Search

Background Achieving lasting remission for at least 2 years is a good indicator for favourable prognosis long term after Diffuse large B-cell lymphoma (DLBCL). The aim of this study was to provide real-world probabilities, useful in risk communication and clinical decision-making, of the chance for lasting remissions by clinical characteristics. Methods DLBCL patients in remission after primary treatment recorded in the Swedish Lymphoma register 2007–2014 (n = 2941) were followed for relapse and death using multistate models to study patient trajectories. Flexible parametric models were used to estimate transition rates. Results At 2 years, 80.7% (95% CI: 79.0–82.2) of the patients were predicted to remain in remission and 13.2% (95% CI: 11.9–14.6) to have relapsed. The relapse risk peaked at 7 months, and the annual decline of patients in remission stabilised after 2 years. The majority of patients in the second remission transitioned into a new relapse. The probability of a lasting remission was reduced by 20.4% units for patients with IPI 4–5 compared to patients with IPI 0–1, and time in remission was shortened by 3.5 months. Conclusion The long-term prognosis was overall favourable with 80% achieving durable first remissions. However, prognosis varied by clinical subgroups and relapsing patients seldom achieved durable second remissions.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical fitness. The combined MCL International Prognostic Index (MIPI-c) allows to predict prognosis using clinical factors (MIPI) and the Ki-67 index. However, high p53 expression as surrogate for TP53 alterations has demonstrated to be an independent predictor for poor outcome. We aimed to define a clear high-risk group based on the combination of MIPI, Ki-67 and p53 expression/TP53 alteration. A total of 684 patients from the prospective European MCL-Younger and MCL-Elderly trials were evaluable. The classification of high-risk disease (HRD) as high-risk MIPI-c or p53 expression > 50% versus low-risk disease (LRD) as low, low-intermediate or high-intermediate MIPI-c and p53 expression ≤ 50% allowed to characterize two distinct groups with highly divergent outcome. Patients with HRD had significantly shorter median failure-free survival (FFS) (1.1 vs. 5.6 years, p

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive neoplasms with poor outcomes, commonly affecting older patients with comorbidities. This study aims to describe outcomes of older patients with PTCL in a large international cohort. Patients aged ≥70 years with PTCL diagnosed from 1 January 2010 to 31 December 2015 in the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) were identified. Data on comorbidity were retrospectively collected according to the Charlson Comorbidity Index (CCI), and clinical outcomes were extracted. A total of 891 patients were included (SLR, n = 173; CCR, n = 718). Median age was 77 (SLR) and 78 (CCR) years. Included subtypes were as follows: angioimmunoblastic T-cell lymphoma, n = 226; anaplastic large-cell lymphoma, n = 122; enteropathy-associated T-cell lymphoma (EATL), n = 31; hepatosplenic TCL, n = 7; natural killer–/T-cell lymphoma, n = 62; PTCL not otherwise specified, n = 443. CCI data were available in 775 patients (87%), and CCI scores were divided into the groups CCI = 0 (39%), CCI = 1 (22%), and CCI > 1 (39%). Median age did not differ among the CCI groups (P = .72). Patients with a CCI > 1 had a worse median overall survival (4.4 months) compared with patients with CCI = 0 (11.9 months) and CCI = 1 (8.4 months; P < .001). Comorbidity and advancing age in as little as 5-year increments are important adverse factors in this group. Most patients died of lymphoma within a year from diagnosis, underscoring the importance of developing new treatments.

Inadequate molecular and clinical stratification of the patients with high-risk diffuse large B-cell lymphoma (DLBCL) is a clinical challenge hampering the establishment of personalized therapeutic options. We studied the translational significance of liquid biopsy in a uniformly treated trial cohort. Pretreatment circulating tumor DNA (ctDNA) revealed hidden clinical and biological heterogeneity, and high ctDNA burden determined increased risk of relapse and death independently of conventional risk factors. Genomic dissection of pretreatment ctDNA revealed translationally relevant phenotypic, molecular, and prognostic information that extended beyond diagnostic tissue biopsies. During therapy, chemorefractory lymphomas exhibited diverging ctDNA kinetics, whereas end-of-therapy negativity for minimal residual disease (MRD) characterized cured patients and resolved clinical enigmas, including false residual PET positivity. Furthermore, we discovered fragmentation disparities in the cell-free DNA that characterize lymphoma-derived ctDNA and, as a proof-of-concept for their clinical application, used machine learning to show that end-of-therapy fragmentation patterns predict outcome. Altogether, we have discovered novel molecular determinants in the liquid biopsy that can noninvasively guide treatment decisions.

