7025 Background: ctDNA is a minimally invasive method for detecting MRD in various malignancies. MRD negativity (MRD neg ) has been linked to improved PFS and durable disease control, including after liso-cel treatment in R/R large B-cell lymphoma. The prognostic value of MRD after chimeric antigen receptor (CAR) T cell therapy in R/R FL has not been established. We report an exploratory MRD analysis from TRANSCEND FL (NCT04245839), in which pts had high rates of deep and durable responses after liso-cel. Methods: Of 103 efficacy-evaluable pts with third-line or later (3L+) FL, 89 (86%) had ctDNA samples, of whom 90% (80/89) had evaluable ctDNA and efficacy data after liso-cel infusion. Tumor-derived phased variants were primarily identified from screening (baseline) plasma or tumor tissue when plasma was insufficient, using PhasED-Seq. Post-treatment ctDNA-MRD was assessed at months (M) 1 and 3 after infusion for all pts, and at M24 for ongoing responders. MRD positivity (MRD pos ) was defined as ctDNA above the assay detection threshold (lower limit of detection of 0.7 parts per million, with sample-specific sensitivity dependent on DNA input). Results: MRD neg was achieved by 89% (71/80) of evaluable pts from TRANSCEND FL. Among pts with a best overall response of CR, 93% (71/76) of them achieved MRD neg . ctDNA clearance increased over time, with MRD neg rates of 68% (52/76) at M1, 83% (63/67) at M3, and 97% (57/59) at M24. In contrast, pts with PR, SD, or PD (n=4) never achieved MRD neg . Baseline ctDNA levels were not associated with PFS after liso-cel treatment. MRD neg after infusion was associated with longer PFS compared with MRD pos ( P <0.001). In addition, MRD status at M3 (HR, 7.0 [95% CI, 3.0–16.2]) showed a stronger correlation with PFS than at M1 (HR, 3.0 [95% CI, 1.3–6.8]), with 36-M PFS rates of 80% for MRD neg (n=63) versus 38% for MRD pos (n=13) pts. Multivariate analysis controlling for PET findings confirmed the independent prognostic value of MRD for PFS. Importantly, PFS was longer for pts with both CR by PET and MRD neg at M3 (n=62) compared to pts with CR and MRD pos (n=9; HR, 5.0, [95% CI, 1.8-13.4]), with 36-M PFS rates of 81% versus 56%, respectively, suggesting that combining MRD with PET may provide additional prognostic information for long-term outcomes. Conclusions: Liso-cel induced deep molecular responses in pts with 3L+ FL with most pts (89%) achieving MRD neg after infusion. Although baseline ctDNA levels were not associated with PFS, MRD neg after infusion was significantly associated with improved PFS, highlighting the therapeutic benefit of liso-cel regardless of tumor burden before treatment. These findings support the potential of ctDNA-based MRD as a prognostic biomarker in FL and underscore that liso-cel is a key treatment option capable of inducing MRD neg and durable clinical outcomes in pts with 3L+ R/R FL. Clinical trial information: NCT04245839 .

BACKGROUND:Effective treatments with deep and durable responses for relapsed or refractory marginal zone lymphoma (MZL) are lacking. The objective of the primary analysis from the MZL cohort of TRANSCEND FL was to evaluate the efficacy and safety of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel. METHODS:In this phase 2, single-arm, multicohort study, patients from 30 sites in the USA, Canada, Europe, and Japan with relapsed or refractory MZL who had at least two previous lines of systemic therapy were eligible to receive lisocabtagene maraleucel (100 × 106 CAR+ T cells). Bridging therapy was allowed. The primary endpoint was overall response rate per independent review committee by CT by use of Lugano 2014 criteria (null hypothesis ≤50%). This study is registered with ClinicalTrials.gov, NCT04245839, and is ongoing. FINDINGS:Of 77 leukapheresed patients recruited between November 11, 2020, and August 24, 2023, 67 received lisocabtagene maraleucel and 66 were efficacy evaluable. MZL subtypes included nodal (n=32 [48%]), splenic (n=18 [27%]), and extranodal-mucosa-associated lymphoid tissue (n=17 [25%]). Median (IQR) previous lines of systemic therapy was 3 (2-4). Median on-study follow-up was 24·1 months. The primary endpoint was met, with an overall response rate of 95% (n=63; 95% CI, 87·3-99·1; one-sided p<0·0001). All patients experienced a treatment-related adverse event. Grade 3 cytokine release syndrome or neurological events occurred in three (4%) patients each (no grade 4-5 events). 11 (16%) patients had grade ≥3 infections: six (9%) patients during the 90-day treatment-emergent period and seven (10%) during the post-treatment-emergent period. INTERPRETATION:In patients with relapsed or refractory MZL, lisocabtagene maraleucel showed high rates of durable responses. The safety profile was manageable, with no new safety signals. These results support lisocabtagene maraleucel as a new treatment option for patients with relapsed or refractory MZL. FUNDING:Celgene, a Bristol-Myers Squibb Company.

