Given the rapidly evolving treatment landscape for diffuse large B-cell lymphoma (DLBCL), we performed a contemporary analysis of survival outcomes in patients aged ≥18 years with DLBCL at the population level using linked administrative data sets in Ontario, Canada (ICES). Among 8675 patients (median age, 67 years; 44% female) treated with frontline rituximab-based therapy, 1675 (19%) were treated with second-line therapy (2L). The 2-year and 5-year overall survival (OS) from 2L were 33% and 26%, respectively. Univariate analysis demonstrated that curative-intent therapy (autologous stem cell transplantation [ASCT]) (58% of patients) was associated with better OS than palliative radiotherapy (hazard ratio [HR], 0.56; P < .0001). Patients aged ≥60 years showed inferior OS than those aged <60 years (age 60-69 years: HR, 1.35; P =.0002; aged 70-79 years: HR, 1.64; P < .0001; age ≥80 years: HR, 2.08; P < .0001). In addition, early relapse was associated with worse outcomes than relapses occurring after 2 years (<3 months: HR, 1.45; P =.0002; 3-6 months: HR, 1.51; P =.0001; 6-12 months: HR, 1.88; P < .0001). Multivariable analysis confirmed these associations while accounting for lactate dehydrogenase, comorbidity burden, frailty, and income. Exploratory analysis indicated that third-line chimeric antigen receptor T-cell (CAR-T) therapy was associated with improved outcomes compared to a historical cohort of patients treated with palliative therapy before 2020 (2-year OS 56% vs 21%). This population-based analysis suggests that curative-intent therapy (ASCT and CAR-T) is associated with improved OS over conventional treatment approaches. The outcomes presented here provide benchmarks for future analyses aimed at assessing the effects of novel treatments in the 2L on outcomes.

Purpose Many patients with primary mediastinal B-cell lymphoma (PMBCL) achieve only a partial metabolic response (PMR) after initial systemic therapy. However, limited data exist on their outcomes. This study aimed to characterize outcomes in patients with PMBCL who achieve PMR and identify factors guiding appropriate treatment for these patients. Methods and Materials We reviewed patients PMBCL patients treated at 2 independent cancer centers from January 2009 through September 2021. Using the modified Lugano criteria (2014), end-of-chemotherapy positron emission tomography (PET) scan results were evaluated to assess response. Progression-free survival (PFS) and overall survival (OS) rates from the end-of-chemotherapy PET scan date were estimated using the Kaplan-Meier method. Results A total of 151 patients with PMBCL aged between 15 and 65 years were initiated on systemic therapy and underwent a fluorodeoxyglucose PET scan to evaluate response. Of these, 55 (36%) achieved incomplete metabolic response (IMR) (Deauville score [DS] 4 or 5): 13 (8%) progressed on systemic therapy (a DS score of 5), and 42 (27%) achieved a PMR (a DS score of 4). The 4-year PFS and OS rates for all patients (N = 55) with IMR were 73% and 72%, respectively. PMR management included consolidative radiation therapy (RT) in 36 patients (86%), further chemotherapy in 3 patients (7%), and observation in 3 patients (7%). Four-year PFS and OS among all patients with PMR were 83% and 81%, respectively, and 89% and 87% among those receiving RT. Patients with PMR with maximum standard unit value (SUVmax) > 5 had a lower 4-year PFS (74%) compared with those with SUVmax ≤ 5 (95%), although this difference did not achieve statistical significance (P = .07). None of the 3 patients with PMR under observation relapsed. Conclusions Patients with PMBCL often have an IMR. PMR (a DS score of 4) managed with subsequent RT is associated with excellent outcomes. SUVmax may identify patients who may require more or less intensive treatment.

