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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.

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).

Background Response to modern treatment strategies, which combine cytotoxic compounds with immune stimulatory agents and targeted treatment is highly variable among MCL patients. Thus, providing prognostic and predictive markers for risk adapted therapy is warranted and molecular information that can help in patient stratification is a necessity. In relapsed MCL, biopsies are rarely available and molecular information from tumor tissue is often lacking. Today, the main tool to access risk is the MCL international prognostic index (MIPI), which does not include detailed biological information of relevance for different treatment options. To enable continuous monitoring of patients, non-invasive companion diagnostic tools are needed which can further reduce cost and patient distress and enable efficient measurements of biological markers. Methods We have assessed if serum-based protein profiling can identify immune related proteins that stratify relapsed MCL patients based on risk. Overall, 371 scFv targeting 158 proteins were assessed using an antibody microarray platform. We profiled patients (n = 44) who had been treated within the MCL6-Philemon trial combining targeted and immune-modulatory treatment. Results The downstream processing led to the identification of the relapsed immune signature (RIS) consisting of 11 proteins with potential to stratify patients with long and short overall survival (OS). Moreover, in this population, MIPI alone failed to separate high, intermediate and low risk patients, but a combined index based on MIPI together with RIS, MIPIris, showed improved performance and significantly stratified all three risk groups based on OS. Conclusions Our results show that addition of biological parameters to previous prognostic indices improves patient stratification among patients treated with BTK inhibitor triplet combination, particularly, in the identification of an extreme high risk group.

Eskelund et al examined clonal hematopoiesis (CH) in a cohort of patients with mantle cell lymphoma (MCL) treated with first-line chemotherapy and autologous stem cell transplantation. In young, good-risk MCL patients, CH after first-line therapy arises almost entirely from preexisting clones, stabilizes after a period of expansion posttransplantation, and does not negatively impact survival.

A chemotherapy regimen defines the drug or drugs to be used, the dosage, and the frequency and duration of drug administration for the treatment of a given cancer diagnosis. For successful and safe...

This is the peer reviewed version of the following article: Naudin, S., Margalef, M.S., Hosnijeh, F.S., Nieters, A., Kyrø, C. Tjønneland, A. ... Ferrari, P. (2020) Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study. International Journal of Cancer, 147(6):1649-1656, which has been published in final form at https://doi.org/10.1002/ijc.32977. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) were evaluated in a large‐scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow‐up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1‐standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1‐SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.

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.

Immunotherapy in cancer takes advantage of the exquisite specificity, potency, and flexibility of the immune system to eliminate alien tumor cells. It involves strategies to activate the entire immune defense, by unlocking mechanisms developed by tumor cells to escape from surrounding immune cells, as well as engineered antibody and cellular therapies. What is important to note is that these are therapeutics with curative potential. The earliest example of immune therapy is allogeneic stem cell transplantation, introduced in 1957, which is still an important modality in hematology, most notably in myeloid malignancies. In this review, we discuss developmental trends of immunotherapy in hematological malignancies, focusing on some of the strategies that we believe will have the most impact on future clinical practice in this field. In particular, we delineate novel developments for therapies that have already been introduced into the clinic, such as immune checkpoint inhibition and chimeric antigen receptor T-cell therapies. Finally, we discuss the therapeutic potential of emerging strategies based on T-cell receptors and adoptive transfer of allogeneic natural killer cells.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton’s tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.

BackgroundThe possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies.AimTo pin-point biologically relevant changes in pre- and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients.MethodsPre- and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points.ResultsProteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre- and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS).ConclusionWe show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.

