Ghesquières, Hervé

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Abstract Background: Despite recent therapeutic advances in AS cHL, PET-adaptive chemotherapy-based regimens remain a first-line treatment option, especially for patients (pts) without access to novel agents. Most PET-adaptive regiments start with either 2 cycles of escBEACOPP (escBEACOPP2) or ABVD (ABVD2) prior to interim PET assessment (iPET), followed by treatment de-escalation or intensification by iPET result. There have been no direct comparisons of escBEACOPP2 vs ABVD2 PET-adaptive regimens. Additionally, the AS-Hodgkin Lymphoma International Prognostication Index (A-HIPI) score (Rodday JCO 2023) has not been fully explored in escBEACOPP2 regimens. Therefore, we utilized multiple analytic approaches to compare outcomes of PET-adaptive escBEACOPP2 and ABVD2 regimens, while adjusting for and assessing the effect of the baseline A-HIPI score. Methods: Through the global HoLISTIC Consortium (www.hodgkinconsortium.com), we obtained individual patient data from 4 AS clinical trials of newly diagnosed cHL pts treated with PET-adaptive escBEACOPP2 (AHL2011) or ABVD2 (SWOG0816, RATHL, HD0607) regimens. Pts were restricted to age 18 to 65 years (y), stage IIB-IV, and PET-adapted treatment arms. Positive iPET was based on Deauville score >3. Treatment effects of escBEACOPP2 vs ABVD2 (reference) on 5y progression-free survival (PFS) and overall survival (OS) were first evaluated using Cox models. Importantly, baseline disease risk was adjusted for using the 5y PFS or OS A-HIPI score (including stage, sex, age, bulk, lymphocyte count, albumin, white blood cell count), where higher scores indicate higher predicted risk (scale 1-100). The A-HIPI was modeled per 1 standard deviation (SD) increase. Our multistate model (MSM) comprised 4 health states: diagnosis, sustained remission at 1yr, treatment failure, and death from any cause. Pts all started in the diagnosis state and transitioned to other states without return to prior states. We assessed the impact of treatment on transitions (except binary sustained remission at 1y) that involved ≥5 pts per treatment group, adjusting for A-HIPI for all transitions. All effects are reported as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Results: 2,381 AS cHL pts were included (n=372 for escBEACOPP2, n=2009 for ABVD2). For escBEACOPP2 and ABVD2 groups (median follow-up 60 and 56 months), respectively, the mean baseline A-HIPI scores (i.e., predicted 5y PFS event rate) were 25.1 (SD=6.3) and 22.9 (SD=6.5), the rates of positive iPET were 11.3% and 17.0%, 5y PFS was 87.0% and 79.5%, and 5y OS was 96.3% and 94.6%. In Cox models, escBEACOPP2 was associated with significantly improved PFS compared to ABVD2 (aHR=0.54, 95% CI=0.39-0.73); the aHR for OS was 0.67 (95% CI=0.37-1.19). Notably, higher risk A-HIPI score was associated with significantly worse PFS (aHR=1.42, 95% CI=1.31-1.54) and OS (aHR=1.60, 95% CI=1.47-1.76), independent of treatment. In the MSM, the effect of escBEACOPP2 compared to ABVD2 regimens was modeled in 3 transitions with adjustment for A-HIPI score: those treated with escBEACOPP2 had lower likelihood of treatment failure with (aHR=0.38, 95% CI=0.22-0.66) or without (aHR=0.61, 95% CI=0.40-0.92) sustained remission at 1y; the aHR for treatment failure to death was 0.55 (95% CI=0.25-1.22). Higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure and death without sustained remission at 1y (aHR=1.43, 95% CI=1.28-1.61 and aHR=2.50, 95% CI=1.80-3.49, respectively). Furthermore, higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure after achieving sustained remission at 1y (aHR=1.29, 95% CI=1.12-1.48) as well as death after treatment failure (aHR=1.54, 95% CI=1.27-1.86). Conclusions: Comparing newly diagnosed adult AS cHL PET-adaptive regimens with adjustment for baseline A-HIPI score, we found pts treated with escBEACOPP2 on AHL2011 had improved PFS versus pooled pt data from 3 ABVD2 trials. Using MSM, we further demonstrated that escBEACOPP2 was associated with a lower likelihood of treatment failure with or without achieving sustained remission at 1yr. In addition, baseline A-HIPI score was associated with PFS and OS, which was independent of treatment. Finally, higher baseline A-HIPI scores maintained prognostic impact throughout the disease course, including increased risk of treatment failure for pts in remission at 1yr and death after treatment failure.