Adult T-cell leukaemia/lymphoma (ATLL) is a rare, aggressive haematological malignancy linked to human T-cell leukaemia virus type I (HTLV-1) and associated with poor outcomes. Despite its higher prevalence in HTLV-1-endemic regions, the relationship between clinical characteristics and patients' sociocultural background remains underexplored. We retrospectively analysed 79 ATLL patients treated at our institution (1993-2023). The median age at diagnosis was 47 years, and 72% of patients were of Caribbean origin. Median progression-free and overall survival were 10.2 and 16.2 months, respectively, with only five patients receiving allogeneic stem cell transplantation. Central nervous system (CNS) involvement at diagnosis occurred in 22% of patients and was associated with worse outcomes, while 14% experienced CNS relapse within a median of 4.9 months. Using the Ontario Marginalization Index, we found higher levels of material, household/dwelling and racialized/newcomer-related marginalization compared to the general Greater Toronto Area population, though these factors were not linked to poorer outcomes. Our findings reveal that ATLL patients in this cohort were predominantly of Caribbean descent, presented at a young age and faced significant CNS involvement and poor survival outcomes, underscoring ATLL as an unmet clinical need.

Outcomes following CD19 chimeric antigen receptor (CAR) T-cell therapy in third-line treatment and beyond for patients with large B-cell lymphoma (LBCL) refractory to both an anthracycline during initial and platinum-based salvage therapy, referred to as double refractory (DR), are not well-described. It is also unclear if these patients may be less likely to proceed to CAR T-cell infusion. Our objectives were to assess third-line CAR T-cell survival outcomes in DR- and non-DR (NDR)-LBCL cohorts including the failure rates to proceed to cell infusion. Review of 199 patients with LBCL referred for CAR T-cell treatment at our center, demonstrates that the DR-LBCL patients (n = 68) have an inferior 12-month (overall survival [OS], 47.1% vs 66.7%, respectively;) when compared to the patients with NDR-LBCL (n = 131). This OS difference is driven by a higher failure rate to proceed to CAR T-cell infusion (32% vs 18%). For patients unable to proceed to CAR T-cell infusion median OS was 2.56 months; DR-LBCL 1.94 months vs NDR-LBCL 3.42 months. The 12-month OS (65% vs 72.3%) and 6-month progression-free survival (46.5% vs 57.2%) of patients with DR- and NDR-LBCL proceeding to CAR T-cell infusion, appears similar. Our study highlights a high-risk subgroup characterized by inferior OS with challenges in getting to CAR T-cell infusion and could benefit from different management approaches such as novel bridging or "off-the-shelf" strategies.

BACKGROUND:Given the intensive resources required to conduct economic analyses in clinical trials, a key need is identifying scalable measures of costs. Contact days-days with health care contact outside the home-may represent such a practical measure. METHODS:We conducted a secondary analysis of a trial that evaluated two pre-transplant chemotherapy regimens for lymphoma. We used trial resource use and patient-reported data to calculate contact days, direct costs, and indirect costs such as lost productivity. We assessed the association between the number of contact days and cost outcomes using linear regression models and Pearson correlation coefficients. RESULTS:Contact days were moderately correlated with direct costs (r = .47, $762/ contact day, P < .0001), and strongly correlated with direct costs in the DHAP arm (r = 0.60, $727/ contact day, P < .0001). Contact days were very weakly correlated with pooled indirect costs (r 0.19, $60/ contact day, P = .0003). Among the 3 indirect cost outcomes, the relationship was strongest with paid caregiving hours (r = 0.33, 1.8 hours/ contact day, P < .0001) and weakest for unpaid hours provided by informal care partners (r = .06, .7 hours/ contact day, P = .247). Results were robust when zeroing out costs of hospitalization in the arm receiving inpatient chemotherapy and when evaluating indirect costs among patients working full-time. CONCLUSIONS:Contact days have the potential as a surrogate measure of direct health system costs, which deserves further exploration. The weak correlation with indirect cost outcomes suggests that the extent of true patient and care partner burdens extends beyond just the number of contact days.Trial registration: ClinicalTrials.gov Identifier: NCT00078949.

