Swedish Lymphoma Registry Research Articles

Evaluation of coverage, generalisability and validity of the U-CAN lymphoma biobank in Sweden: A comparison with nationwide registers.

Validation of biobanks and large cancer cohorts is essential in ensuring high-quality research results. We examined the coverage, generalisability and validity of the lymphoma collection of the Uppsala-Umeå Comprehensive Cancer Consortium (U-CAN) biobank in Sweden, one of the largest cancer biobanks in Europe. Up until 2022, 889 lymphoma patients in U-CAN Uppsala had available samples, and 329 in U-CAN Umeå. Patients diagnosed in the U-CAN Uppsala area 2011-2021 (n = 843) were linked to the nationwide Swedish Lymphoma Register, and a subset diagnosed before 2019 (n = 727) to population-based registers. The coverage was 39% of all lymphoma patients between 2011 and 2019 diagnosed in the U-CAN Uppsala area, with a pandemic decline to 10% during 2020-2021. The patients included had superior overall survival (hazard ratio = 0.70 [95% confidence interval, CI: 0.60-0.82]) than all lymphoma patients in Sweden. They had better performance status, were younger (odds ratio [OR] = 0.21 [95% CI: 0.13-0.34]) and had less comorbidities (OR = 0.66 [95% CI: 0.56-0.78]). However, cause-specific survival and stage distribution were similar. The questionnaire data captured less comorbidities compared to the national registers. Evaluations of biobanks are important, as even population-based biobanks such as U-CAN select younger patients with higher socioeconomical status and better performance status. However, the similar cause-specific survival as in the registries suggests U-CANs usefulness for prognostic biomarker studies.

The National Swedish Lymphoma Register - a systematic validation of data quality.

The Swedish Lymphoma Register (SLR) was initiated in the year 2000 with the aim to monitor quality of care in diagnostics, treatment and outcome of all lymphomas diagnosed nationally among adults. Here, we present the first systematic validation of SLR records as a basis for improved register quality and patient care. We evaluated timeliness and completeness of register records among patients diagnosed with lymphoma in the SLR (n = 16,905) compared with the National Cancer Register for the period 2013-2020. Comparability was assessed through evaluation of coding routines against national and international guidelines. Accuracy of 42 variables was evaluated through re-abstraction of data from medical records among 600 randomly selected patients diagnosed in 2016-2017 and treated across all six Swedish healthcare regions. Results: Completeness was high, >95% per year for the period 2013-2018, and >89% for 2019-2020 compared to the National Cancer Register. One in four patients was registered within 3 months, and 89.9% within 2 years of diagnosis. Registration instructions and coding procedures followed the prespecified guidelines. Missingness was generally low (<5%), but high for occasional variables, for example, those describing maintenance and consolidative treatment. Exact agreement of categorical variables was high overall (>80% for 24/34 variables), especially for treatment-related data (>80% for 17/19 variables). Completeness and accuracy are high in the SLR, while timeliness could be improved. Finetuning of variable registration guided by this validation can further improve reliability of register reports and advance service to lymphoma patients and health care in the future.

The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas

AbstractLittle is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse–enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Treatment sequencing and impact of number of treatment lines on survival in follicular lymphoma: A national population-based study.

Follicular lymphoma (FL) is a clinically heterogeneous disease. The need for treatment, treatment sequencing, number of treatment lines, and its association with survival have not been described in a population-based setting. We identified all patients diagnosed with FL in the Swedish Lymphoma register from 2007 to 2014, followed until 2020, with detailed data on progression/relapse, transformation, and 2nd and further lines of therapy. During a median follow-up of 6.8 years, 1226 patients (69%) received 1st systemic treatment, 358 patients (20%) were managed with watch-and-wait (WaW) only, and 188 (10%) patients were treated with radiotherapy and did not require additional therapy during the study period. Among patients starting systemic treatment, 496 (40%), 224 (18%), and 88 (7%) received 2nd-, 3rd-, or 4th-line therapy, respectively. The 10-year cause-specific cumulative incidence of transformation was 13%. Among patients managed with 1st line R-single, R-CHOP, or BR, 54%, 33%, and 29% required 2nd line, respectively. The cumulative probability of starting subsequent treatment within 2 years was 26% after 1st line and 35% after 2nd line treatment. Two-year OS following 1st, 2nd, 3rd, and 4th line systemic treatment was 84%, 70%, 52%, and 36%, respectively, and remained similar when excluding transformations. We conclude that a substantial proportion of FL patients can be managed with WaW for a long period of time, while patients who require multiple treatment lines constitute a group with a large clinical unmet need. These results constitute valuable real-world reference data for FL.

Impact of the COVID-19 pandemic on lymphoma incidence and short-term survival - a Swedish Lymphoma Register Study.