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR-2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi-based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6-20.0) in the overall cohort, 5.5 months (95% CI 3.9-8.2) in 91 patients without post-BTKi therapy, and 23.8 months (95% CI 18.9-30.1) in 149 patients who received post-BTKi therapy (excluding chimeric antigen receptor T-cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post-BTKi therapy, with lenalidomide-containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post-BTKi therapy was 9.7 months (95% CI 6.3-12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.

Studies on late effects in mantle cell lymphoma (MCL) patients are increasingly important as survival is improving and novel targeted drugs are being introduced, however knowledge about late effects is limited. The aim of this population-based study was to describe the magnitude and panorama of late effects among patients treated with or without high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT). The study cohort included all MCL patients, recorded in the Swedish Lymphoma Register, 18-69 years old, diagnosed 2000-2014 (total n=620, treated with HD-ASCT n=247) and 1:10 matched healthy comparators. Patients and comparators were followed via the national Patient Register and Cause-of-Death-Register, from 12 months after diagnosis/matching until December 2017. Incidence rate ratios of numbers of outpatient visits, hospitalizations and bed days were estimated using negative binomial regression models. In relation to the matched comparators, the rate of specialist and hospital visits was significantly higher among MCL patients (IRR 2.0, 95% CI: 1.8-2.2 and 7.2, 95% CI: 6.3-8.3, respectively). MCL patients had especially high relative risks of infectious, respiratory and blood disorders. Within this observation period, no difference in rate of these complications, including secondary neoplasms, was observed between HD-ASCT and non-HD-ASCT treated patients. The majority of patients died from their lymphoma and not from another cause or treatment complication. Taken together, our results imply that the vast majority of the post-treatment healthcare needs are related to the lymphoma disease itself, thus, indicating the need for more efficient treatment options.

Mantle cell lymphoma (MCL) is a rare, often aggressive type of B-cell lymphoma with poor survival and no cure. Cancer and cancer treatment has a negative impact on health-related quality of life (HRQOL) both during active disease and in the long term, and improvement of HRQOL is a crucial objective of cancer therapy in older patients and no curative intent. Baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Here, we explored HRQOL, and its association with survival, by the EORTC QLQ-C30 questionnaire, before, during and after chemotherapy in a patient cohort with mantle cell lymphoma, treated within the NLG-MCL4 trial, designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment. Fifty-one patients were enrolled, median age was 71 years (range 62-84), 37 were men (73%). Pre-treatment HRQOL was similar to scores from the reference population with healthy individuals. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. There was a correlation between physical function (p=0.001) and role function (p=0.006) at baseline and WHO performance status, but not with other clinical or genetic prognostic factors. None of the baseline factors were predictive for treatment related to HRQOL in this cohort. Pre-treatment physical (p=0.011) and role function (p=0.032) were independent factors associated with overall survival, and physical function (p=0.002) was also associated with progression free survival. These findings may possibly be used to design support during treatment and improve rehabilitation. Further investigations are needed for assessment of long-term HRQOL. This article is protected by copyright. All rights reserved.

Mantle cell lymphoma (MCL) is characterized by marked differences in outcome, emphasizing the need for strong prognostic biomarkers. Here, we explore expression patterns and prognostic relevance of circular RNAs (circRNAs), a group of endogenous non-coding RNA molecules, in MCL. We profiled the circRNA expression landscape using RNA-sequencing and explored the prognostic potential of 40 abundant circRNAs in samples from the Nordic MCL2 and MCL3 clinical trials, using NanoString nCounter Technology. We report a circRNA-based signature (circSCORE) developed in the training cohort MCL2 that is highly predictive of time to progression (TTP) and lymphoma-specific survival (LSS). The dismal outcome observed in the large proportion of patients assigned to the circSCORE high-risk group was confirmed in the independent validation cohort MCL3, both in terms of TTP (HR 3.0; P = 0.0004) and LSS (HR 3.6; P = 0.001). In Cox multiple regression analysis incorporating MIPI, Ki67 index, blastoid morphology and presence of TP53 mutations, circSCORE retained prognostic significance for TTP (HR 3.2; P = 0.01) and LSS (HR 4.6; P = 0.01). In conclusion, circRNAs are promising prognostic biomarkers in MCL and circSCORE improves identification of high-risk disease among younger patients treated with cytarabine-containing chemoimmunotherapy and autologous stem cell transplant.