BACKGROUND:Initial results of this study, reported after a median follow-up close to 4 years, demonstrated improved time to initiation of new treatment (TTNT) for patients with advanced stage, asymptomatic, low tumour burden follicular lymphoma who received early rituximab monotherapy when compared with watchful waiting. Given the long natural history of follicular lymphoma, the trial was extended to further assess TTNT with longer follow-up. Mature data are presented here. METHODS:In this open-label, randomised, phase 3 trial, conducted at 118 centres in five countries, adult patients with asymptomatic, stage II-IV, grade 1-3a low tumour burden follicular lymphoma and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned (1:1:1) between watchful waiting, rituximab induction (375 mg/m2, intravenous) weekly for four doses (rituximab induction group) and rituximab induction followed by rituximab maintenance at the same dose every 8 weeks for 12 doses (rituximab maintenance group). The rituximab induction group closed early on Sept 30, 2007, and the study was amended to a two-arm trial. The primary endpoint was TTNT, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT00112931, and recruitment and follow-up are complete. FINDINGS:Between Oct 15, 2004, and May 1, 2009, 455 patients were randomly assigned, including 183 to watchful waiting, 82 to rituximab induction, and 190 to rituximab maintenance. Median follow-up was 14·7 years (IQR 13·3-15·6). At 15 years, 65% (95% CI 56-72) of patients in the rituximab maintenance group, 48% (36-60) in the rituximab induction group, and 34% (27-42) in the watchful waiting group had not started new treatment. Median TTNT was not yet reached (95% CI 15·6-not estimable) in the rituximab maintenance group, 14·8 years (7·5-not reached) in the rituximab induction group, and 5·6 years (3·8-8·4) in the watchful waiting group. TTNT was longer in both the rituximab induction and rituximab maintenance groups compared with the watchful waiting group (rituximab induction vs watchful waiting: hazard ratio [HR] 0·55 [95% CI 0·38-0·80], p=0·0019; rituximab maintenance vs watchful waiting: HR 0·36 [0·26-0·50], p<0·0001). INTERPRETATION:These mature data with 15 years of follow-up confirm that early rituximab monotherapy substantially delays the need for new treatment for patients with advanced stage, asymptomatic low tumour burden follicular lymphoma, providing an evidence base for its use in this setting and confirming its value for patients who seek to defer or avoid treatment with chemotherapy. FUNDING:Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