PURPOSE:Although deep targeted DNA sequencing of liquid biopsies has shown prognostic utility in large B-cell lymphoma (LBCL), the routine clinical adoption of these assays remains limited because of their high costs. MATERIALS AND METHODS:Here, leveraging a well-annotated cohort encompassing both frontline and relapsed/refractory (R/R) LBCL, we profiled patient plasma samples with two complementary modalities-ultra-low-pass whole-genome sequencing (ULP-WGS) and deep targeted DNA sequencing, the former being a cost-effective method to profile large scale chromosomal abnormalities and estimate tumor burden. RESULTS:Our findings revealed a strong association of high cell-free tumor burden by both genomic profiling modalities with established measures of tumor burden and patient survival. Notably, the associations with survival remained statistically significant after accounting for international prognostic index scoring. Furthermore, we showed that del(17p) in circulating tumor DNA as detected by ULP-WGS was strongly associated with TP53 mutation status and predicted for significantly inferior outcome in frontline LBCL patients but not in patients with R/R LBCL. CONCLUSION:Our study demonstrates that ULP-WGS can provide robust prognostic biomarkers for both frontline and R/R LBCL, highlighting its broad applicability for risk stratification.

Background The frontline treatment of patients with symptomatic mantle cell lymphoma (MCL) requiring treatment varies in practice. In Ontario, Canada, transplant-eligible (TE) patients have been treated with chemoimmunotherapy followed by autologous stem cell transplant (ASCT). In 2013, R-CHOP alternating with R-DHAP prior to ASCT replaced R-CHOP alone as standard of care based on the European MCL Younger trial (Hermine JCO 2022). Although this regimen improves progression-free survival, there remains concern about its toxicity. For transplant-ineligible (TI) patients, the standard of care has evolved over time. Evidence in support of bendamustine-rituximab (BR) efficacy in indolent lymphoma resulted in its increased use in TI patients with MCL over the last decade. However, real-world data are lacking on toxicities of this regimen compared to other chemoimmunotherapy. We aimed to characterize survival and healthcare utilization outcomes of patients with MCL using current treatment approaches. Methods We conducted a retrospective population-based study of patients with MCL using healthcare administrative databases from Ontario, Canada, from 2005 to 2020. Patients were defined as TE if they were less than 70 years old at the time of treatment initiation, and received either R-CHOP or R-CHOP/R-DHAP. Patients were defined as TI if they were 70 years or greater at the time of treatment initiation, and treated with BR or other forms of chemoimmunotherapy. The primary outcome was 5-year overall survival (OS), from the time of first treatment to death or end of the study period. Secondary outcomes were toxicities of treatment and healthcare utilization. Cox regression analyses were used to assess the impact of demographic and treatment variables on OS. Results A total of 918 patients with MCL were included in this study; 426 were TE and 492 TI. For TE patients, 254 were treated with R-CHOP, and 172 with R-CHOP/R-DHAP. The median age of patients in both groups was 60 years (range 36-70 years, p=0.37). Patients treated with R-CHOP alone were followed for a mean of 6.01 years, and patients treated with R-CHOP/R-DHAP for a mean of 3.38 years. Maintenance rituximab (MR) was used in 70.5% of patients treated with R-CHOP and 77.3% of patients treated with R-CHOP/R-DHAP (p=0.12). ASCT was received by 53.5% of patients treated with R-CHOP and 83.7% of patients treated with R-CHOP/R-DHAP (p<0.01). 5-year OS of patients treated with R-CHOP/R-DHAP was 70.5% vs 62.0% for patients treated with R-CHOP regardless of transplant status ( Figure 1A hazard ratio [HR] 0.75, 95% CI 0.51-1.10). Of the 270 patients who received ASCT within 1 year of treatment initiation, survival was not impacted by prior receipt of R-CHOP alone or R-CHOP/R-DHAP (HR for R-CHOP/R-DHAP vs. R-CHOP 0.76, 95% CI 0.42-1.39). A higher proportion of patients treated with R-CHOP/R-DHAP required hospital admissions for fever, infection, neutropenia, and renal toxicity, compared to R-CHOP alone ( Table 1). There was no difference between regimens in the number of patients requiring emergency department (ED) visits between regimens (p=0.39). 492 TI patients were included; 303 treated with BR and 189 treated with other regimens, most commonly R-CHOP (n=62) or R-CVP (n=108). The median age of patients in both groups was 77 years (range 71-94 years, p=0.17), and there was no significant difference in comorbidities (p=0.23). MR was more commonly used after BR compared to historical regimens (72.6% vs. 54.5%, p<0.01). 5-year unadjusted OS of patients treated with BR was 40.3% and 27.5% for patients treated with R-CHOP/R-CVP ( Figure 1B), with significantly lower mortality with the use of BR (HR 0.68, 95% CI 0.51-0.89). After adjusting for age, sex, comorbidities, and MR, this was no longer significant (HR 0.86, 95% CI 0.65-1.14). MR use was associated with significantly lower mortality (HR 0.33, 95% CI 0.24-0.44). More patients treated with BR had hospital admissions for neutropenia and febrile neutropenia ( Table 1). Conclusion In this large population-based study of patients with MCL, R-CHOP/R-DHAP prior to ASCT showed a trend toward improved 5-year OS, though not significant. For TI patients, BR resulted in superior OS compared to other regimens with similar rates of toxicities, however this was not significant after adjusting for use of MR, suggesting other regimens followed by MR may be a reasonable alternatives.