The COVID-19 pandemic posed a large challenge for healthcare systems across the world. Comprehensive data on the impact of the COVID-19 pandemic on incidence and mortality in lymphoma are lacking. Using data from the Swedish lymphoma register, we compare incidence and 1-year survival of lymphoma patients in Sweden before (2017-2019) and during the pandemic (2020 and 2021). Fewer patients were diagnosed with lymphomas during March-June 2020, but the annual incidence rates for 2020 and 2021 were similar to those of 2017-2019. A larger proportion of patients presented with stage IV disease during 2021. There were no differences in other base-line characteristics nor application of active treatment in pre-pandemic and pandemic years. One-year overall survival was not inferior among lymphoma patients during the pandemic years compared to pre-pandemic years i.e., 2017-2019. The COVID-19 pandemic had limited impact on the incidence and mortality of lymphoma in Sweden.

Machine Learning-Based Survival Prediction Models for Progression-Free and Overall Survival in Advanced-Stage Hodgkin Lymphoma.

Patients diagnosed with advanced-stage Hodgkin lymphoma (aHL) have historically been risk-stratified using the International Prognostic Score (IPS). This study investigated if a machine learning (ML) approach could outperform existing models when it comes to predicting overall survival (OS) and progression-free survival (PFS). This study used patient data from the Danish National Lymphoma Register for model development (development cohort). The ML model was developed using stacking, which combines several predictive survival models (Cox proportional hazard, flexible parametric model, IPS, principal component, penalized regression) into a single model, and was compared with two versions of IPS (IPS-3 and IPS-7) and the newly developed aHL international prognostic index (A-HIPI). Internal model validation was performed using nested cross-validation, and external validation was performed using patient data from the Swedish Lymphoma Register and Cancer Registry of Norway (validation cohort). In total, 707 and 760 patients with aHL were included in the development and validation cohorts, respectively. Examining model performance for OS in the development cohort, the concordance index (C-index) for the ML model, IPS-7, IPS-3, and A-HIPI was found to be 0.789, 0.608, 0.650, and 0.768, respectively. The corresponding estimates in the validation cohort were 0.749, 0.700, 0.663, and 0.741. For PFS, the ML model achieved the highest C-index in both cohorts (0.665 in the development cohort and 0.691 in the validation cohort). The time-varying AUCs for both the ML model and the A-HIPI were consistently higher in both cohorts compared with the IPS models within the first 5 years after diagnosis. The new prognostic model for aHL on the basis of ML techniques demonstrated a substantial improvement compared with the IPS models, but yielded a limited improvement in predictive performance compared with the A-HIPI.

An International Multicohort Study of Conditional Survival and Cause of Death after Achieving Event-Free Survival at 24 Months in Patients with Mantle Cell Lymphoma

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Nationwide Assessment of Patient Trajectories in Mantle Cell Lymphoma: The Swedish MCLcomplete Project.

Mantle cell lymphoma (MCL) is a B-cell malignancy currently considered incurable. Although some patients obtain prolonged remission after first-line chemoimmunotherapy, many will need several treatment lines. Here, we present a nationwide assessment of treatment strategies, time to progression and survival in MCL. All patients diagnosed with MCL 2006-2018 were identified in the Swedish Lymphoma Register. Information on all lines of therapy was extracted from the medical records. Overall and progression-free survival (OS and PFS) were assessed through August 2021. In total, 1367 patients were included (median age, 71 years) and median follow-up was 6.8 years. Two hundred and one (15%) were managed initially with watch-and-wait, but 1235 (90%) eventually received treatment. The most frequently used first-line regimens were rituximab-bendamustine (BR) (n = 368; 30%) and Nordic MCL2 (n = 342; 28%). During follow-up, 630 patients (46%) experienced relapse/progression and 546 (40%) received second-line treatment. The most frequently used second-line regimen was BR (n = 185; 34%) but otherwise a wide variety of second-line treatments were used. Further, 382 and 228 patients experienced a second or third relapse/progression, respectively. Median PFS after first (PFS-1), second (PFS-2), third (PFS-3), and fourth (PFS-4) treatment lines was 29.4, 8.9, 4.3, and 2.7 months. Patients with early progression, defined as a PFS-1 <24 months, had an inferior median OS of 13 versus 37 months in patients with later relapse. For patients treated with frontline BR, however, time to relapse had no impact on later outcome. By use of nationwide population-based data, we provide important benchmarks for future studies of all treatment lines in MCL.