Abstract Aggressive B-cell non-Hodgkin lymphomas represent a clinically heterogeneous group of malignancies characterized by rapid progression and varied molecular features. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non-Hodgkin lymphoma and encompasses a biologically diverse group of diseases, now classified into 18 molecular subtypes (Alaggio et al. Leukemia, 2022). While first-line R-CHOP therapy cures approximately 60% of patients (Coiffier et al. N Engl J Med. 2002), those with relapsed or refractory (R/R) disease face poor outcomes. Although CAR T-cell therapies (e.g. axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) have improved outcomes, access remains limited due to logistical and disease-related constraints (Locke et al. N Engl J Med. 2022). More recently, bispecific CD20xCD3 antibodies such as epcoritamab and glofitamab have shown clinical activity in the R/R setting after ≥2 prior lines, with complete response (CR) rates of ~40% (Dickinson et al. N Engl J Med. 2022; Thieblemont et al. J Clin Oncol. 2023). However, treatment sequencing and mechanisms of resistance to CD20-targeted therapies remain areas of active investigation. One emerging resistance mechanism to CD20 bispecific antibodies is the downregulation or loss of CD20 expression, which has been associated with treatment failure and disease progression (Bannard et al. Clin. Cancer Research, 2022). This highlights the need for novel strategies to overcome CD20 resistance. Dapolsertib (MEN1703) is a first-in-class dual PIM/FLT3 kinase inhibitor that targets key oncogenic and survival pathways in hematologic malignancies. PIM kinases (PIM1, PIM2, PIM3) regulate translation, metabolism, apoptosis, and immune modulation. Overexpression and mutations in PIM genes are associated with poor prognosis in DLBCL, particularly in the ABC subtype, and are known to cooperate with MYC and BCL6 (Szydłowski et al. Cancer Res. 2021). Simultaneous inhibition of all three PIMs downregulates MYC and induces marked cytotoxicity in preclinical models. In AML, dapolsertib has demonstrated preliminary clinical single-agent activity, with ~10% CR/CRi reported in the DIAMOND study (NCT03008187; Martinelli et al. Blood Neoplasia, in press). Dapolsertib has also shown strong antitumor activity in lymphoma models, both in vitro and in vivo (Bellon et al. Mol Cancer. 2023). Notably, dapolsertib demonstrated synergy with anti-CD20 antibody, rituximab, providing a rationale for combination strategies (Szydłowski et al. Cancer Res. 2021). The rationale for combining dapolsertib with a CD20 bispecific antibody lies in its potential to modulate survival pathways, sensitize malignant B-cells to immunotherapy, and circumvent resistance mechanisms such as CD20 loss by inducing CD20 expression. JASPIS-01 (NCT06534437) is an ongoing, international multicenter, Phase 2 study evaluating dapolsertib as monotherapy or in combination with glofitamab in patients with R/R aggressive B-cell lymphoma after ≥2 prior lines of therapy. The trial consists of three parts: a safety run-in (Part 1), optional enrichment (Part 2), and a potential randomized comparison vs. glofitamab (Part 3). Part 1 will include 2 groups of patients. Group 1 comprises bispecific-naïve patients randomized to a prospective dose-optimization evaluation of the combination with dapolsertib. Patients receive either 125 mg on a 2 weeks on / 1 week off schedule or 150 mg on a 1 week on / 2 weeks off schedule for up to 12 cycles to investigate optimal therapeutic window. Group 2 comprises patients who exhausted therapeutic standard options and who will receive dapolsertib monotherapy at 125 mg on a 2 weeks on / 1 week off schedule until intolerable toxicity or disease progression. The initial safety run-in (Parts 1 of both groups) informs dose selection for Part 2. Dose continuation in Part 2 will be guided by Data and Safety Monitoring Board safety assessments after ≥2 completed treatment cycles. The primary objectives are to assess safety, tolerability, and preliminary anti-lymphoma activity. Key endpoints include incidence of adverse events, overall/complete response rates, and duration of response. As of July 11, 2025, Part 1 is enrolling in France, Poland, Spain and the UK with additional sites activation ongoing.