Background: The outcome for diffuse large B-cell lymphoma (DLBCL) patients has improved with the immunochemotherapy combination R-CHOP. An increased rate of heart failure is well documented following this treatment, whereas incidence and outcome of other cardiac complications, for example myocardial infarction, are less well known. Method: We identified 3548 curatively treated DLBCL patients in Sweden diagnosed between 2007 and 2014, and 35474 matched lymphoma-free general population comparators. The incidence, characteristics and outcome of acute myocardial infarctions (AMIs) were assessed using population-based registers up to 11 years after diagnosis. The rate of AMI was estimated using flexible parametric models. Results: Overall, a 33% excess rate of AMI was observed among DLBCL patients compared with the general population (HR: 1.33, 95% CI: 1.14–1.55). The excess rate was highest during the first year after diagnosis and diminished after 2 years. High age, male sex and comorbidity were the strongest risk factors for AMI. Older patients (>70 years) with mild comorbidities (i.e. hypertension or diabetes) had a 61% higher AMI rate than comparators (HR: 1.61, 95% CI: 1.10–2.35), whereas the corresponding excess rate was 28% for patients with severe comorbidities (HR: 1.28, 95% CI: 1.01–1.64). Among younger patients (≤70), a short-term excess rate of AMI was limited to those with severe comorbidities. There was no difference in AMI characteristics, pharmacological treatment or 30-day survival among patients and comparators. Conclusion: DLBCL patients have an increased risk of AMI, especially during the first 2 years, which calls for improved cardiac monitoring guided by age and comorbidities. Importantly, DLBCL was not associated with differential AMI management or survival. (Less)

Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton’s tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.

We performed a national population-based study of all patients diagnosed with diffuse large B-cell lymphoma (DLBCL) in Sweden in 2007–2014 to assess treatment intent and risk of relapsed/refractory disease, including central nervous system (CNS) relapse, in the presence of competing risks. Overall, 84% of patients started treatment with curative intent (anthracycline-based) (n = 3550, median age 69 years), whereas 14% did not (n = 594, median age 84 years) (for 2% the intent was uncertain). Patients treated with curative intent had a 5-year OS of 65.3% (95% CI: 63.7–66.9). The median OS among non-curatively treated patients was 2.9 months. The 5-year cumulative incidence of relapsed/refractory disease in curative patients was 23.1% (95% CI: 21.7–24.6, n = 847). The 2-year cumulative incidence of CNS relapse was 3.0% (95% CI: 2.5–3.6, n = 118) overall, and 8.0% (95% CI: 6.0–10.6, n = 48) among patients with high CNS-IPI (4–6), when considering other relapse locations and death as competing events. The incidence of relapsed/refractory DLBCL overall and in the CNS was lower than in previous reports, still one in seven patients was not considered fit enough to start standard immunochemotherapy at diagnosis. These results are important for quantification of groups of DLBCL patients with poor prognosis requiring completely different types of interventions.

PURPOSE: Personalized therapies are leading to an increasing number of marketing authorizations based on single-arm trials, which increases the demand for better post-authorization monitoring strategies. The aim of the present study was to estimate the power over time as data accrue in population-based registries for detecting deviations from the expected efficacy/safety of chimeric antigen receptor T cell (CAR-T) therapy approved for relapsed/refractory large B-cell lymphoma (RR-LBCL).METHODS: The number of real-world RR-LBCL patients was projected over time in a general population of 5, 15, and 25 million citizens using lymphoma registry data. For each scenario, we computed the power over time for detecting significant deviations in efficacy (1-year overall survival [1yOS]) when comparing to historical controls (SCHOLAR-1 study; 1yOS, 28%) and RR-LBCL patients treated with CAR-T cell therapy in a single-arm trial (ZUMA-1; 1yOS, 59%) as well as deviations in selected adverse events (grade ≥3 aphasia) from the ZUMA-1 trial. We assumed a 10% absolute deviation in 1yOS (efficacy) and a relative increase of 50% in grade ≥3 aphasia (safety).RESULTS: Assuming a general population of 5, 15, and 25 million, the accrual time needed to achieve 80% power for detecting a significant increase over the 1yOS reported in SCHOLAR-1 was 9, 4, and 3 years, respectively, while 80% power for detecting a significant decrease in 1yOS compared to ZUMA-1 required 10.5, 4.5, and 3 years of data accrual, respectively. However, corresponding estimates for aphasia were >20, 8, and 5 years, respectively.CONCLUSIONS: Projections of the statistical power for detecting important deviations in efficacy/safety from that reported in pivotal clinical trials(s) provide critical information about the expected performance of post-authorization monitoring programs.

Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.