Background Procarbazine-containing chemotherapy regimens are associated with cytopenias and infertility, suggesting stem-cell toxicity. When treating Hodgkin lymphoma, procarbazine in escalated-dose bleomycin- etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisolone (eBEACOPP) is increasingly replaced with dacarbazine (eBEACOPDac) to reduce toxicity. We aimed to investigate the impact of this drug substitution on the mutation burden in stem cells, patient survival, and toxicity. Methods In this two-part retrospective, observational study, we first compared mutational landscapes in haematopoietic stem and progenitor cells (HSPCs) from patients with advanced-stage Hodgkin lymphoma in remission for at least 6 months who had been treated with eBEACOPDac (eBEACOPDac cohort), eBEACOPP (real- world eBEACOPP cohort), or doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD); in buccal DNA from five children of a female patient with classical Hodgkin lymphoma treated with eBEACOPP before conceiving the third child; in sperm DNA from a patient with mild oligospermia treated with eBEACOPP; and in caecal adenocarcinoma and healthy colon tissue from a survivor of Hodgkin lymphoma treated with chlorambucil- vinblastine-procarbazine-prednisolone. For the second part, we analysed efficacy and toxicity data from adult patients (aged >16 years) treated with first-line eBEACOPDac (eBEACOPDac cohort) at 25 centres across UK, Ireland, and France; efficacy was compared with the German HD18 eBEACOPP trial data and toxicity with a UK real- world dataset. Participants in the German HD18 and UK real-world datasets were adults (aged >16 years) with previously untreated Hodgkin lymphoma, treated with first-line eBEACOPP. We had two co-primary objectives: to define the comparative stem-cell mutation burden and mutational signatures after treatment with or without procarbazine-containing chemotherapy (first study part); and to determine progression-free survival of patients with Hodgkin lymphoma treated with eBEACOPP or eBEACOPDac (second study part). Secondary objectives included overall survival and explored differences in specific toxicity outcomes, including transfusion requirements and measures of reproductive health (second study part). Findings In the first part of the study (mutational analysis), patients treated with eBEACOPP (n=5) exhibited a higher burden of point mutations in HSPCs compared with those treated with eBEACOPDac (n=4) or ABVD (n=3; excess mutations 1150 [95% CI 934-1366] vs 290 [241-339] vs 186 [116-254]). Two novel mutational signatures, SBSA (SBS25-like) and SBSB, were identified in HSPCs and in a single neoplastic and healthy colon sample from patients who received procarbazine-containing chemotherapy. SBSB was also identified in germline DNA of three children conceived after eBEACOPP and in sperm of a male patient treated with eBEACOPP. SBSC was detected in patients treated with either ABVD or eBEACOPDac. In the second part of the study (efficacy and toxicity analysis), dacarbazine substitution did not appear to compromise efficacy or safety. 312 patients treated with eBEACOPDac (eBEACOPDac cohort; treated 2017-22, 186 [60%] male, median follow-up 360 months [IQR 252-501]) had a 3-year progression-free survival of 933% (95% CI 903-964), which was similar to the 933% [95% CI 921-944]) progression-free survival seen in 1945 patients in the German HD18 eBEACOPP trial (treated 2008-14, 1183 [61%] male, median follow-up 570 months [354-647]). Patients treated with eBEACOPDac required fewer blood transfusions (mean 170 units [SD 277] vs 369 units [389]; p<00001), demonstrated higher post-chemotherapy sperm concentrations (median 234 million per mL [IQR 110-6323] vs 00 million per mL [00-0001]; p=00040), and had earlier resumption of menstrual periods (mean 504 months [SD 307] vs 877 months [557]; p=00036) compared with 73 patients treated with eBEACOPP in the UK real-world dataset. Interpretation Procarbazine induces a higher mutation burden and novel mutational signatures in patients with Hodgkin lymphoma treated with eBEACOPP and their germline DNA, raising concerns for the genomic health of survivors of Hodgkin lymphoma and hereditary consequences for their offspring. However, replacing procarbazine with dacarbazine appears to mitigate gonadal and stem-cell toxicity while maintaining similar clinical efficacy.