HYPOGAMMAGLOBULINEMIA AT DIAGNOSIS IS ASSOCIATED WITH INFERIOR SURVIVAL AND HIGHER RISK OF INFECTIONS IN DIFFUSE LARGE B CELL LYMPHOMA: A RETROSPECTIVE STUDY FROM SWEDEN

Introduction: Low level of antibody production does not only increase the risk of infections, but also the incidence of malignancies, especially lymphoma. The primary aim of this study was to explore if hypogammaglobulinemia in untreated diffuse large B cell lymphoma (DLBCL) was associated with inferior overall survival (OS) or inferior progression free survival (PFS). Secondary aims were to assess the relationships between low immunoglobulins (Ig), other laboratory tests and infections. Methods: Using data from the Swedish Lymphoma Register (SLR), we identified all adult patients (18 years or older) diagnosed with DLBCL, receiving anthracycline-based curative therapy during year 2001–2015 in two health regions in southern Sweden (one university hospital and one region hospital). Data from the SLR were supplemented by patient record review, including data on baseline Ig levels and infections of CTC-AE grade 3–5 (in-hospital stay and intravenous antibiotics). Survival was analyzed by Kaplan-Meier estimates. Simple and multivariate linear regression were performed to determine relationships between laboratory tests and number of infections. Results: 596 patients were included, median age was 69 years (20–96), 57% were men, median OS 72 months, and median PFS 64 months. Median follow-up time for living patients was 106 months (62–117). 25% had low Ig, defined as any deficiency, 18% had low IgG, 37% lymphopenia and 13% both low Ig and lymphopenia. Hypogammaglobulinemia was associated with inferior OS (HR 1.4, 95% CI 1.0–1.9, p-value 0.018) and inferior PFS (HR 1.3, 95% CI 1.0–1.7, p-value 0.032). The combination of low Ig and lymphopenia aggravated OS (HR 1.2, 95% CI 1.0–1.2, p-value 0.023) and PFS (HR 1.2, 95% CI 1.0–1.3, p-value 0.002). Hypogammaglobulinemia was also associated with a higher number of infections (p-value 0.021), adjusted for International Prognostic Index (IPI) the associations weakened (p-value 0.097). The combination of low Ig and lymphopenia was not related to more infections than low Ig alone. Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: MCL is considered incurable, but outcomes are improving in the evolving treatment landscape. Event-free survival status at a landmark (e.g., 24 months) after frontline IC may help identify patients who will subsequently do well, which would be useful for patient counseling, care planning, and trial design. We evaluated conditional survival and cause of death in MCL patients who achieve EFS24 after frontline immunochemotherapy (IC). Methods: Outcomes after frontline IC were evaluated in 3 cohorts: Mayo/Iowa MER prospective clinic-based cohort, BC Cancer retrospective population-based cohort, and Swedish Lymphoma Register. For each cohort, 2 treatment eras were defined based on the specifics of local treatment patterns (Figure 1 A). Overall survival (OS) after diagnosis and after achieving EFS24 was compared to the background age and sex matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER, patients treated in Era M1 (2002–2009; n = 110) and M2 (2010–2015; n = 127) both had inferior OS compared to the US general population. A lower SMR (2.43 vs. 3.95) in Era M2 suggested a narrower gap in OS versus the general population. Lymphoma was the leading cause of death in both eras. In Era M1, patients achieving EFS24 still had inferior OS compared to the general population (SMR = 2.81, 95% CI: 1.98–3.88), and lymphoma remained the leading cause of death. However, in Era M2, patients achieving EFS24 had similar OS compared to the general population (SMR = 1.35, 95% CI: 0.83–2.09), and lymphoma was no longer the leading cause of death (Figure 1 B&E). In the BC cohort, patients treated in Era B2 (6/2013–2019; n = 188) versus Era B1 (2003–5/2013; n = 250) had a narrower gap in OS compared to the British Columbia population (SMR 4.53 vs. 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 versus B1 (SMR 3.56 vs. 4.99). After achieving EFS24, lymphoma was the leading cause of death for patients in Era B1 but not in Era B2 (Figure 1 C&E). Similar results were seen in the Swedish cohort. The gap in OS compared to the general Swedish population was narrower in Era S2 (2013–2018; n = 439) vs. S1 (2006–2012; n = 442), both after frontline IC (SMR 4.8 vs. 5.4) and after achieving EFS24 (SMR 2.6 vs. 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Figure 1 D&E). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. Y. Wang Consultant or advisory role: Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene (all compensation to my institution) Honoraria: Kite (to my institution) Research funding: Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab (all to my institution) B. K Link Consultant or advisory role: Genentech, MEI Inc V. Diego Consultant or advisory role: Janssen, BeiGene, AstraZeneca, Merck, Kite/Gilead, BMS/Celgene, AbbVie, ONO therapeutics, Zetagen, Roche Honoraria: Janssen, BeiGene, AstraZeneca, Merck, Kite/Gilead, BMS/Celgene, AbbVie, ONO therapeutics, Zetagen, Roche Research funding: Roche, AstraZeneca (to institution)