To better understand the role of individual and lifestyle factors in human disease, an exposome‐wide association study was performed to investigate within a single‐study anthropometry measures and lifestyle factors previously associated with B‐cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed‐up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B‐cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL., What's new? The “exposome” includes all non‐genetic exposures (e.g. diet, viral, environmental, etc.), with the goal of understanding how those exposures may affect an individual's health. In this study, the authors used a technique called “EWAS” (exposome‐wide association study) to identify multiple factors that are associated with B‐cell lymphoma (BCL) risk. Their results confirm both previously reported risk factors and protective factors. In addition, they identify several previously unknown associations. These new insights, gained via the analysis of multiple exposures, suggest that traditional single‐factor approaches may be suboptimal compared with an EWAS approach.

Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

Supplemental Digital Content is available in the text, While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6–182), 5-year progression-free survival (PFS) was 45% (95% CI: 35–54) and 5-year overall survival (OS) was 71% (95% CI: 62–79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.

In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the “MIPI-genetic” (“MIPI- g”). The “MIPI-g” improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. (Trial registered at clinicaltrials.gov identifier: NCT02354313).

Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. The clinical features, treatment, and prognosis are not well characterized. We performed a multicenter retrospective study of CNS MZL. Twenty‐six patients were identified: half with primary and half with secondary CNS involvement. The median age was 59 years (range 26‐78), 62% female and 79% with ECOG performance status ≤ 1. The most common disease site was the dura (50%). Treatment was determined by the treating physician and varied substantially. After a median follow up of 1.9 years, the estimated 2‐year progression‐free (PFS) and overall survival (OS) rates were 59% and 80%, respectively. Secondary CNS MZL was associated with 2‐year OS of 58%. CNS MZL is rare, but relative to other forms of CNS lymphoma, outcomes appear favorable, particularly among the subset of patients with dural presentation and primary CNS presentation., Marginal zone lymphoma of the central nervous system (CNS MZL) is rare. In this multicenter retrospective study of 26 patients, the estimated 2‐year overall survival rate was 80%. Outcomes appear favorable, particularly among the subset of patients with primary dural presentation.

Patients with diffuse large B-cell lymphoma (DLBCL) who fail to complete planned treatment with R-CHOP due to toxicity are sparsely described. We investigated the extent of failure to complete treatment (six cycles or more, or three cycles + RT for patients with stage I disease) with R-CHOP for reasons unrelated to non-response, the determinants of such failure and the outcome among these patients. Three thousand one hundred and forty nine adult DLBCL patients who started primary treatment with R-CHOP were identified through the Swedish lymphoma register 2007-2014. Of these, 147 (5%) stopped prematurely after 1-3 cycles of R-CHOP for reasons unrelated to non-response, 168 (5%) after 4-5 cycles and 2639 patients (84%) completed planned treatment. Additionally, 195 (6%) patients did not complete treatment due to non-response or death before treatment end. In a multivariable logistic regression model, age > 75 years, poor performance status, extranodal disease and Charlson Comorbidity Index >= 1 were significantly associated with failure to complete planned R-CHOP treatment for other reasons than non-response. Non-completion of treatment strongly correlated with survival. Five-year overall survival for patients who received 1-3 cycles was 26% (95% CI: 19%-33%), 49% (95% CI: 41%-57%) for 4-5 cycles and 76% (74%-77%) for patients who completed treatment. Failure to complete planned R-CHOP treatment is an important clinical issue associated with inferior survival. Old age and poor performance status most strongly predict such failure. These results indicate a need for improved treatment tailoring for patients with certain baseline demographics to improve tolerability and chance for treatment completion.

Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.

Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.