Abstract Introduction Short diagnosis-to-treatment interval (DTI) is associated with aggressive disease biology and inferior outcomes in diffuse large B-cell lymphoma (DLBCL), and is recognized as a potential source of selection bias in clinical trials if not properly addressed. However, its prognostic significance in follicular lymphoma (FL) remains poorly characterized. We aimed to evaluate the prognostic significance of DTI in newly diagnosed FL patients who received frontline (1L) immunochemotherapy (IC), using a large international dataset and an independent external validation cohort. Methods For the discovery dataset, we evaluated patients diagnosed between 2002 and 2018 from ten observational cohorts as part of the FLIPI24 Consortium. External validation was conducted using data from patients enrolled in the Lymphoma Epidemiology of Outcomes (LEO) Cohort between 2010 and 2015. All patients had FL grade 1–3A and received 1L IC within 100 days of diagnosis. Patients with a concurrent DLBCL were excluded. Missing baseline laboratory values were addressed via multiple imputation. The primary endpoint was event-free survival at 24 months (EFS24); secondary endpoint was 5-year overall survival (OS), both calculated from treatment initiation. DTI was analyzed as continuous (via splines) and dichotomized variable (≤14 vs >14 days; as defined in DLBCL). Results In the discovery cohort (n=3,907), median age was 61 years (IQR 53–69), and 50% were male; 49% of patients were high-risk according to FLIPI, 26% according to PRIMA-PI, and 38% according to FLIPI24. Included patients received R-CHOP (54%), R-CVP (26%), or B-R (20%) as 1L treatment, followed by anti-CD20 maintenance in 60%. The median DTI was 30 days (IQR 17–48). Using the 14-day cut-off, 851 patients (22%) had short DTI. These patients had more adverse baseline characteristics, including B symptoms (42% vs 32%, P<0.01), ECOG performance status ≥2 (15% vs 8%, P<0.01), elevated LDH (51% vs 40%, P<0.01), hemoglobin <12 g/dL (30% vs 17%, P<0.01), and elevated β2-microglobulin (56% vs 44%, P<0.01). Prognostic indices (PIs) were also more frequently high-risk in the short-DTI group: FLIPI (56% vs 47%), PRIMA-PI (36% vs 24%), and FLIPI24 (51% vs 34%, all P<0.01). Spline modeling showed a decreasing EFS24 rate with increasing DTI, reaching a plateau at 30–40 days. In logistic regression model, each additional week of DTI improved EFS24 (OR 0.92, P<0.01). DTI attenuated but remained prognostic after adjusting for PIs (OR 0.93 for FLIPI, 0.95 for PRIMA-PI, 0.96 for FLIPI24, all P<0.01). When analyzed as a dichotomized variable, short DTI was associated with inferior EFS24: OR 1.74 adjusted for FLIPI, 1.63 for PRIMA-PI, and 1.53 for FLIPI24 (all P<0.01). The 2-year EFS of short vs long DTI groups was 71% vs 82% (HR 1.50, 95% CI 1.34–1.67, P<0.01), 5-year OS was 80% vs 86% (HR 1.38, 95% CI 1.21–1.56, P<0.01), and the 5-year cumulative risk of histologic transformation was 7.7% vs. 5.4% (P<0.01). In the validation cohort (n=516), median age was 61 years (IQR 52–69 years), 55% were male; 36% of patients were high-risk according to FLIPI; 29% according to PRIMA-PI, and 33% according to FLIPI24. Patients received B-R (59%) or R-CHOP (41%) as 1L treatment. The median DTI was 31 days (IQR 19–48), 84 patients (16%) had DTI ≤14 days. Similar patterns were observed; patients with short DTI had adverse baseline characteristics, PIs, and shorter 2-year EFS (72% vs 84%, HR 1.69, 95% CI 1.13–2.55, P=0.01). DTI remained associated with EFS24 when analyzed as a continuous variable (per week: OR 0.88 unadjusted, 0.90 with FLIPI, 0.89 with PRIMA-PI, and 0.89 with FLIPI24), and dichotomized (≤14 vs >14 days: OR 1.83 adjusted for FLIPI, 1.88 for PRIMA-PI, and 1.73 for FLIPI24). Conclusion Short DTI, defined as ≤14 days (observed in 22% of FL patients vs 46% in DLBCL), is a strong and independent predictor of inferior outcomes in newly diagnosed FL patients treated with IC. While DTI correlates with adverse baseline features and established PIs, it retains independent prognostic value. Although a 14-day threshold is reasonable for risk modeling, DTI contains greater informational value when modeled as a continuous variable. Among PIs, FLIPI24 most strongly attenuated the DTI effect, underscoring its superior discriminative power over FLIPI and PRIMA-PI. Clinical trials designs should mitigate any potential barriers to enrollment of FL patients requiring urgent therapy.