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Most patients diagnosed with diffuse large B-cell lymphoma (DLBCL) are cured with primary immunochemotherapy, but about one in four experience relapsed/refractory (R/R) disease with worsened outcome. In recent years, new targeted and cellular treatments are becoming available in trials or clinical routine primarily in the R/R setting. However, only a fraction of R/R DLBCL patients are offered these new treatments. We aimed to assess the impact of new treatment options on trends in survival among all patients with DLBCL in Sweden. Methods: We identified all patients diagnosed with DLBCL in the Swedish Lymphoma Register (SLR) 2007–2021, and followed through 31 December 2022. Patients with primary CNS, mediastinal B-cell or transformed low-grade lymphoma were excluded. SLR holds data on age, sex, performance status, stage and lactate dehydrogenase at diagnosis, enabling calculation of the age-adjusted International Prognostic Index (aaIPI) score. We estimated overall (OS) and relative survival (RS) by calendar year of diagnosis in three-year periods. Two-year RS was estimated with the Pohar-Perme method adjusting for age, sex, diagnosis year and aaIPI. Differences in RS were evaluated using the log-rank type test proposed by Graffeo et al. Results: Overall, 8,808 patients were diagnosed with DLBCL during the study period (median age 72 years, range 18–105, 57% male). In the full cohort, 2-year OS was 66% among patients diagnosed 2007–2009, increasing to 71% for 2019–2021 (poverall < 0.001, Figure 1A). Improvements in 2-year RS were noted across all groups by age, sex and aaIPI score. However, by age, improvements were primarily observed among patients aged 60–69 and 80+ years (Figure 1B). By risk group, improvements were mainly noted among young high-risk patients (aaIPI 2–3, age <70 years) and among older patients (70+ years) independently of aaIPI (Figure 1C). In young high-risk patients, the 2-year RS increased from 71% among patients diagnosed 2007–2009, to 83% among patients diagnosed 2019–2021 (poverall < 0.001). The research was funded by: Swedish Cancer Society Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies No conflicts of interests pertinent to the abstract.

How to choose between curative radiotherapy or chemotherapy in low stage MCL?—a population‐based analysis of outcome in patients with stage I‐II MCL in Sweden

Introduction: The optimal primary treatment of mantle cell lymphoma is not yet defined with respect to long-term disease control and manageable toxicity. A few patients with MCL present with limited stage disease and for these, involved node radiotherapy may be a well tolerable alternative to immunochemotherapy regimens. Here, we aim to evaluate progression free survival (PFS) and overall survival (OS) in relation to given treatment and prognostic factors in patients with stage I-II MCL. Methods: The study was based on patients diagnosed with MCL in Sweden 2006–2018 according to the Swedish Lymphoma Register (SLR), which is a nationwide population-based register with a reported coverage of 95%. Data were supplemented by review of medical records for all patients. Survival analyses were made by Kaplan-Meier estimates with end of given treatment as start of follow-up (FU). Results: Out of all patients (n = 1412), we identified a cohort of 173 patients reported with Ann Arbor I-II or Musshoff PeI according to standard staging procedure. Median age was 71(22–93) years, 88% had ECOG 0–1 and 31% were scored high-risk MIPI at diagnosis. Primary treatment included single RT (n = 48, 28%) of which curative radiation dose ≥24 Gy in 37 (21%) patients, Immunochemotherapy (ICT) (n = 94, 54%) including R-bendamustine (n = 34), Nordic MCL2 protocol (n = 28), R-CHOP (n = 14), and ICT with consolidative RT in 12 (7%) (CRT). At a median FU time of 5.40 (0.01–15.46) years (y), median OS in the cohort was 9.56 y (95% CI: 6.60-NR). 5-y-OS (95% CI) after ICT was 0.64(0.53–0.73), after single RT ≥24 Gy 0.84(0.67–0.92) and 0.58(0.27–0.80) after CRT (Figure 1a). Median progression-free survival (PFS) in the cohort was 3.55 y (95% CI: 2.53–6.08). 5-y-PFS (95% CI) was 0.47 (0.36–0.58) after ICT, 0.40 (0.24–0.55) after single RT ≥24 Gy and 0.55 (0.23–0.78) after CRT (Figure 1b). The research was funded by: Mrs Berta Kamprad´s foundation. The research was made possible in part by research funding from Janssen Pharmaceuticals AB Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chemotherapy, Radiation Therapy No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: In mantle cell lymphoma (MCL), time to relapse is a critical factor, and patients experiencing disease progression within 24 months from treatment start (POD24) have inferior survival. However, the cut-off at 24 months is arbitrary and potentially overly simplified. We aimed to quantify the impact of the timing of disease progression on overall survival, stratified by the most common first-line treatment concepts (Nordic-MCL, R-Bendamustin, and R-CHOP). Methods: Using the population-based Swedish lymphoma register, we identified all systemically treated MCL patients diagnosed between 2006 and 2018. We supplemented this with information on progression and relapse from medical chart reviews through 2022. Patients were categorized based on first-line treatment (Nordic MCL regimen, R-Bendamustin, R-CHOP, and others). POD was defined as a lack of response to primary therapy (progressive disease [PD]) or an initial response followed by a relapse. To assess the impact of POD timing on survival, we used an illness-death model with transition rates estimated using flexible parametric survival models to predict the five-year overall survival (OS) conditional on either being progression-free or experiencing POD as a smooth function of time since primary treatment. Results: A total of 1193 patients receiving systemic treatment were included. The median age at diagnosis was 70 years, and patients were followed for a median of 4 years (range 0–16 years, alive patients, six years). 33% of patients received R-Bendamustin (n = 387, median age 75 years), 30% received the Nordic MCL regimen (n = 351, median age 62 years), and 23% received R-CHOP (n = 276, median age 72 years). Almost half of the patients (48%, n = 571) experienced POD during follow-up. The five-year OS from treatment start was 47%, and progression-free survival was 32%. Among patients treated in the first line with either R-Bendamustin or the Nordic MCL protocol, those with a POD had substantially lower 5-year OS compared to patients who remained progression-free, also for POD occurring up to six years after primary treatment. For patients treated with R-CHOP, the impact of POD was largest if it occurred within 2–3 years after first-line therapy. Keyword: Aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Late effects in patients with mantle cell lymphoma treated with or without autologous stem cell transplantation.

