and is in long term remission. All 6 patients who achieved a complete remission after BV proceeded to alloHSCT, 1/6 from fully matched sibling donor, 3/6 from haploidentical donors, 2/6 from matched unrelated donors. Conditioning regimen was myeloablative for 5/6 patients, using Cyclophosphamide/total body irradiation +/- Campath depending on donor source; one patient received intermediate intensity conditioning with BEAM (BCNU, etoposide, cytarabine, melphalan)-Campath. With a median follow up of 55 months (range 4–133), all 6 patients are alive and 5/6 (83%) remain in remission with no need for further treatment; 1/6 patients relapsed 8 months post-transplant. This patient was re-challenged with BV, with the addition of donor lymphocytes infusions (DLI) and achieved a complete remission. Conclusions: Salvage treatment with single agent BV followed by alloHSCT is effective in adolescents with relapsed ALCL and lead to durable responses in a cohort of patients with high prevalence of high-risk features (advanced stage, SC/LH pattern, CD3+, early relapse after first line treatment). Interestingly, in one patient who relapsed after alloHSCT, BV and DLI were successful in inducing another complete remission. Keywords: Molecular Targeted Therapies, Non-Hodgkin (Pediatric, Adolescent, and Young Adult), Stem Cell Transplant No conflicts of interests pertinent to the abstract.