Background: In precision medicine era, we need to develop tools that better predict treatment response with, for e.g. immuno-oncology drugs. One hypothesis is that diverse treatment response is governed by differences in the tumor microenvironment (TME) both within the tumor and surrounding areas. Thus, novel ways to measure the heterogeneity within defined immune-cell populations is the key and now possible by using spatially-resolved multiplexed platforms. Here, we have investigated the phenotype of four T-cell subtypes both within and excluded from the tumor-rich regions in a large cohort of primary mantle cell lymphoma (MCL) patients. We propose that profiling different cell populations could potentially provide insight into patient prognosis and identify clinically actionable targets, but also in understanding whether tumor cells locally re-educate T-cells through cell-to-cell interaction or by soluble factors Method: We analyzed archival FFPE presented as tissue microarrays of 196 cores from 104 MCL patients, collected from the Biobank of Lymphoma of Southern Sweden, by using the, GeoMX-digital spatial profiler (DSP, Nanostring Inc.). Cellular regions of interest were selected by immunofluorescense staining of CD8, CD3 and CD57 to identify four subpopulations of T cells - early cytotoxic (CD3+ CD8+ CD57-), early non-cytotoxic (CD3+ CD8- CD57-), late cytotoxic (CD3+ CD8+ CD57+) and late non-cytotoxic (CD3+ CD8- CD57+). 601 regions distributed among the four T-cell subtypes were collected from both within the tumor-rich and tumor deficient zones and probed for 69 proteins for sub-characterization. Result: Our results show that the distribution and expression profile of all subpopulations differ considerably based on their position relative to the tumor. Using linear mixed effects model to account for effect of multiple sampling per patient, we observed higher cytolytic activity (upregulation of granzyme A and B) (FDR cut-off < 0.05) in early cytotoxic and late non-cytotoxic cells, within the tumor-rich zone compared to the tumor-deficient area. In contrast, proteins such as STING, VISTA, neurofibromin and fibronectin were consecutively upregulated in all subtypes in tumor-deficient zones. We also observe differential expression profiles for proteins involved in for example cell death regulation and apoptotic signaling pathways. Our analysis provide insight into effector functions important for response to treatment in MCL. Conclusion: This study reveals the phenotypic differences of T-cell subsets in MCL with a higher resolution compared to previous studies. The spatially-resolved analysis shows that the proximity to tumor cells highly affect the profile of different T-cell subsets and that further analysis of re-education mechanisms should be pursued. This study advance the understanding of the MCL tissue microenvironment and for the basis for connecting such differences to clinical outcome. Citation Format: Lavanya Lokhande, Joana de Matos Rodrigues, Anna Sandstrom Gerdtsson, Anna Porwit, Mats Jerkeman, Sara Ek. Profiling T-cell subpopulations based on spatial proteome in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6327.