Comorbidity impacts survival in B-cell lymphoma patients, but the influence in peripheral T-cell lymphomas (PTCLs) has been little studied. To investigate the impact of comorbidity on outcome in PTCL, we identified adult patients with newly diagnosed PTCL from 2000 to 2009 in the Swedish Lymphoma Registry. Data on comorbidity at diagnosis were retrospectively collected according to the Charlson Comorbidity Index (CCI). Comorbid conditions were present in 263 out of 694 (38%) patients. A CCI score of ≥2 was associated with inferior overall survival (OS) (hazard ratio [HR] 1.63, P .001) and progression-free survival (HR 1.54, P .001) in multivariate analysis. In patients undergoing front-line autologous stem cell transplantation (auto SCT), CCI0 was associated with inferior OS (HR 2.40, P = .013). Chemotherapy regimens were classified as curative or low-intensity treatments. Among patients aged ≥75 years (n = 214), low-intensity and curative treatment groups had similar OS (HR 0.8, P = .6), also when adjusted for CCI. In summary, our results demonstrate CCI to be independently associated with survival in PTCLs. Even limited comorbidity impacted survival after front-line auto SCT, which needs to be considered in treatment decisions. Intensive anthracycline-based chemotherapy in elderly PTCL patients might be of limited benefit.

Background: Peripheral T cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphoid neoplasms with poor outcomes. Many patients are elderly with increased comorbidities. Single-center retrospective studies describe outcomes in elderly PTCL patients and suggest comorbidity adversely affects outcomes. Little is known about the treatment, outcomes and impact of comorbidity in a large cohort of elderly PTCL patients. This study aims to describe outcomes of elderly PTCL patients in a large unselected international patient cohort. Methods: Patients with PTCL age ≥ 70 diagnosed from January 1, 2010 - December 31, 2015 in the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) were identified. The SLR covers ~ 95% of adult lymphoma patients in Sweden and the CCR includes information on all cancers diagnosed in California. Patients with precursor T-cell malignancies, primary cutaneous lymphomas, and leukemic subtypes were excluded. Data on comorbidity at diagnosis were retrospectively collected according to the Charlson Comorbidity Index (CCI) and clinical outcomes of the cohort were extracted. Statistical analysis: Patient characteristics, clinical variables and outcomes were summarized using descriptive statistics and compared by Chi-square or Fisher's exact test. Outcomes of interest included overall survival (OS) and cause of death. Kaplan-Meier estimates of OS stratified by groups were calculated and presented in figures. Median OS was reported with 95% confidence interval (CI). Comparisons between groups for OS were done by log-rank test. Univariate and multiple Cox proportional hazards models provided hazards ratio estimates and 95% CI for risk factors. Tests for significance were two-tailed and a p-value less than the 0.05 significance level was considered statistically significant. Analyses were performed using software SAS version 9.4 (2013). Results: A total of 839 patients were included (SLR, n = 176, CCR, n = 663). Median age was 78 (SLR) and 79 (CCR) years, respectively. Included subtypes were AITL, n = 226; ALCL, n = 122; EATL, n = 31; Hepatosplenic TCL, n = 7; NK/T-cell lymphoma, n = 10; and PTCL NOS, n = 443. ECOG performance status was not available. CCI data was available in 731 patients (87 %), and CCI scores were divided into groups = 0-1 (61 %) and CCI > 1 (39 %). Male patients more often had a CCI score > 1 (p = 0.024). No other significant baseline differences were seen between the 2 groups (Table 1). Patients in the SLR more often received multiagent treatment compared to the CCR (63 % vs 44 %, p < 0.001). Age > 80 years, CCI > 1 and advanced Ann Arbor stage (III-IV) were significant prognostic factors for worse outcome. No difference in survival was seen between men and women nor the SLR and CCR (Table 2). Patients with a CCI >1 had a statistically significant worse survival compared to patients with a CCI =0-1 (0.36 years v 0.91 years, p=0.0001). Of the PTCL subtypes, AITL patients had a significantly better outcome (median OS = 1.26 years) compared to ALCL (OS = 0.57 years) and PTCL NOS (OS = 0.66 years). Patients receiving multiagent therapy had improved survival compared to patients not receiving multiagent therapy. When comparing OS in patients diagnosed in 2010-2012 with 2013-2015, no improvement was seen for the later period (Figures 1-4). Lymphoma was the most common cause of death with > 70 % of deaths related to lymphoma irrespective of CCI score (Table 3). Discussion: At the time of submission, this study presents the largest international cohort of elderly patients with PTCL. Prognosis is poor and comorbidity seems to further worsen . In contrast to younger patient series, patients with AITL had a better survival than patients with PTCL NOS and ALCL, and were more common in the CCR than in the SLR. Multiagent treatment was associated with improved outcome. A possible confounder could be that fit patients are also the ones receiving treatment, and it is a setback that adjustment for ECOG was not possible, making treatment data somewhat difficult to interpret. As expected, advanced stage (Ann Arbor III-IV) was associated with worse survival. Conclusion: We believe this is one of the largest cohorts presented in elderly patients with PTCL. Comorbidity is an important adverse factor in this group, whereas treatment seems to improve outcome. The majority of these patients die of lymphoma within a year from diagnosis, and development of new treatments represents an unmet clinical need. Disclosures Jerkeman: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Roche: Research Funding.