The tissue architecture of classic Hodgkin Lymphoma (CHL) is ｕｎｉｑｕｅ among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities. ### Competing Interest Statement T.A. declares no competing financial interests. C.S. has performed consultancy for Bayer and has received research funding from Epizyme and Trillium Therapeutics.

Background Chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory large B-cell lymphoma (R/R LBCL) is now standard of care in Canada. Only a limited number of centres provide this therapy. There are limited data on disparities related to social determinants on outcomes and influence on access. Purpose The aim of this study was to assess the impact of socioeconomic status, as measured by the Ontario Marginalization Index (ON-Marg), on the likelihood of undergoing CAR-T after referral and treatment outcomes in patients with R/R LBCL. This was a retrospective review of patients 18 years or older with R/R LBCL referred from Ontario centres to Princess Margaret Cancer Centre (PM) between April 2020 and November 2023 for CAR-T therapy. The ON-Marg consists of four dimensions: material resources (MR), racialized and newcomer population (RN), age and labor force (AL), and household and dwellings (HD). Descriptive statistics were used to analyze baseline characteristics and the four dimensions of ON-Marg. Each dimension was divided into quintiles, ranging from 1 (low marginalization) to 5 (high marginalization). Need for interpreter at consent, rural vs urban setting, and median household income determined by national census data were also explored. The cohort was grouped into median household income tertiles of <$83000, $83000-104000 and >$104000, which were chosen to allow for similar size cohorts. Results We included 163 patients; 77% received CAR T-cell therapy while 23% did not. The median age was 60 years (range: 20-81), and 64% were male. The median follow-up was 17.51 months (95% CI 14.69-21.26). Our analysis showed no significant disparities in the likelihood of receiving CAR T-cell therapy across the quintiles of the four marginalization dimensions. In terms of the MR, 24% of the patients who underwent CAR T-cell treatment were allocated in quintile 1, 67% in quintiles 2-4, and 9% in quintile 5. Among the patients who did not, 22% were in quintile 1, 68% in quintiles 2-4, and 11% in quintile 5 (p=0.91). Similarly, in the RN dimension, 14% of the patients who received treatment were in quintile 1, 63% in quintiles 2-4, and 23% in quintile 5. Among those who did not receive it, 14% were in quintile 1, 62% in quintiles 2-4, and 24% in quintile 5 (p=0.98). In the AL dimension, quintile 1 accounted for 19% of the patients who received CAR T-cell therapy, quintiles 2-4 for 60%, and quintile 5 for 21%. For the patients who did not receive treatment, quintile 1 was 22%, quintiles 2-4 were 51%, and quintile 5 was 27% (p=0.66). For the HD dimension, quintile 1 consisted of 26% of patients who received treatment and 27% who did not, quintiles 2-4 had 56% and 41%, and quintile 5 had 17% and 32% respectively (p=0.11). No significant delays among marginalization groups were found in terms of the time from referral to the initial appointment (all p>0.05), the date of the initial appointment to the date of infusion (all p>0.05) or the date of progression to the date of infusion (all p>0.05). Of the 126 patients who received CAR T-cell therapy, there were 39 deaths from all causes, with a 12-month overall survival (OS) rate of 63.8%. OS outcomes did not show any significant differences between marginalization groups in any of the four dimensions that were evaluated (MR p=0.52, RN p=0.53, AL p=0.77, HD p=0.70). There were no significant OS differences between urban/rural patients (p=0.21), use of interpreter (p=0.42) or by income tertile (p=0.37). There were 74 events of progression or death, with a 12-month progression free survival (PFS) rate of 43.3%. Similar to the OS analysis, PFS did not reveal any significant differences among marginalization groups (MR p=0.077, RN p=0.62, AL p=0.81, HD p=0.51). There were no significant PFS differences between urban/rural patients (p=0.32), use of interpreter (p=0.37) or by income tertile (p=0.36). CRS and ICANS were observed in 86% and 29% of the patients. No significant differences in these toxicities were found when evaluated based on the different marginalization groups, income tertiles, use of interpreter and urban/rural status. Conclusions This study did not find any statistically significant evidence of an impact of socioeconomic status on the likelihood of receiving CAR T-cell therapy or on treatment toxicity or outcomes in a single payer universal health care system. A limitation requiring further analysis is only referred patients were included.