Introduction: The CAR T cell therapy liso-cel showed promising efficacy and safety in patients with 3L+ R/R MZL in TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study (Palomba ML, et al. Hematol Oncol 2025). Here, we present corresponding data for PROs. Methods: Adults with R/R MZL after ≥2 prior lines of therapy (3L+), including those previously treated with a combination of an anti-CD20 antibody and alkylating agent, or who had relapsed disease after HSCT, were enrolled. After leukapheresis, lymphodepleting chemotherapy (LDC), and optional bridging therapy, patients received 1 infusion of liso-cel (100×106 CAR+ T cells). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 items (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Lymphoma “Additional Concerns” Subscale (FACT-LymS), and EQ-5D-5L on the following schedule: pretreatment (≤7 days before LDC; baseline); before infusion on day of liso-cel infusion (Day 1); on Days 15 and 29, and Months 2, 3, 6, 9, 12, 18, and 24 after infusion; and at end of study assessment. Results focus on 8 key PRO scales: 6 primary domains from the EORTC QLQ-C30 (global health status/quality of life [QOL], physical functioning, role functioning, cognitive functioning, fatigue, and pain), the FACT-LymS subscale assessing lymphoma-specific symptoms, and the EQ-5D-5L visual analog score (VAS). Unless otherwise stated, analyses were performed in all liso-cel–treated patients with assessments at baseline and ≥1 postbaseline visit. Linear mixed-effects models for repeated measures were used to calculate least squares (LS) mean change from baseline to Month 18 visit, with responses available for ≥30 patients. The proportion of patients with clinically meaningful changes from baseline were summarized using published thresholds for “meaningful within-patient change.” Time to confirmed improvement in PROs was assessed in all PRO-evaluable liso-cel–treated patients who had potential for meaningful within-patient change as assessed by the Kaplan-Meier method. Results: Among 67 liso-cel–treated patients with 3L+ R/R MZL, 60 were evaluable for EORTC QLQ-C30 analysis (median age, 63 years; 57% male; 55% White). Disease subtypes included extranodal (23%), nodal (48%), and splenic (28%) MZL. Assessment completion rates were >80% across visits up to Month 18 visit. At baseline, mean scores across primary EORTC QLQ-C30 domains were comparable to or slightly above general population norms in Europe and the US. LS mean changes from baseline showed an initial deterioration in EORTC QLQ-C30 primary domains between Day 1 and Day 15, followed by improvements between Day 15 and Month 2 in 5 domains (all except cognitive functioning, which remained stable throughout, reflecting consistently higher scores than the mean general population norms in Europe and the US). These improvements were generally maintained or further enhanced beyond Month 3, with mean scores at Month 18 remaining above baseline values. Additionally, 4 primary domains (global health status/QOL, physical functioning, role functioning, and fatigue) exceeded the threshold for clinically meaningful improvement. Patients demonstrated improvement in lymphoma specific symptoms as assessed by FACT-LymS starting at Day 15, reaching clinically meaningful improvement by Month 2 and remaining improved through Month 18. Patients showed improvement in the EQ-5D-5L VAS as early as Day 15 reaching the minimum threshold to be considered clinically meaningful at Month 6 and remaining improved through Month 12. Across all PROs, the majority of patients (58%–94%, depending on domain and visit) experienced either improvement or no change in primary domains from Day 29 onward. Median time to confirmed improvement was within 4 months for EORTC QLQ-C30 domains and FACT-LymS. Conclusions: In TRANSCEND FL, most patients with 3L+ R/R MZL experienced clinically meaningful improvements in PROs after liso-cel treatment, including symptom relief, enhanced functioning, and improved QOL. The study represents one of the biggest efforts to characterize PROs in patients with 3L+ R/R MZL and provides valuable insights into the patient experience following treatment with liso-cel. The PRO results complement the clinical efficacy and safety profile of liso-cel in 3L+ R/R MZL, reinforcing its potential to become standard of care in this setting.

Kaplan-Meier curves for progression-free survival and overall survival by loncastuximab tesirine response.

Traditionally, patients with asymptomatic, advanced-stage follicular lymphoma were managed with a watchful-waiting approach until disease progression. The 'Watch and Wait' Phase-3 randomised international trial examined whether rituximab could delay the need for treatment and the effect on quality of life (QoL). In this article, we present the long-term results of the QoL aspect of the trial. Patients were randomised to watchful-waiting (Arm A), rituximab induction (Arm B) or rituximab induction followed by maintenance (Arm C). We present the QoL outcomes from 180 patients (Arm A), 188 patients (Arm C) and an exploratory analysis of 82 (Arm B) compared to 81 and 84 patients concurrently randomised to arms A and C. Arm C reported greater improvement in emotional well-being overtime (Month 37, p = 0.0078) and were significantly more likely to feel in control of their situation than watchful-waiting patients (Month 25, p = 0.0004; Month 37, p = 0.0476). Watchful-waiting patients were significantly more likely to avoid thinking about their illness, did not find learning about their illness helped them and were more likely to attach unpleasant connotations to clinic visits (Month 7, p = 0.0032; Month 13, p = 0.0015; Month 25, p = 0.0104). These results demonstrate improved QoL scores in the induction and maintenance rituximab arm, indicating that rituximab was not detrimental to QoL and resulted in an improved QoL in some domains.