Introduction: Mantle cell lymphoma (MCL) is an incurable disease and we have previously shown that presence of CD163+ cells in the tumor microenvironment in MCL is associated with an adverse outcome. We therefore profiled CD163+ cells to better understand their impact on this tumor and identify possible targetable markers. We hypothesize that, not only the presence of CD163+ cells, a marker of M2 macrophages, in the tumor tissue, but also the spatial context of CD163+ cells might be relevant for MCL development and treatment response. Material and Methods: Sixty-nine protein targets were measured by the Nanostring GeoMx Digital Spatial Profiler. This method allowed for preserved spatial context, in tissue microarrays from a population-based cohort of de novo MCL patients while investigating different markers. A total of 235 cores from 131 different patients were sampled. Regions of interest for CD20+, CD3+ and CD163+ cells were selected, with more than 600 areas of illumination (AOI) collected. From those, 85 AOI, belonging to 61 patients, were from CD163+ cells. These were subsequently classified according to their spatial profile: CD163+ cells within the tumor area and CD163+ cells excluded from the tumor area. Differentially expressed proteins between different tissue types were also explored. Results: Among the highest expressed proteins in the CD163 AOI were CD45, HLA-DR and CD68. The higher expression of both HLA-DR and CD68 suggests that macrophages in MCL microenvironment may display mixed phenotypes between pro- and anti-inflammatory stages, the called M1 and M2 polarization types. Interestingly, p53 and Ki67 were highly correlated among the CD163 AOI collected, which might suggest higher aggressiveness of CD163+ cells. We explored the differently expressed proteins between CD163 AOI sampled located within the tumor and excluded from the tumor/tumor barrier. We identified significant differences in the expressed proteins between the two groups, such as p53, VISTA, ARG1, LAG3 and HLA-DR. p53 was higher in the CD163 AOI within the tumor area, whereas VISTA was highest expressed in CD163 AOI excluded from the tumor cells/tumor barrier. Among the 85 CD163+ AOIs, 47 were sampled from lymph node biopsies, 14 from bone marrow, 10 from tonsil samples, four from the gastrointestinal tract, six from other tissue types and four from unknown origin. Principal component analysis and k-means clustering showed that most of bone marrow and gastrointestinal tract biopsies clustered apart from the remaining samples, with a few differentially expressed proteins, such as NF1 and CD66b. Conclusions: Our study demonstrates that spatial localization within the MCL tumor affects the expression of CD163+ macrophages, adding to the premise that macrophages in tumor are not easily characterized by the concept of M1 and M2 types. Our results shed light on targetable features of the MCL tumor microenvironment. Citation Format: Joana Matos Rodrigues, Lavanya Lokhande, Anna Gerdtsson, Anna Nikkarinen, Peter Hollander, Anna Porwit, Ingrid Glimelius, Mats Jerkeman, Sara Ek. Spatially resolved multiplexed analysisreveals how macrophages adapt to the mantle cell lymphoma microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2026.

LBA7502 Background: Elderly patients (pts) with MCL are unsuitable for intensive chemotherapy or transplantation due to excessive toxicities. Single-agent ibrutinib (Ibr), a first-in-class, oral Bruton’s tyrosine kinase inhibitor (BTKi), has transformed the care of pts with relapsed or refractory MCL with durable activity. We conducted a phase III trial (SHINE; NCT01776840) to evaluate combining Ibr with a standard chemoimmunotherapy (BR) and R maintenance in older pts with untreated MCL. Methods: Pts aged ≥ 65 years, enrolled between May 2013 and November 2014 from 183 sites across all geographical regions, were stratified by simplified MIPI score (low vs intermediate vs high risk) and were randomized 1:1 to Ibr (560 mg orally daily) or placebo (Pbo), plus 6 cycles of B (90 mg/m2) and R (375 mg/m2). Pts who achieved an objective response received R maintenance, administered every 8 weeks for up to 12 additional doses in both arms. Ibr and Pbo were administered until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: A total of 523 pts were randomized to Ibr + BR (n = 261) or Pbo + BR (n = 262). Median age was 71 years (range, 65–87), 65.6% of pts had low/intermediate simplified MIPI, and 8.6% had blastoid/pleiomorphic histology. At the primary analysis, median follow up was 84.7 months. The primary endpoint was met as PFS was significantly improved in the Ibr arm vs the Pbo arm (hazard ratio, 0.75; one-sided P = 0.011). Median PFS was 80.6 months with Ibr in combination with BR and R maintenance, a 50% improvement over Pbo in combination with BR and R maintenance (median PFS of 52.9 months). The complete response rate was 65.5% in the Ibr arm and 57.6% in the Pbo arm ( P = 0.0567). There was no difference in overall survival between treatment arms ( P = 0.648). Time to next treatment was longer in the Ibr arm compared with the Pbo arm ( P < 0.001). Fifty-two (19.9%) and 106 (40.5%) pts received subsequent anti-lymphoma therapy in the Ibr and Pbo arms, respectively; 41/106 (38.7%) received a second-line BTKi in the Pbo arm. Rates of grade 3 or 4 treatment-emergent adverse events were 81.5% and 77.3% in the Ibr and Pbo arms, respectively. Of adverse events of clinical interest for BTKis, atrial fibrillation was reported in 13.9% and 6.5% of pts in the Ibr and Pbo arms, respectively. Rates of major hemorrhage, hypertension, arthralgia, and secondary primary malignancies were similar in both arms. Quality of life was also similar in both arms. Conclusions: This phase III study in untreated MCL demonstrated that Ibr combined with BR and R maintenance significantly improved PFS compared with standard chemoimmunotherapy, with a median PFS of 6.7 years. The safety profile was consistent with the known profiles of the individual drugs. Clinical trial information: NCT01776840.