Background Mantle cell lymphoma (MCL) is a B-cell malignancy, with increasing incidence. It is currently not considered curable. Although a proportion of patients obtain prolonged remission after first line chemoimmunotherapy, most patients will experience several lines of therapy. Hitherto, population based data of the complete care trajectories for patients with MCL have not been available, limiting our knowledge to that from single centre experiences. Here, we present the initial data from a nationwide attempt to collect all available data from all patients diagnosed with MCL. Methods Patients with a primary diagnosis of MCL in 2006-2018 were identified in the Swedish Lymphoma Register and followed until March 6, 2020. The register contains information about clinical characteristics, prognostic factors, primary treatment, treatment response and relapse. Information on further lines of therapy, including treatment response and progression/relapse was extracted through medical chart review in all patients. Results In total, 1411 patients were diagnosed with MCL during the period 2006-2018. Currently, complete data are available for 445 (32%). The most frequently used first line regimens were R-bendamustine (n=131, 29%) and Nordic MCL2 (n=102, 21%). 31 patients (7%) were managed with an initial watch and wait strategy. 87 patients (19%) received consolidation with an autologous stem cell transplant, and 51 (11%) patients received rituximab maintenance. After a median follow-up of 49 months (IQR 25-81), 279 patients (63%) did not experience any relapse, and the median age for patients without relapse was higher compared to the relapse group (73 vs 70 years). 166 patients (37%) experienced a first relapse or progression. The most frequently used second line regimen was R-bendamustine (n=49, 30%). 102 (21%) and 51 (11%) experienced a second or third relapse/progression, respectively. The median PFS after 1st (PFS-1), 2nd, (PFS-2), 3rd (PFS-3) and 4th (PFS-4) lines of therapy were 40, 11, 6, and 4 months. Patients with early progression, defined as a PFS-1 Conclusion In this population-based series, mainly treated with conventional chemoimmunotherapy, 63% of patients diagnosed with MCL did not experience relapse/progression after a median follow-up of 40 months - due to death before relapse or continuous remission. In addition, PFS and OS continue to drop with successive lines of therapies. Early progression, both after 1st and after 2nd line therapy is associated with markedly impaired OS -identifying patient populations in need of novel treatment strategies. Figure 1 A. Progression-free survival (PFS) in 445 patients with mantle cell lymphoma (MCL) diagnosed in Sweden 2006-2018 according to first line regimen. B. Overall survival (OS) according to time to relapse (PFS -1 < 24 months or >24 months). Figure Disclosures Jerkeman: Abbvie: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Roche: Research Funding. Weibull:Janssen Cilag: Research Funding. Smedby:Celgene: Consultancy; Janssen: Research Funding; Takeda: Research Funding.