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839 .

Background: In the primary analysis of TRANSCEND FL (NCT04245839), a global, phase 2 study, liso-cel showed an ORR of 97%, CR rate of 94%, and favorable safety in pts with second-line (2L) or later R/R FL. Here, we report results in pts with third-line or later (3L+) and 2L FL with high-risk disease features after approximately 2 y of follow-up. Methods: Eligible pts with R/R FL included 3L+ and 2L pts with progression of disease ≤ 24 mo (POD24) of diagnosis after treatment with anti-CD20 antibody and an alkylator ≤ 6 mo of FL diagnosis and/or modified Groupe d'Etude des Lymphomes Folliculaires (mGELF) criteria. All pts received ≥ 1 prior combination systemic therapy, including an anti-CD20 antibody and an alkylator. Pts received liso-cel (100 × 106 CAR+ T cells) after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee (IRC) by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response (DOR) and PFS by IRC assessment, OS, safety, cellular kinetics, and pt-reported outcomes (PRO). Time to next treatment (TTNT; time from index date to the start date of subsequent systemic treatment or death from any cause, whichever occurred first) and PFS2 (time from index date to the first documented PD, per investigator assessment, or death from any cause after the start date of the subsequent line of therapy) were analyzed post hoc. Results: At data cutoff (January 10, 2024), 107 3L+ and 23 2L high-risk FL pts had received liso-cel and were evaluable for safety; 103 3L+ and 23 2L pts were efficacy evaluable. In pts with 3L+ FL, median (range) age was 62 y (23-80), 89% had Ann Arbor stage III/IV disease, and 57% were high risk per FLIPI. Forty-three percent of pts had POD24 (per eligibility criteria), 53% met mGELF criteria, and 64% were double refractory to anti-CD20 antibody and an alkylator. In pts with 2L FL, median (range) age was 53 y (34-69), 74% had Ann Arbor stage III/IV disease, 30% were high risk per FLIPI, 52% had POD24, 70% met mGELF criteria, and 48% were double refractory to anti-CD20 antibody and an alkylator. Median (range) on-study follow-up was 30.0 mo (0.3-39.6) for 3L+ and 29.5 mo (1.0-38.2) for 2L. For 3L+, ORR and CR rate (95% CI) were 97.1% (91.7-99.4) and 94.2% (87.8-97.8), respectively; for 2L, ORR and CR rate were both 95.7% (78.1-99.9). In 3L+ and 2L pts, medians continued to be not reached for all time-to-event analyses. In 3L+ pts, 24-mo (95% CI) DOR was 74.6% (64.8-82.1), PFS was 72.5% (62.7-80.1), OS was 88.2% (80.1-93.1), probability of TTNT was 80.1% (70.8-86.7), and probability of PFS2 was 76.6% (57.7-87.9). In 2L pts, 24-mo (95% CI) DOR was 86.4% (63.4-95.4), PFS was 82.6% (60.1-93.1), OS was 95.7% (72.9-99.4), probability of TTNT was 91.3% (69.5-97.8), and probability of PFS2 was 91.1% (68.8-97.7). Persistence of liso-cel transgene was observed up to Month 30 in 25% (7/28 pts) and 17% (1/6 pts) for 3L+ and 2L pts, respectively. PRO data showed durable improvements across domains for most pts. The safety profile with longer median follow-up was manageable and consistent with the primary analysis (18.9-mo median follow-up). As reported in the primary analysis, incidence of grade ≥ 3 cytokine release syndrome (CRS) was 1% (no grade 4/5), grade ≥ 3 neurological events (NEs) were 2% (no grade 4/5), and prolonged cytopenia was 22% (most recovered to grade ≤ 2 by Day 90). There were 9 pts who had second primary malignancies (7%; 7 in the 3L+ cohort and 2 in the 2L cohort), with 5 reported since the primary analysis (malignant melanoma, colorectal cancer, mucoepidermoid carcinoma, myelodysplastic syndrome, and basal cell carcinoma [1 each]). No secondary T-cell malignancies were reported. In the leukapheresed set, there were 16 on-study deaths, of which 1 occurred before liso-cel infusion and 2 occurred since the primary analysis due to PD, 1 pt each in the 3L and 4L+ cohorts. In patients who received liso-cel in the outpatient setting (n = 14; 3L+, n = 13; 2L, n = 1), no pts had experienced grade ≥ 3 CRS, NEs, or prolonged cytopenia at data cutoff. Conclusions: With 2-y follow-up in pts with 3L+ and 2L high-risk R/R FL who received a single administration of liso-cel, ORR and CR rates were above 94%, with sustained high rates of 24-mo DOR, PFS, and OS, and no new safety signals. These data support liso-cel as a highly efficacious and safe treatment option for pts with R/R FL.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.