Studies on late effects in patients with mantle cell lymphoma (MCL) are becoming 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 patients with MCL, recorded in the Swedish Lymphoma Register, aged 18 to 69 years, diagnosed between 2000 and 2014 (N= 620; treated with HD-ASCT, n= 247) and 1:10 matched healthy comparators. Patients and comparators were followed up via the National Patient Register and Cause of Death Register, from 12 months after diagnosis or matching to December 2017. Incidence rate ratios of the 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 patients with MCL. Patients with MCL had especially high relative risks of infectious, respiratory, and blood disorders. Within this observation period, no difference in the rate of these complications, including secondary neoplasms, was observed between patients treated with and without HD-ASCT. Most of the patients died from their lymphoma and not from another cause or treatment complication. Taken together, our results imply that most of the posttreatment health care needs are related to the lymphoma disease itself, thus, indicating the need for more efficient treatment options.

Survival by First-line Treatment Type and Timing of Progression Among Follicular Lymphoma Patients: A National Population-based Study in Sweden.

In follicular lymphoma (FL), progression of disease ≤24 months (POD24) has emerged as an important prognostic marker for overall survival (OS). We aimed to investigate survival more broadly by timing of progression and treatment in a national population-based setting. We identified 948 stage II-IV indolent FL patients in the Swedish Lymphoma Register diagnosed 2007-2014 who received first-line systemic therapy, followed through 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by first POD at any time during follow-up using Cox regression. OS was predicted by POD using an illness-death model. During a median follow-up of 6.1 years (IQR: 3.5-8.4), 414 patients experienced POD (44%), of which 270 (65%) occurred ≤24 months. POD was represented by a transformation in 15% of cases. Compared to progression-free patients, POD increased all-cause mortality across treatments, but less so among patients treated with rituximab(R)-single (HR = 4.54, 95% CI: 2.76-7.47) than R-chemotherapy (HR = 8.17, 95% CI: 6.09-10.94). The effect of POD was similar following R-CHOP (HR = 8.97, 95% CI: 6.14-13.10) and BR (HR = 10.29, 95% CI: 5.60-18.91). The negative impact of POD on survival remained for progressions up to 5 years after R-chemotherapy, but was restricted to 2 years after R-single. After R-chemotherapy, the 5-year OS conditional on POD occurring at 12, 24, and 60 months was 34%, 46%, and 57% respectively, versus 78%, 82%, and 83% if progression-free. To conclude, POD before but also beyond 24 months is associated with worse survival, illustrating the need for individualized management for optimal care of FL patients.

Outcome of limited-stage peripheral T-Cell lymphoma after CHOP(-like) therapy: A population based study of 239 patients from the Nordic lymphoma epidemiology group.

