Citations

Abstract Patients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have “primary refractory disease.” However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.

Abstract Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

SummaryMultiagent chemoimmunotherapy remains the standard of care treatment for Burkitt lymphoma leading to a cure in the majority of cases. However, frontline treatment regimens are associated with a significant risk of treatment related toxicity especially in elderly and immunocompromised patients. Additionally, prognosis remains dismal in refractory/relapsed Burkitt lymphoma. Thus, novel therapies are required to not only improve outcomes in relapsed/refractory Burkitt lymphoma but also minimize frontline treatment related toxicities. Recurrent genomic changes and signalling pathway alterations that have been implicated in the Burkitt lymphomagenesis include cell cycle dysregulation, cell proliferation, inhibition of apoptosis, epigenetic dysregulation and tonic B‐cell receptor‐phosphatidylinositol 3‐kinase (BCR‐PI3K) signalling. Here, we will discuss novel targeted therapy approaches using small molecule inhibitors that could pave the way to the future treatment landscape based on the understanding of recurrent genomic changes and signalling pathway alterations in the lymphomagenesis of adult Burkitt lymphoma.

Abstract Background Although CAR T-cell therapy has achieved remarkable response in patients (pts) with B-cell non-Hodgkin’s lymphoma (NHL), 20-30% of pts still have primary refractory disease (PD1), and another 30-40% relapse (PD2). We and others have shown that monocytes can modulate T-cell functions and impact clinical response to chemoimmunotherapy in NHL. Given that monocytes nadir and recovery kinetics differ from lymphocytes post lymphodepletion chemotherapy, we hypothesize that monocyte phenotype at peak CAR-T expansion and in the early month post CAR-T can modulate immune responses. Methods scRNAseq were performed on peripheral blood mononuclear cells of NHL pts prior to lymphodepletion chemotherapy (pre), at peak CAR-T expansion (peak), and one month following CAR-T (M1). Seurat v4.3.0 was used for unsupervised hierarchical clustering analysis. Lugano criteria was used to determine clinical responses which were categorized as CR (complete remission), PD1, or PD2. Results We analyzed 129,981 monocytes from 77 samples of 32 pts (16 CR, 4 PD1, 12 PD2) and 5 healthy controls. Unsupervised hierarchical clustering analysis identified 13 monocyte clusters: 4 classical monocyte (CM) clusters with transcriptome profiles for enriched signaling in IL-6, TGFβ, EMT, and p53; 2 intermediate monocyte (IM) clusters enriched for IL-1 or CD38 signaling; 2 non-classical monocytes (NM), one with increased CD36 expression; 3 monocytic MDSC clusters with enrichment of TGFβ, SIRPα, and HIF1α signaling; and 2 lymphoma-associated monocytes, expressing CD163 or CD169. At Pre and Peak, the distribution of the monocyte clusters was similar in pts with CR, PD2, or PD1, with only a slight decrease in the percent of NM in the PD2 group at Pre and slight increase of CD36 NM in PD1 at Peak. Compared to Pre, all pts had increased percent of CD36 NM and IL-1 IM at Peak. Interestingly, while the distribution of monocyte clusters was similar at Pre and Peak across clinical responses, GSEA showed that monocytes in CR pts, compared to PD1 and PD2, had gene expression enrichment of MYC target V2 pathway at Pre and TGFβ pathway at Peak. At M1, pts in PD1 had increased percent of p53 and TGFβ CM and decreased percent of NM. In contrast, pts with CR had decreased percent of IL-6 CM, p53 CM, TGFβ CM, IL-1 IM and increased percent of NM. Notably, as pts with CR and PD2 may appear similar clinically at M1, pts with PD2, compared to CR, have increased IL-6 CM, IL-1 IM, and decreased NM. In addition, GSEA showed that PD2 pts had increased IFNα response. Our results demonstrate that monocyte phenotype differences at Pre and Peak could be associated with CAR-T clinical response, and that persistent inflammatory monocyte signaling at M1 in pts with clinical response is associated with relapse. These data suggest a role for development of monocyte biomarkers to predict response and therapeutic targeting. Citation Format: Andre de Menezes Silva Corraes, Panwen Wang, Radhika Bansal, Henan Zhang, Zuoyi Shao, Kevin Regan, Eider Moreno Cortes, Arushi Khurana, Nora Bennani, Yucai Wang, Paul Hampel, Jonas Paludo, Patrick Johnston, Hemant Murthy, Madiha Iqbal, Stephen Ansell, Javier Munoz, Allison Rosenthal, Mohamed Kharfan-Dabaja, Januario Castro, Saad Kenderian, Haidong Dong, Ying Li, Yi Lin. Monocyte transcriptome profiles associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19-directed CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4001.