PURPOSE Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed. METHODS The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L immunochemotherapy setting was performed using the prospective observational Lymphoma Epidemiology of Outcomes (LEO) cohort (N = 565) and three randomized phase III trials (N = 3,192); extension to all patients with FL (any 1L therapy) was performed in the LEO cohort (N = 1,445) and its Molecular Epidemiology Resource subcohort (N = 1,074). RESULTS The FLIPI24 model uses age and four blood-based variables (hemoglobin, lactate dehydrogenase, beta-2 microglobulin, and WBC count). FLIPI24 showed consistent performance across validation and extension data sets, which was superior to existing prognostic tools. Across the four external immunochemotherapy validation data sets, patients with high-risk FLIPI24 (23%-32% of patients) had significantly higher 24-month event rates (22%-35%) and inferior 5-year overall survival (77%-83%) compared with patients with low-risk FLIPI24 (29%-31% of patients, 24-month event rates: 10%-12%; 5-year OS: 96%-97%). Results were consistent when evaluating lymphoma-related death and when extended to all patients with FL. CONCLUSION The FLIPI24 model robustly stratifies, at diagnosis, patients with FL at increased risk of lymphoma-related death versus patients with very low lymphoma-related mortality during the first decade after diagnosis. FLIPI24 can be used to enrich future clinical trial designs in newly diagnosed FL.

PURPOSE In patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), brentuximab vedotin (BV) as monotherapy or combined with either lenalidomide (Len) or rituximab (R) has demonstrated efficacy with acceptable safety. We evaluated the efficacy and safety of BV + Len + R versus placebo + Len + R in patients with R/R DLBCL. METHODS ECHELON-3 is a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial comparing BV + Len + R with placebo + Len + R in patients with R/R DLBCL. Patients received BV or placebo once every 3 weeks, Len once daily, and R once every 3 weeks. The primary end point was overall survival (OS), and secondary end points included investigator-assessed progression-free survival (PFS) and objective response rate (ORR). A prespecified interim analysis was performed after 134 OS events, with two-sided P = .0232 as the efficacy boundary. RESULTS Patients (N = 230) were randomly assigned to receive BV + Len + R (n = 112) or placebo + Len + R (n = 118). Two patients in the placebo arm did not receive treatment. With a median follow-up of 16.4 months, the median OS was 13.8 months with BV + Len + R versus 8.5 months with placebo + Len + R (hazard ratio, 0.63 [95% CI, 0.45 to 0.89]; two-sided P = .009). The median PFS was 4.2 months with BV + Len + R versus 2.6 months with placebo + Len + R (hazard ratio, 0.53 [95% CI, 0.38 to 0.73]; two-sided P < .001). The ORR was 64% ([95% CI, 55 to 73]; two-sided P < .001) with BV + Len + R and 42% (95% CI, 33 to 51) with placebo + Len + R; complete response rates were 40% and 19%, respectively. Treatment-emergent adverse events (AEs) occurred in 97% of patients in both arms. In both arms, the most common treatment-emergent AEs were neutropenia, thrombocytopenia, diarrhea, and anemia. CONCLUSION BV + Len + R demonstrated a statistically significant survival benefit with a manageable safety profile in heavily pretreated patients with R/R DLBCL.