Peripheral T-Cell Lymphomas (PTCLs) are rare, aggressive lymphomas with poor outcomes, but limited-stage disease is infrequent and not well-described. This study reports outcomes and prognostic factors in limited-stage nodal PTCLs in a binational population-based setting. Patients were identified from the Danish and Swedish lymphoma registries. Adults diagnosed with limited-stage nodal PTCL (stage I-II) and treated with CHOP(-like) therapy ±radiotherapy between 2000 and 2014 were included. Medical records were reviewed by local investigators. A total of 239 patients with a median age of 62 years were included; 67% received 6-8cycles of CHOP(-like) therapy and 22% received 3-4cycles, of which 59% also received radiotherapy. Autologous stem cell transplant consolidation was administered to 16% of all patients. Median follow-up was 127 months with 5-years overall survival (OS) of 58% (95% CI: 53-65) and progression-free survival (PFS) of 53% (95% CI: 47-59). In multivariable analysis, age ≥ 60 years and B-symptoms were unfavorable and ALK+ anaplastic large cell T-Cell lymphoma was favorable for survival outcomes. There was no difference in treatment-specific outcome (3-4cycles vs. 6-8cycles of CHOP(-like) ± radiotherapy). Low-risk patients (age < 60 without B-symptoms) had a 5-year OS of 77% (95% CI 67-89%). In the present study of limited-stage nodal PTCL, survival after curative intent chemotherapy +/- radiotherapy was inferior to that of limited-stage diffuse large B-cell lymphoma, but a subgroup of young patients without B-symptoms had very good outcomes. Treatment outcomes after 3-4cycles versus 6-8cycles of CHOP(-like) therapy were comparable.

CNS Relapse in T-Cell Lymphoma Index: A Risk Score to Predict Central Nervous System Relapse in Patients with T-Cell Lymphomas

Background: Central nervous system (CNS) relapse (CNSr) in patients with aggressive non-Hodgkin lymphoma is uncommon but carries a high morbidity and mortality. Data in T- and NK-cell lymphomas (TCL) are sparse, though the few small case series describing CNSr in TCL report an incidence up to 9% with median overall survival (mOS) less than 3 months (mo). We previously reported a large (n=75) case series of CNSr in TCL (Abstract #1382, ASH 2021). Herein, we developed a prediction score for CNSr in newly diagnosed patients with TCL. Methods: We retrospectively collected clinicopathologic and treatment data from 19 US academic centers from patients diagnosed with TCL between 1/1/09-1/1/19 who experienced CNSr (CNSr cohort). We combined these data with that from patients diagnosed with TCL without CNSr from a single institution (Penn cohort) to create a training set (T-set) enriched for patients with CNSr. Patients with leukemic or cutaneous TCL subtypes were excluded. We applied a LASSO Cox proportional hazards model to the T-set to create a predictive score for factors associated with CNSr and validated this score in an independent population-based validation set (V-set) from the Swedish Lymphoma Registry, which was not enriched for CNSr. Results: We evaluated data from 91 and 135 patients in the CNSr and Penn cohorts, respectively, which were combined to form the T-set and compared them to the V-set (n=745). Median age in the T-set was lower than in the V-set (60 vs 67; p<0.001). The most common TCL subtypes in the T-set and V-set were peripheral TCL, not otherwise specified (PTCL, NOS; 23% vs 34%, respectively; p=0.002), TCL with T-follicular helper phenotype (23% vs 14%, respectively; p=0.001), and ALK-negative anaplastic large cell lymphoma (18% vs 15%, respectively; p=0.352). CNS prophylaxis, defined as intrathecal therapy or high-dose methotrexate, was more common in the V-set than in the T-set (15% vs 9%, respectively; p=0.012). Rates of stem cell transplantation (SCT) as consolidation in first remission (CR1) did not differ significantly between the T-set and V-set (p=0.140). The median follow-up time was 37.6 mo in the T-set and 95.9 mo in the V-set. The median progression free survival (mPFS) and mOS after diagnosis were 9.8 mo and 33.2 mo in the T-set, respectively, and 8.5 mo and 17.9 mo in the V set, respectively. Within the T-set, mPFS and mOS were shorter for patients in the CNSr cohort vs the Penn cohort (6.0 mo vs 37.1 mo [p<0.001] and 17.3 mo vs 78.1 mo [p<0.001], respectively). In univariate analysis of the CNSr-enriched T-set, CNS prophylaxis, SCT in CR1, or frontline etoposide did not significantly decrease the risk of CNSr. Using several clinicopathologic characteristics, we fitted a LASSO Cox proportional hazards model to the T-set, which selected histology, LDH, stage, B-symptoms, and ≥2 sites of extranodal involvement (ENI) for a weighted risk score of CNSr (Fig. 1A). Variables most strongly associated with CNSr were PTCL, NOS (HR 2.64), enteropathy-associated TCL (HR 2.92), and ≥2 sites of ENI (HR 2.66). We stratified the T-set into tertiles based on weighted scores (x), which was low-risk if x≤0.14, intermediate-risk if 0.14<x ≤1.11, or high-risk if x>1.11. Cumulative incidence of CNSr in each respective group was 19.6%, 55.1%, and 83.7%. When the same cutoffs were applied to weighted scores in the V-set, we confirmed separation into distinct low-, intermediate-, and high-risk groups with cumulative incidences of CNSr of 1.9%, 4.9%, and 7.3%, respectively (Fig. 1B). As the V-set population was not enriched for CNSr, the relative incidence is expectedly lower compared to the T-set. Compared to the low-risk group in the V-set, risk of CNSr was significantly increased in the high-risk group (HR 5.72, p=0.002) and increased with a trend toward significance in the intermediate-risk group (HR 3.35, p=0.057). Conclusions: In a cohort of patients with TCL enriched for CNSr, we were able to characterize several risk factors associated with CNSr and developed a predictive CNSr in T-cell lymphoma Index (CITI) that could stratify patients into 3 distinct risk groups. PTCL, NOS, EATL, and ≥2 sites of ENI had the highest impact on risk of CNSr. The CITI score was validated in an independent population-based cohort. Although CNSr was uncommon even in high-risk patients (7.3%), our data will inform clinical decision making and may allow for identification of patients with TCL at high-risk of CNSr in future studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Sequencing and Survival in Follicular Lymphoma: A National Population-Based Study