Abstract Background: Although CAR T-cell therapy has achieved remarkable response rates in adult patients (pts) with relapsed and refractory B-cell non-Hodgkin’s lymphoma (NHL), 20-30% of pts still have primary refractory disease, and 30-40% of pts relapse, often within 6 months of therapy. Given that durable clinical response can be achieved without CAR T cell persistence, we hypothesized that durable remission is correlated with the expansion of tumor-reactive T-cell receptor (TCR) clones following CAR T-cell infusion. To assess this, we examined the TCR repertoire of adult pts with B-NHL who received CD19 CAR T-cell (axi-cel) therapy to identify correlates of clinical response. Methods: Single-cell (sc) RNA sequencing (seq) and scTCR-seq were performed on peripheral blood mononuclear cells from B-NHL pts before lymphodepletion chemotherapy (pre), at peak CAR-T expansion (peak), and one month following CAR-T (M1). scRNAseq and scTCR-seq data were processed using CellRanger v7.0.1, which were then analyzed using Immunarch (v0.9.0) for TCR clonality and sample diversity. Diversity was assessed using the Gini coefficient to indicate clone size inequality (0 = maximum diversity). TCR diversity and phenotype of expanded and emerged TCR clones post CAR-T were compared across clinical response categories: CR (complete remission for at least 6 months), PD1 (primary refractory), and PD2 (relapsed after partial or complete response). Results: We analyzed 107,035 T cells from 77 serial samples of 32 pts (16 CR, 4 PD1, 12 PD2) and 5 healthy controls. Compared to pts with PD1 and PD2, pts with CR had a larger Gini coefficient for TCR clones at M1 relative to Pre and Peak. The Gini coefficient was the largest for tumor recirculating CD8 T effector memory (Tem) and activated CD8 peripheral memory (Tpm) cells at M1 for pts with CR. Examining the repertoire of emerged and expanded TCR clones at Peak and M1 from Pre, pts with PD2, compared to pts with CR, had a higher percentage of activated CD8 T peripheral memory (Tpm) and T regulatory cells (Treg) among the emerged clones and activated CD8 Tpm among the expanded clones. Patients with PD1, relative to patients with CR, had more proliferating and non-activated CD8 Tpm among the expanded and emerged clones. Conclusion: NHL pts with CR after CAR-T had more robust clonal expansion of T cells, particularly tumor recirculating CD8 Tem and activated CD8 Tpm, compared to pts with relapsed or refractory disease. In contrast, pts with relapsed or refractory disease had an expansion of TCR clones with a larger proportion of CD8 Tpm and Tregs. Endogenous tumor-reactive TCR expansion may help predict favorable clinical response following CAR T-cell therapy. Citation Format: Aiman J. Faruqi, Panwen Wang, Radhika Bansal, Andre De Menezes Silva Corraes, Henan Zhang, Zuoyi Shao, Kevin Regan, Eider Moreno Cortes, Arushi Khurana, Nora Bennani, Yucai Wang, Paul Hampel, Jonas Paludo, Patrick Johnston, Hemant Murthy, Madiha Iqbal, Stephen Ansell, Javier Munoz, Allison Rosenthal, Mohamed Kharfan Dabaja, Januario E. Castro, Saad Kenderian, Haidong Dong, Ying Li, Yi Lin. T-cell receptor repertoire changes associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19 CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 53.