Purpose The improved survival for mantle cell lymphoma (MCL) patients calls for updated knowledge about long-term adverse effects of treatment. We recently showed that younger MCL patients (≤65 years of age) selected for rituximab-cytarabine containing regimens and a consolidating high-dose chemotherapy with stem cell transplantation (HD-ASCT) had a 42% reduced all-cause mortality compared to patients selected for less intensive regimens with rituximab-bendamustine and/or rituximab-CHOP based treatment without HD-ASCT (non-HD-ASCT) (Blood Advances 2021, PMID: 3371034). The aim here was to describe long-term side-effects and outcome from these different treatment strategies. Methods We conducted a population-based cohort study including all Swedish MCL patients diagnosed between 2000 and 2014, and 1:10 matched comparators. First, transplantation-related mortality and acute side effects (within 60 days of HD-ASCT) were described. Next, for the analysis of late effects, we took a landmark approach with follow-up starting at 12 months after diagnosis (i.e., assuming treatment completion). Hazard ratios with 95% confidence intervals (CIs) of first hospital visit/admission/death due to a specific disease group (based on ICD chapters) were estimated using Cox regression models, comparing the rates among HD-ASCT and non-HD-ASCT patients to those among the comparators. Additionally, the 5-year cumulative incidence of death due to MCL, other malignancy, cardiovascular disease, or remaining causes was described for both patient treatment groups (HD-ASCT and non-HD-ASCT) and comparators. Results A total of 620 MCL patients were included with a median follow-up from diagnosis of 4.1 years (range: 0-15.7). In total, 280 (45%) received HD-ASCT (median age 58, range 32-69) and 340 (55%) R-CHOP/R-Bendamustin and non-HD-ASCT (median age 65, range 22-69). Four out of 280 (1.5%) HD-ASCT treated patients died within 60 days of their transplantation. Acute side effects of transplantation were mainly infections and diseases of the circulatory or digestive systems. In relation to the 6,200 matched comparators (median age 63, range 22-70) the rate of hospital visits/admissions/death after 12 months was significantly higher among MCL patients (irrespective of treatment intensity) for neoplasms (excluding MCL), other blood disorders, infections, respiratory, genitourinary, digestive, and skin disorders (Figure 1A). Patients treated with HD-ASCT did not experience a higher rate of late effects than those treated without HD-ASCT, for any of the disease groups (Figure 1A). The 5-year cumulative incidence of MCL-specific death in HD-ASCT treated patients was 0.23 (95% CI: 0.18-0.30) and 0.32 (95% CI: 0.26-0.38) in non-HD-ASCT treated patients (Figure 1B). Fatal long-term (≥12 months) side effects were rare in HD-ASCT treated patients, and the absolute majority of MCL patients died from their lymphoma and not from a complication. Conclusions MCL patients have a higher risk of long-term complications than comparators particularly in the disease groups respiratory disorder, blood disorders (other than MCL) and infections. Intensive first-line treatment including HD-ASCT was however associated with a similar rate of long-term side-effects in all disease groups as among patients selected for less intensive treatments and non-HD-ASCT. Hence, given the previously shown favourable long-term survival associated with HD-ASCT, it appears that this treatment should not be avoided based on fear of neither fatal acute side effects nor more long-term side effects. Instead symptomatic lymphoma disease and death from the lymphoma seem to drive the majority of long-term health problems in MCL patients regardless of treatment intensity. Figure 1. A) Hazard ratios for hospital visits/admissions/deaths due to specific disease groups (based on ICD chapters) among MCL patients and comparators, stratified by treatment with consolidative autologous stem cell transplant (ASCT) or (non-ASCT). All models were adjusted for age at diagnosis, sex, calendar year of diagnosis, and Charlson comorbidity index. Grey dots; comparators, blue dots MCL patients (non-ASCT-treated) and red dots MCL patients (ASCT treated) B) Cumulative incidence of death due to MCL, other malignancies, cardiovascular disease (CVD), and other causes among MCL patients without (upper panel) and with (lower panel) ASCT. Figure 1 Figure 1. Disclosures Ekberg: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Smedby: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Albertsson-Lindblad: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Jerkeman: Jansen-Cilag, AbbVie, Gilead, Celgene: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support, Research Funding. Weibull: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Glimelius: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support.