Introduction Age correlates with survival in patients (pts) with DLBCL, which has a median age at diagnosis of 67 y. Recent therapeutic advances, including bispecifics and cell therapy, have promising efficacy, but safety and accessibility continue to be limited for older pts. The randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with brentuximab vedotin (BV) + lenalidomide (Len) + rituximab (R; BV+Len+R) vs placebo+Len+R in pts with R/R DLBCL after ≥ 2 prior systemic therapies who were ineligible for hematopoietic stem cell transplant and/or chimeric antigen receptor (CAR) T-cell therapy. Here, we present safety and efficacy in pts aged ≥65 y. Methods In ECHELON-3, pts were randomized 1:1 to receive BV (1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with R (375 mg/m2) q3w and Len (20 mg) once daily. Granulocyte colony-stimulating factor was required in all cycles. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. Other secondary endpoints included detailed safety and tolerability. This subgroup analysis comprises pts aged ≥65 y. P values are descriptive. Results A total of 155 pts aged ≥65 y were enrolled from April 2021 to November 2023 and randomized to BV+Len+R (n=79) or placebo+Len+R (n=76). The median age was 75 y (range, 65-89 y); 54% of pts were male, 59% were White, and 19% were Asian. Twenty-three percent and 54% had Ann Arbor stage III and IV disease, respectively, and 64% had high-intermediate or high International Prognostic Index scores (3-5) at enrollment. The most common DLBCL subtype was DLBCL not otherwise specified (58%). Twenty-nine percent of pts had transformed DLBCL. Approximately half (49%) of pts had primary refractory disease, and 81% had disease refractory to their most recent prior line of therapy. Seventy percent of pts had &lt;1% CD30 expression via IHC; 48% of cases had germinal center B-cell origin. Prior CAR-T was reported in 21.9% of pts. At a median follow-up of 16.8 mo (95% CI, 14.3-19.5 mo), median OS was 15.9 mo (95% CI, 11.7 mo-not estimable [NE]) with BV+Len+R vs 8.5 mo (95% CI, 5.5-11.5 mo) with placebo+Len+R (hazard ratio [HR], 0.540; 95% CI, 0.351-0.830; P=.0043). Median PFS was 5.7 mo (95% CI, 4.1-12.7 mo) with BV+Len+R vs 2.8 mo (95% CI, 1.9-4.1 mo) with placebo+Len+R (HR, 0.478; 95% CI, 0.318-0.718; P=.0003). ORR was 70.9% (95% CI, 59.6%-80.6%) with BV+Len+R vs 46.1% (95% CI, 34.5%-57.9%) with placebo+Len+R (P=.0020); complete response (CR) rate was 45.6% vs 19.7%, respectively. Median time to CR was 1.61 mo with both BV+Len+R and placebo+Len+R (range, 1.2-7.3 vs 0.7-4.6 mo, respectively). Median duration of CR was 18.9 mo (95% CI, 12.4 mo-NE) with BV+Len+R vs 5.4 mo (95% CI, 2.8 mo-NE) with placebo+Len+R (HR, 0.416; 95% CI, 0.139-1.250). In total, 154 pts were evaluable for safety analysis (75 pts in placebo+Len+R group). The median number of cycles was 5 (range, 1-34) vs 3 (range, 1-31) in the BV+Len+R and placebo+Len+R groups, respectively. The percentage of pts with any treatment-emergent adverse event (TEAE) was similar between groups (97% with BV+Len+R and 99% with placebo+Len+R); grade ≥3 TEAEs occurred in 89% of pts in the BV+Len+R group and 76% in the placebo+Len+R group. Serious TEAEs and TEAEs leading to death were reported more frequently in the BV+Len+R group (62% and 13%, respectively) than the placebo+Len+R group (47% and 8%, respectively). More pts discontinued study treatment due to TEAEs in the BV+Len+R group than the placebo+Len+R group (20% vs 8%). In total, 39% of pts on BV+Len+R had a peripheral neuropathy event vs 27% of pts on placebo+Len+R; however, the majority of cases were grade 1 (22% and 17%, respectively). Additional information on older pts will be presented. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes in pts aged ≥65 y, which is consistent with the overall ECHELON-3 population (median age 74 y; 70.5% of pts aged ≥65 y in BV+Len+R group). Differences in some safety endpoints are likely attributable to longer duration of treatment in the BV+Len+R group. No clinically meaningful safety trends in pts aged ≥65 y were identified. These results suggest that BV+Len+R may be an effective treatment option in older pts with R/R DLBCL.