Introduction: In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in R/R LBCL, 11% and 31% of patients (pts) experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic evenets), respectively. To minimize the toxicities seen with axi-cel, a safety management cohort, Cohort 6 (N=40), was added to evaluate whether prophylactic (ppx) corticosteroids (CS) could decrease grade ≥ 3 CRS or ICANS. The 2-year update of ZUMA-1 Cohort 6 showed no grade ≥3 CRS and 15% grade ≥3 ICANS without any difference in objective response rate (ORR) or complete response rate (CR) when compared to cohorts 1+2 (Oluwole Blood 2022). The FDA had previously approved an update to the prescribing information for axi-cel to include use of ppx CS across all approved indications in January 2022. However, ppx CS is not a mandatory standard treatment and we sought to establish the clinical outcomes in the real-world practice. Methods: To assess the clinical outcomes of pts receiving ppx CS, we conducted a multicenter retrospective analysis of pts with R/R LBCL who were treated with axi-cel since the FDA approval of ppx CS in January 2022. Baseline characteristics, toxicities, and efficacy were compared between the no ppx and ppx CS groups. CRS and ICANS were graded based on ASTCT 2019 guidelines. Event-free survival (EFS) was defined as time from axi-cel infusion to progression, re-treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death due to any cause. Results: A total of 66 pts at 5 centers received axi-cel between Jan 31, 2022, and June 20, 2023. Thirty-five (52%) pts received ppx CS, with a median age of 63 years (26-85 years). By histology, 75% (n=50) of the pts had DLBCL, 13.6% (n=9) had high grade B-cell lymphoma (HGBL), 9.1% (n=6) had transformed follicular lymphoma (TFL) and 1.5% (n=1) primary mediastinal LBCL (PMBCL). 59% of the pts (n=37) had IPI >2 and 66% (n=43) had stage III/IV disease. The baseline characteristics at the time of apheresis are shown in Table 1 and were comparable between the 2 groups, except for more HGBL, fewer prior lines of therapy and longer median time from apheresis to axi-cel infusion in the ppx CS group. Among the entire cohort, only 37% (n=25) met ZUMA-1 eligibility criteria at the time of lymphodepletion, and 67% (n=44) needed bridging therapy. Any grade CRS occurred in 88% (n=58) of the pts, with grade ≥2 CRS in 38% (n=25). Any grade ICANS occurred in 55% (n=37) of the pts, with grade ≥2 ICANS in 41% (n=27). Any grade ICANS was significantly lower in the ppx CS group than the no ppx group (45.7% vs 65.5%). The rates of any grade CRS, grade ≥2 CRS, grade ≥2 ICANS, the median time to CRS onset, ICANS onset, CRS duration, and ICANS duration were comparable between the 2 groups. Tocilizumab and steroids use was similar between two groups with a trend towards less ICU admission in patients in the ppx CS group. Overall, 14 (21%) pts developed infectious complications within 30 days of axi-cel infusion. The day 30 ORR was 84% and was comparable between the 2 groups (77% in the ppx group vs 93% in the no ppx group). The CR was 45.7% in ppx CS group compared to 65.5% in no ppx group. At a median follow up of 219 days (27-1178), 37 (56.1%) pts had progressed and 25 (37.9%) pts had died. The number of days to progress was significantly lower in the ppx CS arm. The median EFS and OS were not significant between the 2 groups. Conclusions: This multicenter retrospective study showed that the efficacy of treatment with axi-cel in R/R LBCL did not decrease with the use of ppx CS. No significant differences in efficacy or CAR-T-associated toxicities were noted in the 2 groups, potentially due to selective use with patients at presumed higher risk of severe CRS and ICANS. A larger dataset and longer follow-up is needed for risk-stratified analysis and the study is ongoing.