Introduction BI-1206 is a fully human anti-FcγRIIB antagonistic monoclonal antibody. BI-1206 enhances the activity of anti-CD20 antibodies such as rituximab by blocking the interaction of the anti-CD20 with this inhibitory receptor. This combination may overcome resistance to rituximab and enhance its activity. Methods The safety and tolerability profile of BI-1206 in combination with rituximab is currently investigated in the Phase 1/2a clinical trial 17-BI-1206-02. The study population includes subjects with follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) who have relapsed or are refractory to rituximab. Induction therapy consists of four weekly administrations of rituximab and three administrations of BI-1206, both given as i.v. infusions. In the first week of treatment rituximab is administered as single agent. In the following three weeks patients receive BI-1206 followed by rituximab. In Phase 1, a 3+3 study design is used, with escalating doses of BI-1206 and a fixed dose of rituximab (375 mg/m 2), with the aim of selecting the RP2D of BI-1206 for the expansion cohort (Phase 2a). Patients showing clinical benefit are eligible for continued maintenance therapy with dosing of BI-1206 and rituximab every 8 weeks for up to 7 cycles. The assessment of the pharmacokinetics (PK) of BI-1206 includes non-compartmental analysis (NCA), and the assessment of the pharmacodynamics (PD) includes B cell depletion, FcγRIIB expression and BI-1206 receptor occupancy (RO). Results With a cut-off date of July 20 th, 2021, 16 subjects have received doses of up to 100 mg BI-1206 in combination with rituximab (375 mg/m 2). Nine out of these received all four doses and were evaluated for therapeutic benefit. Three subjects were diagnosed with MCL, 1 with MZL and 12 with FL. The most frequent adverse advents (AEs) related to BI-1206 have been infusion related reactions (IRRs). These IRRs led to dose limiting toxicities (DLTs) in 4 subjects, 2 experienced G4 platelet drops, and 2 experienced G3 and G4 liver enzyme elevations. No signs of liver damage were observed, and all patients recovered within days of the event, leaving no sequelae. These events have been milder and less frequent after implementation of a novel pre-medication regimen. No DLTs have been observed after implementation of this regimen. Clinical responses were observed already at the starting dose (30 mg). To date three complete responses (CR) have been observed, one at the 30mg and two at the 70mg dose levels. Two complete responses completed maintenance and one is still on maintenance treatment. The two subjects who developed a CR and finished the study have remained in CR over 1,5 and 2,0 years. Three subjects achieved partial responses (PR), one at 30mg and two at 70mg. One patient on 100 mg is experiencing ongoing stable disease at the cut-off date and is on maintenance treatment. One patient with a blastic form of MCL achieved complete depletion of peripheral tumor cells and achieved a PR. Increasing doses (30 mg to 70 or 100 mg) of BI-1206 gave rise to a supra-proportional increase in C max as well as an increase in the half-life of BI-1206. A trend of accumulation after consecutive doses was also seen. When comparing the serum-concentrations against the associated RO% of FcγRIIB there was a trend that higher dose levels were close to fully saturating FcgRIIB receptors for up to 72 hours. It is therefore likely that further increases in dose will give rise to complete receptor saturation, which should be maintained for extended periods of time. Conclusions Preliminary data of the clinical trial 17-BI-1206-02, where BI-1206 is combined with rituximab is promising. BI-1206 has a good safety profile that induced IRRs that are adequately managed with a novel steroid regimen. At a cut-off date of July 20 th, 2021, 3 CR, 3 PR and one SD have been observed among the 12 evaluable patients who completed the induction treatment. Importantly, the CRs have been very long lasting. This at doses associated only with transient receptor saturation. It may be speculated that doses which enable full RO% for a longer period (e.g., the entire dosing interval), may show additional clinical benefit. Since patients are currently undergoing treatment at higher doses, these data will be updated. Disclosures Karlsson: BioInvent International AB: Current Employment. Gertsson: BioInvent International AB: Current Employment. Kilany: BioInvent International AB: Current Employment. Borggren: BioInvent International AB: Current Employment. Abrisqueta: BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Carneiro: Novartis: Membership on an entity's Board of Directors or advisory committees; Pierre-Fabre: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Cordoba: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jerkeman: Jansen-Cilag, AbbVie, Gilead, Celgene: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support, Research Funding. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Sancho: Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Teige: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Mårtensson: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. McAllister: BioInvent International AB: Current Employment, Current equity holder in publicly-traded company.