Li, Ju

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was > 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

7515 Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged < 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, < 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]

Background: Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with indolent non-Hodgkin lymphoma. Patients with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on patients aged ≥ 70 years from the MAGNIFY study. Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg on days 1-21 of a 28-day cycle + rituximab 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 vs rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable FL grade 1-3a and MZL patients (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Post-hoc analyses were performed by analyzing data from patients aged ≥ 70 years at time of study entry. Results: As of November 30, 2019, 393 patients have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of patients ≥ 70 and the overall population are shown in the table. Median PFS in the ≥ 70 subgroup was 36.0 months (95% CI, 28.3-NR). Overall response rate and CR/CRu were 75% and 38%, with a median duration of response that was not reached (95% CI, 27.1-NR). Efficacy results for the overall population are shown in the table. In patients ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in &gt; 10% of patients (febrile neutropenia occurred in 3 patients [2%]). TEAEs led to lenalidomide dose reduction in 69 patients (46%) and discontinuation in 40 patients (26%). Seventy-eight patients ≥ 70 (51%) completed all 12 cycles of induction treatment, and 72 (47%) have entered the maintenance phase. Sixty-one patients ≥ 70 (40%), compared to 35% of patients in overall population, prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 26; 17%), progressive disease (n = 15; 10%), patient withdrawal (n = 12; 8%), death (n = 5; 3%), and other reasons (n = 3; 2%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 patients (n = 10; 7%). Conclusions: Similar to findings in the overall population, R2 treatment in advanced-age patients with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. Table Disclosures Lansigan: BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Andorsky:AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding. Coleman:Novartis Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Incyte Corporation: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding. Yacoub:Novartis: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning:Prisma Health: Current Employment; Abbvie: Consultancy; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi Aventis: Speakers Bureau. Kolibaba:Compass Oncology: Ended employment in the past 24 months; Atara Biotech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; AbbVie: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria; Janssen: Research Funding; Novartix: Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding. Gharibo:Bayer: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Amgen GmbH: Honoraria; Roche: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.

SummaryPatients with aggressive non‐Hodgkin lymphoma (NHL) who relapse after autologous stem cell transplantation (ASCT) have a poor prognosis. Additional therapy is often poorly tolerated, and new treatment modalities are needed. This efficacy and safety study was a retrospective analysis of two phase II trials (NHL‐002 and NHL‐003) that studied single‐agent lenalidomide in patients with relapsed/refractory aggressive NHL with prior (n = 87) compared with no prior ASCT (n = 179). The overall response rate in the ASCT group was 39% [14% complete response (CR)], including 29% in patients with diffuse large B‐cell lymphoma, 63% in mantle cell lymphoma, and 60% in transformed lymphoma. The timing of transplant relative to receiving lenalidomide had no effect on outcomes. Median progression‐free survival for the ASCT group was 3·7 months (16·9 months for patients in CR; 7·3 months for partial responders) at a median 12·5‐month follow‐up. Median response duration was 7·9 months. Regardless of prior ASCT, lenalidomide monotherapy was efficacious in heavily pretreated patients with aggressive, relapsed/refractory NHL, with a safety profile that was consistent with prior studies of single‐agent lenalidomide.