Background: Although marginal zone lymphoma (MZL) typically exhibits an indolent course, transformation to diffuse large B-cell lymphomas (DLBCL) is associated with a poorer outcome and remains a clinical challenge in managing patients with MZL. The limited existing literature reports various cumulative incidence rates, ranging from 2.5% and 4.7% (Finnish Cancer Registry, 1995-2018) to 6.6% and 8.4% (Florida Cancer Registry, 1995-2016) at 5 and 10-years, respectively, likely in part driven by varying study designs, ascertainment, and study population. Similarly, reported outcomes after transformed MZL (tMZL) have been variable. We evaluated the cumulative incidence of histological transformation (HT) to LBCL in a well-characterized prospective cohort of MZL patients from the upper Midwest, USA, and overall survival (OS) after transformation. Methods: Patients ≥ 18 years old with newly diagnosed MZL were prospectively enrolled in the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) cohort from 2002-2015. Clinical and treatment data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death through 2022. Pathology was classified according to WHO 4/4R, including all transformations. The cumulative incidence of HT to LBCL was determined using death as a competing risk. Time to HT (TTHT) was defined as time from the date of MZL diagnosis to the date of transformation. We evaluated potential predictors of HT using a stepwise approach, and derived hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models. To assess predictors of OS after HT, patients ≥ 18 years old with newly diagnosed tMZL (into DLBCL) at Mayo Clinic between 1995 and 2002 (N=7) were combined with the MER cases. Results: We identified 524 patients with MZL in the MER cohort: 362 extranodal (EMZL; lung 18%, stomach 16%, orbit 13%, parotid 10%, skin 10%), 84 splenic (SMZL), and 78 nodal (NMZL). The median age at diagnosis was 63 years (range 18-92); 56% were female, and 83% were non-Hispanic white. During a median follow-up of 18.8 years (95% CI 16.7, NA), there were 25 HT (including 8 patients under observation) and 158 deaths. Eight Ten-year OS was 67% and 77% in the groups with and without HT, respectively. The overall cumulative incidence of HT was 1.5% at 2 years after diagnosis, 2.9% at 5 years, 4.5% at 10 years, and 5.7% at 15 years (Panel 1). The cumulative incidence of HT varied by subtype (e.g., at 5 years: 2%, 4% and 6%, in EMZL, NMZL and SMZL, respectively; Panel 2). The median time to HT also varied by subtype: 76 months (interquartile range (IQR) 43, 81) for EMZL, 30 months (IQR 16, 52) for SMZL, and 18 months (IQR 14, 23) for NMZL. In univariable analysis, predictors of HT were Stage III/IV (HR=3.4, 95% CI 1.36-8.53, p=0.009), elevated LDH (HR=2.98, 95% CI 1.25-7.12, p=0.014), and presence of ≥2 extranodal sites (HR=2.69, 95% CI 1.22-5.94, p=0.014). In multivariable analysis, elevated LDH was the only non-composite predictor of HT (HR=2.65, 95% CI 1.08-6.52, p=0.034). MALT-IPI score 2-3 (HR=3.61, 95% CI 1.06-12.25, p=0.040) and FLIPI score 3-5 (HR=2.19, 95% CI 1.22-8.22, p=0.018) also predicted HT. We analyzed OS after HT in 32 cases of tMZL (21 tEMZL, 7 tSMZL, 4 tNMZL). At HT, median age was 68 years (range 39-89); 24 (80%) patients presented with stage III/IV disease, 11 (58%) with elevated LDH, 12 (55%) with hemoglobin <12g/dL, 3 (14%) with platelet count <100x10 9/L and 9 (39%) with biopsy-proven bone marrow involvement. Twenty-six (81%) were treated with a systemic therapy, mainly CHOP-backbone therapy (R-CHOP n=13, CHOP n=4, R-EPOCH n=3, lenalidomide-R-CHOP n=1). Among these patients, the overall response rate was 85% (n=22/26). Three of the 4 non-responders died within 1 year. At last follow-up, 18/32 (56%) patients had died, and 6/13 (46%) alive patients had relapsed (MZL 3/6, DLBCL 3/6). After HT, 2-, 4- and 10-year OS were 76%, 55% and 55%, respectively. In univariable analysis, the only predictor of OS at HT was age ≥70 (HR 3.57 ,95% CI 1.34-9.48, p=0.011). Conclusion: In this North American prospective cohort of mainly non-Hispanic White patients, we found a low cumulative incidence of HT in MZL of 2.9% and 4.5% at 5- and 10-year, which was consistent with the Finnish findings (Kalashnikov et al., 2023). At HT, age was associated with OS and there was a high response rate to CHOP-backbone therapies.