AbstractPurpose: Significant progress has occurred in developing quantitative PET/CT biomarkers in diffuse large B-cell lymphoma (DLBCL). Total metabolic tumor volume (MTV) is the most extensively studied, enabling assessment of FDG-avid tumor burden associated with outcomes. However, prior studies evaluated the outcome of cytotoxic chemotherapy or chimeric antigen receptor T-cell therapy without data on recently approved FDA agents. Therefore, we aimed to assess the prognosis of PET/CT biomarkers in patients treated with loncastuximab tesirine. Experimental Design: We centrally reviewed screening PET/CT scans of patients with relapsed/refractory DLBCL enrolled in the LOTIS-2 (NCT03589469) study. MTV was obtained by computing individual volumes using the SUV ≥4.0 threshold. Other PET/CT metrics, clinical factors, and the International Metabolic Prognostic Index (IMPI) were evaluated. Logistic regression was used to assess the association between biomarkers and treatment response. Cox regression was used to determine the effect of biomarkers on time-to-event outcomes. We estimated biomarker prediction as continuous and binary variables defined by cutoff points. Results: Across 138 patients included in this study, MTV with a cutoff point of 96 mL was the biomarker associated with the highest predictive performance in univariable and multivariable models to predict failure to achieve complete metabolic response (OR, 5.42; P = 0.002), progression-free survival (HR, 2.68; P = 0.002), and overall survival (HR, 3.09; P < 0.0001). IMPI demonstrated an appropriate performance, however, not better than MTV alone. Conclusions: Pretreatment MTV demonstrated robust risk stratification, with those patients demonstrating high MTV achieving lower responses and survival to loncastuximab tesirine in relapsed/refractory DLBCL.

Therapies that demonstrate durable, long-term responses with manageable safety and tolerability are needed for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer, demonstrated single-agent antitumor activity in the pivotal phase II LOTIS-2 study in heavily pretreated patients with R/R DLBCL. Here we present updated efficacy and safety analyses from LOTIS-2, performed for all patients and in subsets of patients with a complete response (CR), including patients with CR who were event-free (no progressive disease or death) for ≥1 year and ≥2 years from cycle 1, day 1 of treatment. Lonca was administered every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles). As of the final data cutoff (September 15, 2022; median follow-up: 7.8 months [range, 0.3-42.6]), 70 of 145 (48.3%) patients achieved an overall response. Thirty-six (24.8%) patients achieved CR, of which 16 (44%) and 11 (31%) were event-free for ≥1 year and ≥2 years, respectively. In the all-treated population, the median overall survival was 9.5 months; the median progression-free survival was 4.9 months. Among patients with CR, median overall survival and progression-free survival were not reached, with 24-month overall and progression-free survival rates of 68.2% (95% CI: 50.0-81.0) and 72.5% (95% CI: 48.2-86.8), respectively. No new safety concerns were detected. With additional follow-up, Lonca continued to demonstrate durable, long-term responses with manageable safety and tolerability in patients with CR (clinicaltrials gov. Identifier: NCT03589469).

Diffuse large B-cell lymphoma (DLBCL) is