Background Glofitamab, a bispecific antibody with a novel 2:1 (CD20:CD3) format, has shown a high rate of durable complete responses (CRs) and manageable safety in patients with heavily pretreated R/R MCL in a Phase 1/2 study (NCT03075696; Phillips et al. ASH 2022). Here we report updated efficacy and safety data. Methods Patients received obinutuzumab pretreatment (Gpt; 1000mg or 2000mg) 7 days before their first glofitamab dose. Fixed-duration glofitamab was administered intravenously with step-up dosing in Cycle (C)1 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (16mg or 30mg) from C2D1 up to C12. Efficacy endpoints: CR, overall response rate (ORR), duration of CR (DOCR), duration of response (DOR), and progression-free survival (PFS). All patients provided informed consent. Results As of September 4, 2023, 61 patients were enrolled; 60 patients received study treatment (1000mg Gpt, n=16; 2000mg Gpt, n=44). Median number of prior line(s) of therapy (LOT) was 2 (range: 1–5); 73.3% of patients were refractory to the last LOT. Median duration of glofitamab therapy was 7.4 months, and median number of cycles was 12. Of 31 patients who received prior Bruton's tyrosine kinase inhibitor (BTKi) therapy, 29 (93.5%) were BTKi refractory, and 90.0% were refractory to the last LOT. ORR and CR rate were 85.0% and 78.3%, respectively. Median DOCR was 15.4 months; the majority of CRs (28/47; 59.6%) were ongoing at data cut-off. Estimated 12-month DOCR and DOR rates were 71.0% and 66.6%, respectively. Median PFS was 16.8 months (median follow-up: 17.2 months). In post-BTKi patients, ORR and CR rate were 74.2% and 71.0%, respectively. Median DOCR was 12.6 months; median PFS was 8.6 months (median follow-up: 26.1 months). No new safety signals were observed. Cytokine release syndrome was the most common adverse event (42/60, 70.0% [1000mg Gpt, 87.5%; 2000mg Gpt, 63.5%]; Grade 1/2, 58.3%). Conclusions Fixed-duration glofitamab induced durable responses beyond end of treatment and had a manageable safety profile in patients with R/R MCL.