Background: 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 may be one of the most important objectives of cancer therapy. In addition, baseline HRQOL has in other lymphoma populations been shown to be predictive of outcome. Hitherto, there are only few reports on HRQOL in MCL. The primary aim of this study was to explore HRQOL before, during and after chemotherapy in an elderly population with MCL. Secondary aims were to identify predictors for HRQOL, information that can be used for improvement in rehabilitation. Methods: The cohort consisted of patients included in the multicenter open-label phase Ib-II NLG-MCL4 trial (LENA-BERIT), designed to evaluate the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment in elderly patients (>65 years) with MCL. The treatment with R-B stopped after six months, LEN continued for six more months. HRQOL was assessed by the EORTC QLQ-C30 questionnaire pre-treatment, and after 6, 12 and 24 months post study inclusion. For the functional scales and the global quality of life scale a higher score represents a better level of functioning. For the symtom scales and single items, a higher score corresponds to a higher level of symtoms. Patient scores were compared to scores from a reference population sample at baseline. Survival was analysed by Kaplan-Meier estimates, and cox regression multivariate analysis was used to assess survival with adjustments for prognostic factors, age, sex and more. Results: Fifty-one patients were enrolled, 1 patient was excluded based on screen failure. Median age was 71 years (range 62-84), 37 were men (73%). Stratified according to Mantle Cell Lymphoma International Prognostic Index (MIPI), 5 (10%) were low-risk, 18 (38%) intermediate and 26 (52%) high-risk. Follow-up time for living patients were 52 months, and for deceased patients 27 months. Median overall survival time were 52 months. The proportion of patients reporting HRQOL data was at baseline; 48 (96%), after 6 months; 33 (83%), after 12 months; 27 (89%), and after 24 months; 12 (75%). During the first six months of treatment, several functional scores deteriorated, and after 12 months it had stabilised at baseline level or better. The global health status (QoL) improved at 12 months after diagnosis, but then dropped to baseline levels after 2 years. Before treatment, patients exhibited levels of the symptom scores, comparable to the reference population. Six months after start of therapy, the scores for pain, dyspnoea and insomnia were improved, while appetite loss and diarrhoea were impaired. After 12 months, the symptom scales improved to a level superior compared both to baseline and the reference population. The population was divided into two groups, with the median as cut-off values. In the multivariate analysis, including MIPI, gender and the presence of TP53 mutation, impaired pre-treatment physical function, role function and elevated pain score were independent prognostic markers for overall survival. Role function and pain were also independent prognostic markers for progression free survival. Conclusion: In this population of elderly patients with MCL, pre-treatment HRQOL was similar to the reference population. During treatment, HRQOL deteriorated, but reverted to the same level as the reference population after treatment. Pre-treatment physical and role function and pain were independent factors associated with overall survival. These novel findings may be used to design support during treatment and improve rehabilitation. Figure Disclosures Jerkeman: Roche: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Abbvie: Research Funding.