Introduction Patients (pts) with progressive disease after ≥2 prior lines of systemic therapy are unlikely to derive additional benefit from current salvage immunochemotherapies, and survival declines significantly with each subsequent treatment. Pts with refractory disease following second-line therapy have worse outcomes, with reported overall response rates (ORRs) of 1% to 14% and overall survival (OS) of 5 months (Blood. 2017;130[16]:1800-1808). While chimeric antigen receptor (CAR) T-cell therapy has become a preferred strategy in the second- and third-line settings, pts with R/R disease following CAR-T experience dismal survival, with progression-free survival (PFS) and OS as low as 3 and 5 months, respectively, and no agreed standard of care post CAR-T (Blood. 2022;140[24]:2527-2529). The randomized, global, phase 3 ECHELON-3 study (NCT04404283) was conducted in pts with R/R DLBCL after ≥2 prior therapies who were ineligible for hematopoietic stem cell transplant and/or CAR-T. Here, we present subgroup analyses in pts with 2 prior lines of therapy, refractory disease, or prior CAR-T. Methods In these subgroup analyses of ECHELON-3, eligible pts had 2 prior lines of systemic therapy, disease refractory to the last prior therapy, or prior exposure to CAR-T. Pts could qualify for ≥1 subgroup and were analyzed separately. Refractory disease was defined as stable or progressive disease as best overall response to last line of treatment or relapse ≤6 months from the end of treatment. Pts were randomized 1:1 to receive brentuximab vedotin (BV; 1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with rituximab (R; 375 mg/m2) q3w and lenalidomide (Len; 20 mg) once daily. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. P values are descriptive. Results In total, 230 pts were enrolled in ECHELON-3 from April 2021 to November 2023, with a median follow-up of 16.4 months (range, 0.1-31.5 months). Overall, 94 pts with 2 prior lines of systemic therapy were enrolled and randomized to BV+Len+R (n=48) or placebo+Len+R (n=46). Median OS was 16.3 months (95% CI, 12.6 months-not estimable) with BV+Len+R vs 8.5 months (95% CI, 4.1-15.8 months) with placebo+Len+R (hazard ratio [HR], 0.557; 95% CI, 0.317-0.977; P=.0388). Median PFS was 7.1 months (95% CI, 3.6-12.6 months) with BV+Len+R vs 2.7 months (95% CI, 1.4-4.0 months) with placebo+Len+R (HR, 0.462; 95% CI, 0.279-0.764; P=.0020). ORR was 68.8% (95% CI, 53.7%-81.3%) with BV+Len+R vs 43.5% with placebo+Len+R (95% CI, 28.9%-58.9%; P=.0216); complete response (CR) rate was 52.1% vs 13.0%, respectively. Additional data for pts by lines of therapy received will be presented. In total, 194 pts with disease refractory to the most recent systemic therapy were enrolled and randomized to BV+Len+R (n=98) and placebo+Len+R (n=96). Median OS was 11.7 months (95% CI, 8.8-16.3 months) with BV+Len+R vs 5.5 months (95% CI, 3.7-8.5 months) with placebo+Len+R (HR, 0.566; 95% CI, 0.396-0.808; P=.0015). Median PFS was 4.1 months (95% CI, 2.8-5.4 months) with BV+Len+R vs 1.5 months (95% CI, 1.4-2.6 months) with placebo+Len+R (HR, 0.508; 95% CI, 0.363-0.712; P&lt;.0001). ORR was 59.2% (95% CI, 48.8%-69.0%) with BV+Len+R vs 29.2% (95% CI, 20.3%-39.3%) with placebo+Len+R (P&lt;.0001); CR rate was 34.7% vs 11.5%, respectively. Overall, 67 pts who received prior CAR-T were enrolled and randomized to BV+Len+R (n=32) and placebo+Len+R (n=35). Median OS was 15.6 months with BV+Len+R vs 4.4 months with placebo+Len+R (HR, 0.38; 95% CI, 0.2-0.75). Median PFS was 3.0 months with BV+Len+R vs 1.4 months with placebo+Len+R (HR, 0.41; 95% CI, 0.22-0.76). ORR was 65.6% (95% CI, 46.8%-81.4%) with BV+Len+R vs 25.7% (95% CI, 12.5%-43.3%) with placebo+Len+R (P=.0014); CR rate was 37.5% vs 11.4%, respectively. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes, including CR and OS, in pts with 2 prior lines of therapy, disease refractory to prior treatment, or prior CAR-T. This treatment benefit was generally consistent with that observed in the overall ECHELON-3 study population. Therefore, BV+Len+R has the potential to address an unmet need for effective and tolerable therapy in heavily pretreated pts, as described above.