Background Anti-CD19 Chimeric Antigen Receptor T-cell (CAR-T) immunotherapies have been funded in Canada for patients with relapsed-refractory large B-cell lymphoma (RR LBCL) after two lines of systemic therapy since December 2019. However, real-world evidence of CAR-T outcomes has been limited to small series with little comparison to prior standard-of-care management. We compared overall survival (OS), adverse events, and healthcare utilization for a cohort of patients with RR LBCL consecutively treated with CAR-T versus a cohort of historical controls treated with standard-of-care therapy prior to CAR-T approval. Methods This is a propensity-weighted retrospective cohort study of patients with RR LBCL treated at Princess Margaret (PM) Cancer Centre. Using linked clinical and administrative datasets, consecutive patients treated with CAR-T (2020-2022) following provincial funding approval were compared to a matched cohort of historical controls (2012-2017). Patients were followed from index date, defined as the date of progression following 2 lines of chemotherapy (2L) in the historical controls and following last therapy (2L or higher) in the CAR-T patients for up to 3-years, with maximum follow-up to March 31, 2023. Stabilized inverse probability treatment weighting (sIPTW) was used to account for confounding between cohorts (age, sex, lactate dehydrogenase, and comorbidities). Kaplan meier curves and IPTW-weighted Cox proportional hazard regression analyses estimated the adjusted hazard ratio (HR) between treatment cohort and OS. A landmark survival analysis of patients alive at 3 months post-index date addressed immortal time bias. Adverse events (AEs) from inpatient/emergency department [ED] diagnoses and healthcare utilization were reported per 1000 person-days at risk. Results A total of 86 CAR-T patients and 150 historical control patients were evaluable for comparison. Variables were balanced after applying the sIPTW (based on standardized difference <0.1); mean age was 56 years and males comprised 61%. Prior treatment included ASCT in 27.6% CAR-T vs 38.4% historical control patients (standardized difference 0.21; p=0.09). Post-2L progression, 58% of historical controls had no further treatment, 32% received intravenous or oral chemotherapy/targeted agents, 6.2% had an autologous stem cell transplant, and 10% received palliative chemotherapy and/or radiotherapy. CAR-T patients received tisagenlecleucel (33.3%) and axicabtagene ciloleucel (66.7%) CAR-T products. The OS probabilities at 1-, 2-, and 3-years were 68% (95% CI 53-79%), 60% (95% CI 44-73%), and 57% (95% CI 39-71%), respectively, in the CAR-T group, and 18% (95% CI 12-25%), 11% (95% CI 7-17%), and 10% (95% CI 5-16%), respectively, in the control group. The IPTW-adjusted HR for all-cause death was 0.22 (95% CI 0.15-0.33), and landmark survival analysis for all-cause death 3-months post-index date to end of follow-up generated a similar HR of 0.28 (CI 0.19-0.44) in the CAR-T group. CAR-T patients had a lower number of days hospitalized (77.73 [95% CI 75.00-80.57] vs 86.11 [95% CI 83.12-89.21] per 1000 person-day; p<0.001), ICU admissions (0.55 [95% CI 0.36-0.84] vs 1.26 [95% CI 0.94-1.69] per 1000 person-day; p=0.001), and ED visits (4.79 [95% CI 4.10-5.61] vs 2.07 [95% CI 1.65-2.60] per 1000 person-day; p<0.001). Additionally, CAR-T patients had lower events per 1000 person-days of: infection (1.44 [95% CI 1.10-1.87] vs 3.02 [95% CI 2.50-3.64] p<0.001), neutropenia (0.65 [95% CI 0.44-0.96] vs 1.79 [95% CI 1.4-2.29]; p<0.001), febrile neutropenia (0.45 [95% CI0.28-0.72] vs 1.47 [95% CI 1.12-1.92]; p<0.001), gastrointestinal toxicity (0.26 [95% CI 0.14-0.49] vs 0.69 [95% CI 0.46-1.02]), and respiratory infections (0.51 [95% CI 0.33-0.79] vs 0.91 [95% CI 0.65-1.29]; p=0.04). Conclusions CAR T-cell therapy produced a significant and sustained survival benefit versus historical standard-of-care management, with fewer hospitalizations and infections. Despite well-described CAR-T toxicities, historical control patients had more AEs, underscoring the lack of other effective salvage treatments. This study describes one of the largest real-world comparisons of patients with RR LBCL receiving CAR T-cell therapy compared to previous standard-of-care therapies and demonstrates its effectiveness amongst a broad cohort of eligible patients, consistent with the results of pivotal trials.