Background Today, even though most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard immunochemotherapy, 20-30% are refractory to primary therapy or relapse during follow-up with a drastic worsening of the prognosis. In recent years, new promising treatment options including CAR-T cell therapy are becoming available for relapsed/refractory (R/R) DLBCL patients although so far with logistic challenges including disease control and toxicities, and a considerable cost. In view of these challenges, we aimed to estimate the proportion of patients with R/R DLBCL that are likely to be eligible for CAR-T cell therapy in clinical routine, and their expected outcome in the pre-CAR-T era. Methods All patients with DLBCL starting primary therapy with curative intent were identified in the Swedish Lymphoma Register for the period 2007-2014 (N=3550). Primary CNS and primary mediastinal B-cell lymphomas were excluded. Data regarding primary treatment response and relapse was validated through medical chart review in the entire cohort during follow-up until Dec 31st 2017, and information about additional treatment lines including disease characteristics, blood test results, and relapse treatment response was collected. Eligibility for CAR-T cell therapy was estimated retrospectively based on eligibility criteria specified in clinical trials, both at first relapse by applying similar criteria as in the ongoing TRANSFORM, ZUMA-7 or PILOT studies (hereafter termed "CAR-T-2ndline"), and at second relapse applying criteria similar to those specified in the JULIET trial (hereafter termed "CAR-T-3rdline"). Administration of second- and third-line therapies and corresponding response rates were considered as proxies for eligibility and response to bridging therapies. Criteria applied for "CAR-T-2ndline" included R/R DLBCL within 12 months of evaluation date of primary treatment, age 18-75 years, ECOG 0-1, and additional criteria as specified in the TRANSFORM trial (see figure footnote). Criteria applied for "CAR-T-3rdline" included relapse following second-line therapy, age 18-76 years, ECOG 0-1, and additional criteria as in the JULIET trial (see figure footnote). Individuals with missing data on performance status were assumed ineligible. We lacked information about other malignancies in the disease history. Overall survival probabilities were estimated with the Kaplan-Meier method among all R/R DLBCL patients in the trial-specified age intervals and separately among those fulfilling all trial criteria. Results In the cohort of 3550 curatively treated DLBCL patients, 847 (cumulative incidence 23%) experienced R/R disease during a median follow-up of 4.3 years. Median age at first relapse was 71 years (range 18-95 years). Overall, 308 patients ≤75 years experienced progression/relapse within 12 months and were able to start second-line therapy. Of these, 148 patients (17% of all R/R DLBCL patients) fulfilled trial eligibility criteria for "CAR-T-2ndline", of whom 60 responded with at least partial remission (overall response rate, ORR, 41%). At second relapse, 370 patients 76 years or younger received third-line therapy, of whom 55 (6.5% of all R/R DLBCL patients) were deemed eligible for "Car-T-3rdline", and 13 responded (ORR 24%, another 5 patients had SD). Two-year overall survival (OS) among all R/R DLBCL patients ≤75 years receiving second-line therapy was 20% (95% confidence interval, CI, 16-25%) (Fig 1). Among those eligible for "CAR-T-2ndline", 2-year OS was 24% (95% CI 17-31%). Among patients ≤76 years at second relapse, 2-year OS was 18% (95% CI 13-24%), and among those eligible for "CAR-T-3rdline", 21% (95% CI 11-32%). Conclusion In the population-based setting, one in six patients (17%) with R/R DLBCL fitted trial eligibility criteria for CAR-T-cell therapy at first relapse and only one in fifteen patients (6.5%) fitted trial criteria at second relapse at retrospective evaluation. Figures were reduced when adding requirement of response to relapse/bridging therapy. These estimates illustrate to what extent current CAR-T cell therapies may be applied in a routine setting when based on trial criteria, and the need for development of modified and additional therapies in this group. Outcome estimation confirmed a poor outcome in these groups and did not indicate that fulfillment of trial criteria led to selection bias in terms of survival. Disclosures Ekstroem Smedby: Janssen Cilag: Research Funding; Celgene: Other: Advisory Board; Takeda: Research Funding. Harrysson:Janssen Cilag: Research Funding. Jerkeman:Janssen: Research Funding; Roche: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Gilead: Research Funding. Eloranta:Janssen Cilag: Research Funding.

Background: The prognosis for mantle cell lymphoma (MCL) remains poor, particularly for elderly patients. Our aim was to assess the impact of comorbidities on MCL outcome and causes of death. Methods: For all 1,385 MCL patients (1,009 males, 376 females) diagnosed 2000-2014 in Sweden (median age 71 years, range 22-96) comorbidities within 10 years prior to diagnosis were classified according to the Charlson comorbidity index (CCI; 0, 1, 2+). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using flexible parametric models to compare rates of lymphoma-specific and all-cause-mortality by comorbidities. Model-based predictions were used to obtain probabilities of death from lymphoma/other causes. Findings: Severe comorbidity was independently associated with higher all-cause (HR=1·52; 95% CI:1·24-1·85) and lymphoma-specific mortality (HR=1·.31; 95% CI:1·04-1·65), particularly among patients with connective tissue, renal, psychiatric diseases, and dementia. 606 patients (44%) had any comorbidity (CCI 1+) and 388 (28%) severe comorbidity (CCI 2+). Over a median follow-up of 3.7 years (range 0-16), 633 patients (46%) died, the majority (76%) from their lymphoma. Among females with comorbidities, non-lymphoma deaths represented a larger proportion of all deaths, as compared to comorbid males. Interpretation: Since most MCL patients (including comorbid patients) died from lymphoma, more efficient and tolerable lymphoma treatments need to be considered also to patients with severe comorbidity. Patients with renal, psychiatric, or connective tissue disorders need particular attention. However, among females with comorbidities, the likelihood of dying from disorders other than MCL was still considerable, perhaps favoring a more liberal use of a "wait-and-watch" approach. Funding Statement: This study was supported by the Swedish Cancer Society CAN (2012/774). I. Glimelius was supported by The Swedish Cancer Society (CAN 2016/440) and the Swedish Society of Medicine. Declaration of Interests: MJ: Honoraria from Janssen, Gilead, Celgene, Roche, Acerta. Research support from Janssen, Celgene, Abbvie and Gilead. KES: Honoraria from Celgene. Research support from Janssen. IG Honoraria from Janssen. SE has an ongoing role as project manager in a publicprivate real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals NV (contract: 5-63/2015) Ethics Approval Statement: The study was approved by the Regional Board of the Ethical Committee in Stockholm, Sweden (2007/1335-31/4, 2010/1624-32).