Introduction Follicular lymphoma (FL) is characterised by a vast clinical and molecular heterogeneity. Whereas early progression of disease (POD) within 24 months has been identified as an important prognostic factor in different cohorts, potential associations with number of treatment lines, treatment sequencing and survival have not been thoroughly described in real world data. To further identify patient groups with a high need for novel therapeutic strategies in clinical routine and for inclusion in clinical trials we aimed to describe treatment patterns and survival in a national population-based setting. Methods We identified all patients diagnosed with FL in the nationwide Swedish Lymphoma register (coverage >95%) during the period 2007 to 2014, with follow-up through 2020. Information on progression, relapse, transformation and treatments was collected through review of medical records. A total of 2,079 patients were identified. Patients who did not provide informed consent (n=40), were diagnosed with transformed FL (n=144) or grade 3B (n=72), or where medical record data was missing (n=51) were excluded. The main analysis included patients receiving any first-line systemic treatment. Patients who were initially managed with radiotherapy (RT) only or a watch and wait (WaW)-approach were included in the main analysis if/when they received their first systemic treatment. Consolidation treatment including RT, maintenance with anti-CD20 antibody therapy or autologous stem cell transplantation (ASCT) was noted but did not count as separate treatment lines. Overall survival (OS) was illustrated graphically with the Kaplan-Meier method. Results In the final cohort of patients with FL (N=1,772), median age at diagnosis was 65 (18-98) years, and median follow-up time was 6.7 (0.003-13.9) years. Overall, 412 patients (23%) were managed with WaW only during the entire follow-up. Among patients with stage I or limited stage II disease treated curatively with RT at diagnosis (n=304), 60% (n=181) never needed additional therapy. In total, 1,174 patients (66%) received any first systemic treatment. The most common first-line treatment was R-CHOP (425/1,174, 36%), followed by R-single (361, 31%) and BR (184, 16%). The use of R-CHOP as first-line treatment decreased between calendar periods, whereas the use of BR and R-single in first line increased. Among patients starting any first line, 460 (39%) received systemic second-line treatment. Here, BR was most commonly administered (143/460, 31%) followed by R-CHOP (136/460, 30%) and R-single (60/460, 13%). A third-line treatment was administered to 204 patients (17%). Again, BR was most commonly chosen (67, 31%), followed by R-CHOP (41, 19%) and platinum-based chemotherapy (28, 13%). Only 81 (7%) patients required fourth-line treatment, and the maximum number of treatment lines administered were seven. The number of patients treated with the varying regimens in first and subsequent treatment lines are presented as a Sankey plot in Figure 1. Time to next treatment decreased with increasing number of treatment lines, as did OS. Time to next treatment was 2 years on average from the first to second treatment lines, 1.4 years to third line and 1 year to fourth line. The 5-year OS from first-line treatment was 75%, and the corresponding figures following second, third and fourth lines of therapy were 53%, 36% and 24%, respectively (Figure 2). During the whole study period, 173 (15%) patients received systemic treatment due to transformation, 258 (22%) received R-maintenance and 79 (7%) patients underwent ASCT. Conclusion In this national population-based cohort of FL, one in four patients never needed active oncological treatment. Among patients starting any first-line systemic therapy, 39% required a second line, and 18% a third line over a median follow-up of about 7 years. Further, time to next treatment decreased with increasing number of treatment lines and number of treatment lines was associated with dramatically worse survival. We conclude that, in addition to patients with FL experiencing POD24, patients who require multiple treatment lines (≥3) constitute a group with a large clinical unmet need, and methods to identify these patients at an early stage are warranted. The present results provide valuable real-world reference data for the design and interpretation of clinical trials of new treatments in FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment-Related Circulatory Diseases and Mortality in Hodgkin Lymphoma Patients Using Multi-State Modelling and Relative Survival