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Background: Princess Margaret (PM) is the referral centre for antiCD19 CAR T-cell therapy (CART) for a large regional population and currently treats patients from other provinces in Canada. Better understanding of early CART failure may inform selection criteria. Purpose: We evaluated outcomes of all patients referred for CART and explored risk factors for early failure, as defined by failure to receive cells, death within 100 days of infusion or progressive disease (PD) prior to or at day 100 response assessment. Methods: This is a single-centre retrospective review of consecutive adult patients with RR-LBCL referred for CART at PM from April 2020-November 2023 for > 3rd line therapy. Outcomes included progression-free survival (PFS) defined from date of cell infusion/ date of intake (for pts that failed to proceed with CART (PFPC)) to PD/death/last follow-up. Overall survival (OS) defined from date of cell infusion/date of intake (for PFPC) to death/last follow-up. To identify predictors for early failure, a univariate analysis examining the early failure and non-early failure cohort was conducted. Variables examined included: age, stage, ECOG, presence of bulky disease (>7 cm), relapsed vs. refractory, lymphoma subtype, cell of origin, presence of double hit or triple hit lymphoma, and failure to undergo ASCT. Metrics to infusion were examined including dates of CT demonstrating progression post 2L+ therapy, intake, apheresis and infusion. Results: 263 pts were referred for CART during the study period. 192 underwent CART (tisa-cel 47, axi-cel 145) and 71 were referred but did not undergo CART. Of these 71, 14 were found to be ineligible for CART at intake and were excluded. ITT analysis included 57 pts who did not receive CART. For the 57 pts who did not proceed with CART, reasons for not proceeding were identified in 56. Reasons included: patient factors (choice 12(21%), poor functional status 7(13%)), product factors (collection 2(4%), manufacturing 5(9%) and disease factors (progression 22(39%), active CNS disease 5(9%), death 3(5%)). 52% did not proceed with apheresis. Median time from date of progression noted on CT to intake appt was 19 days for tisa-cel (0-177) and 16.5 days for axi-cel (0-113). Median time from date of progression noted on CT to infusion was 50 days (19-100) for tisa-cel and 44 days (28-89) for axi-cel. Median time from apheresis to infusion was 43 days (35-107) for tisa-cel and 33 days (27-74) for axi-cel. There were no significant differences in median days from progression noted on CT to intake or referral to intake between early failure and non-early failure cohorts 15 v. 18 (p=0.603) and 10 v. 8.5 (p=0.128). Response at 100 days post CART was assessed in 192 pts. 83 achieved CR/CMR (43%), 25 achieved PR (13%), 64 (34%) experienced progression, and 2(1%) died before 100 days from toxicity (ICH, frailty post ICU for ICANS); and 100-day status was unknown/pending in 18(9%) patients and were censored. Median follow up time for all patients receiving CART was 12.02 mos (6.28-17.38) from infusion to censored. Median OS for the cohort receiving CART was not reached. 12-month OS for whole CART cohort, tisa-cel and axi-cel cohorts respectively were 66.9% (95% CI 58.9,76), 55.9% (95% CI 42.3, 73.7) and 72.8% (95% CI 63.7,83.2). Median PFS for all infused patients was 8.2 mos (95% CI 1.28, NYR). Median OS for the ITT cohort (CART and no CART) was 57.7 months (95% CI 50.5, 65.8) from intake date with median follow up 13.44 mos (95% CI 7.79,18.5). Median OS for the CART and no CART cohort was 68.8 mos (95% CI, 60.9,77.6) and 12.4 mos (95% CI 5.3, 28.9). A univariate analysis of predictors for early failure was conducted. Those with unknown status at Day 100 were excluded. 234 referred pts were included for analysis and 121(52%) pts met the definition of early failure. Of those who experienced early failure post CART, 62 pts (97%) experienced relapse and 2 pts (3%) died from toxicity. ECOG 2+ at intake (p=0.011) was identified as a predictor. Refractory disease (p=0.056) and presence of double /triple hit lymphoma (p=0.059) trended close to significance. Conclusions: We present the early experience with SOC CART for RR-DLBCL from a large tertiary Canadian centre. Limited RW cohorts have provided ITT results. A large proportion of referred patients experienced early failure, with 23% not receiving CART and 52% experiencing early failure. Novel strategies are required to better outcomes in those at risk of early failure.

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.