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of non-Hodgkin lymphoma (NHL). Despite having an increased risk of NHL, patients with pre-existing autoimmune disease (AID) were excluded from pivotal CAR-T trials due to concerns that CAR-T may exacerbate AID. As a result, there are limited data on the safety and efficacy of CAR-T for NHL in patients with AID. Interestingly, there is also growing evidence that CAR-T can be therapeutically effective for AID, such as in the treatment of systemic lupus erythematosus (SLE). As CAR-T utilization for NHL increases, it is essential to characterize the safety and efficacy of this potentially curative therapy in patients with AID. This study aimed to evaluate the impact of AID on outcomes in patients treated with commercial CD19-targeted CAR-T for NHL. Methods: Following Institutional Review Board approval, we conducted a retrospective analysis of all patients who were treated with commercial CD19-targeted CAR-T for NHL and had a pre-existing AID across the Mayo Clinic Enterprise (Arizona, Florida, and Minnesota) between January 2018 and May 2023. Variables collected included age, gender, NHL type, AID type, and CAR-T product. Efficacy outcomes, including response rates at 6 and 12 months after CAR-T, were collected. Toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were collected and analyzed. Our chart review for AID included SLE, sarcoidosis, ulcerative colitis, celiac disease, pernicious anemia, Crohn's disease, psoriasis, Sjogren's syndrome, hypothyroidism (Hashimoto's disease), hyperthyroidism (Graves' disease), rheumatoid arthritis (RA), vasculitis, scleroderma, and mixed connective tissue disease (MCTD). Results: A total of 235 patients who received commercial CD19-targeted CAR-T for NHL across the Mayo Clinic Enterprise were identified (Table 1). Of these 235 patients, 27 had a pre-existing AID and 208 did not. The median age was 66 years (range 39-81) for patients with AID and 59 years (range 18-88) for patients without AID. Over half of the patients were male (59% of patients with AID and 51% of patients without AID). The most common NHL type was diffuse large B cell lymphoma (41% of patients with AID and 56% of patients without AID). Most patients received axicabtagene ciloleucel (85% of patients with AID and 84% of patients without AID). The most common AID was hypothyroidism (81%, n=22), although other conditions were also identified, including RA (11%, n=3), SLE (4%, n=1), pulmonary sarcoidosis (4%, n=1), psoriasis (4%, n=1), and MCTD (4%, n=1). Two patients had more than one AID. Median follow-up was 18 months (range 1-36) for patients with AID and 14 months (range 2-49) for patients without AID. Six months after CAR-T, the complete response (CR) rate was 77.2% and 45.1% in patients with AID and without AID, respectively (p=0.0042). Twelve months after CAR-T, the CR rate was 50% and 31.4% in patients with AID and without AID, respectively (p=0.0801). CRS of any grade occurred in 78% and 88% of patients with and without AID, respectively. ICANS of any grade occurred in 41% and 54% of patients with and without AID, respectively. Conclusion: AID did not appear to adversely impact the safety or efficacy of CAR-T for NHL. Limitations of our study include the small number of patients with AID and the fact that the most common AID was hypothyroidism. Larger studies are warranted to confirm these findings. Additional data are needed to characterize the impact of CAR-T for NHL on AID outcomes and to describe the effect of disease-modifying antirheumatic drugs on NHL outcomes after CAR-T.

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb <12g/dL for women or <13g/dL for men) in 58%, LDH >UNL in 46%, lymphocytosis (>5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.