Introduction Diseases of the circulatory system (DCS) are some of the most common late effects of Hodgkin lymphoma (HL), primarily due to mediastinal radiotherapy and/or anthracycline-containing chemotherapy (e.g., ABVD and BEACOPP). As DCS is very common in the general population, modelling DCS attributable to HL therapy versus that expected in the general population is relevant to understand the magnitude of DCS reduction that could be achieved with less cardiotoxic therapies. This real-world data study used multi-state modelling and relative survival to estimate treatment-related DCS risk in HL survivors. Material and methods All HL patients registered in the Swedish Lymphoma Register 2000-2018, aged 18-80 years at diagnosis, and treated with anthracycline-containing therapy were included. DCS events were identified in the Swedish National Inpatient Register (ICD-10 codes I00-I99) and defined as the first admission for DCS after HL diagnosis. Sex-, year-, and age-specific DCS incidence rates in the general population were retrieved from public records. Patients were followed from treatment initiation through a series of states: alive and DCS-free, alive and with (excess or expected) DCS, dead without DCS, and dead after DCS. Follow-up ended on date of death, emigration, or December 31st, 2019, whichever came first. All state transitions were modelled separately using flexible parametric survival models, yielding hazard ratios (HR) with 95% confidence intervals (CI). A relative survival model incorporating the expected DCS rates was fitted to allow for estimation of excess DCS, which was then interpreted as treatment-related. Transition probabilities (i.e., the likelihood of being in a state) were predicted for specific patient groups, by sex and low/high (≤200/>200 mg/m2) cumulative anthracycline dose. Results In a total of 1,929 HL patients, the mean age at diagnosis was 42 years, 54% were males, and 49% were treated with high dose anthracycline (Table 1). The distribution of treatments was 66% ABVD, 20% CHOP-like, and 14% BEACOPP. During a median follow-up of 7.6 years (IQR: 4.5-11.0), 145 (7.5%) died without DCS, 377 patients (20%) were diagnosed with DCS, and 87 (5%) died after DCS. Figure 1a shows the sex-specific transition probabilities for a patient with advanced stage disease, diagnosed in 2000, at age 50, and treated with a cumulative anthracycline dose of >200mg/m2 in a ABVD regimen. The probability of being in the treatment-related (excess) DCS state at 10 years after first line treatment was 0.35 (95% CI: 0.09-0.75) for males and 0.41 (95% CI: 0.10-0.81) for females in this patient group. Figure 1b shows the probabilities for limited stage male patients diagnosed in 2000 at age 50, treated with ABVD, by low/high anthracycline dose. Here, the probability of being in the treatment-related (excess) DCS state at 10 years was 0.44 (95% CI: 0.16-0.76) and 0.53 (95% CI: 0.25-0.80) for low and high dose anthracycline patients, respectively. There were no significant differences in treatment-related (excess) DCS incidence rates or post DCS all-cause mortality rates (Table 1). Females had a significantly lower non-DCS mortality rate than males (adj. HR=0.69, 95% CI: 0.49-0.97), as did patients treated with high compared to low anthracycline dose (adj. HR=0.28, 95% CI: 0.18-0.44). Conclusion After 10 years, females had higher risks of treatment-related (excess) DCS compared to males, although not statistically significant and likely due to superior survival. The same was seen for high compared to low cumulative doses of anthracycline. Female sex and high dose anthracycline reduced the non-DCS mortality rate, but not the excess DCS incidence rate. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sex differences in lymphoma incidence and mortality by subtype: A population-based study.

It is well established that the male sex is associated with increased risk for, as well as poorer survival of, most cancers. A similar pattern has been described in lymphomas but has not yet been comprehensively assessed. In this nationwide population-based cohort study, we used the Swedish Lymphoma Register to investigate sex differences in lymphoma subtype incidence and excess mortality in adults (age 18-99) diagnosed in 2000-2019. Male-to-female incidence rate ratios (IRRs) and excess mortality ratios (EMRs) adjusted for age and calendar year were predicted using Poisson regression. We identified 36 795 lymphoma cases, 20 738 (56.4%) in men and 16 057 (43.6%) in women. Men were at significantly higher risk of 14 out of 16 lymphoma subtypes with IRRs ranging from 1.15 (95% confidence interval [CI] 1.09-1.22) in follicular lymphoma to 5.95 (95% CI 4.89-7.24) in hairy cell leukemia. EMRs >1 were seen in 13 out of 16 lymphoma subtypes indicating higher mortality in men, although only statistically significant for classical Hodgkin lymphoma 1.26 (95% CI 1.04-1.54), aggressive lymphoma not otherwise specified 1.29 (95% CI 1.08-1.55), and small lymphocytic lymphoma 1.52 (95% CI 1.11-2.07). A corresponding analysis using data from the Danish Lymphoma Register was performed with comparable results. In conclusion, we demonstrate a significantly higher incidence and trend toward higher mortality in men for most lymphoma subtypes. Future studies with large patient material that include detailed clinicopathological prognostic factors are warranted to further delineate and explain sex differences in lymphoma survival to enable optimal management of lymphoma patients regardless of sex.