Introduction: Chronic inflammation plays a critical role in lymphomagenesis and several dietary factors seem to be involved its regulation. The aim of the current study was to assess the association between the inflammatory potential of the diet and the risk of lymphoma and its subtypes in the European Investigation into Cancer and Nutrition (EPIC) study. Methods: The analysis included 476,160 subjects with an average follow-up of 13.9 years, during which 3,136 lymphomas (135 Hodgkin lymphoma (HL), 2606 non-Hodgkin lymphoma (NHL) and 395 NOS) were identified. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 28 dietary components and their corresponding inflammatory weights. The association between the ISD and lymphoma risk was estimated by hazard ratios (HR) and 95% confidence intervals (CI) calculated by multivariable Cox regression models adjusted for potential confounders. Results: The ISD was not associated with overall lymphoma risk. Among lymphoma subtypes, a positive association between the ISD and mature B-cell NHL (HR for a 1-SD increase: 1.07 (95% CI 1.01; 1.14), p trend = 0.03) was observed. No statistically significant association was found among other subtypes. However, albeit with smaller number of cases, a suggestive association was observed for HL (HR for a 1-SD increase = 1.22 (95% CI 0.94; 1.57), p trend 0.13). Conclusions: Our findings suggested that a high ISD score, reflecting a pro-inflammatory diet, was modestly positively associated with the risk of B-cell lymphoma subtypes. Further large prospective studies on low-grade inflammation induced by diet are warranted to confirm these findings Grant sponsor: Spanish Ministry of Economy and Competitiveness-Carlos III Institute of Health cofunded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe, Grant numbers: [PI13/00061 (to Granada), PI13/01162 (to EPIC-Murcia, Regional Governments of Andalucıa, Asturias, Basque Country, Murcia and Navarra), PI17/01280 and PI14/01219 (to Barcelona), Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP, Spain)]; Grant sponsor: Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), CERCA Programme / Generalitat de Catalunya for institutional support; Grant number (2017SGR1085)

PURPOSE Estimates of short- and long-term survival for young patients with classic Hodgkin lymphoma (cHL) are of considerable interest. We investigated cHL prognosis in the era of contemporary treatment at different milestones during the follow-up. PATIENTS AND METHODS On the basis of a Nordic cohort of 2,582 patients diagnosed at ages 18 to 49 years between 2000 and 2013, 5-year relapse risks and 5-year restricted losses in expectation of lifetime were estimated for all patients and for patients who achieved event-free survival (EFS) for 12 (EFS12), 24 (EFS24), 36 (EFS36) or 60 (EFS60) months. The median follow-up time was 9 years (range, 2.9 to 16.8 years). RESULTS The 5-year overall survival was 95% (95% CI, 94% to 96%). The 5-year risk of relapse was 13.4% (95% CI, 12.1% to 14.8%) overall but decreased to 4.2% (95% CI, 3.8% to 4.6%) given that patients reached EFS24. Relapse risk for patients treated with six to eight courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) was comparable to that of patients treated with six to eight courses of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) despite more adverse risk criteria among patients treated with BEACOPP. Both from diagnosis and if EFS24 was reached, the losses in expectation of lifetime during the following 5 years were small (from diagnosis, 45 days [95% CI, 35 to 54 days] and for patients who reached EFS24, 13 days [95% CI, 7 to 20 days]). In stage-stratified analyses of 5-year restricted loss in expectation of lifetime, patients with stages I to IIA disease had no noteworthy excess risk of death after they reached EFS24, whereas risk remained measurable for patients with stages IIB to IV cHL. CONCLUSION Real-world data on young patients with cHL from the Nordic countries show excellent outcomes. The outlook is particularly favorable for patients who reach EFS24, which supports limited relapse-oriented clinical follow-up.

The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992–2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

European Commission (DG‐SANCO). International Agency for Research on Cancer. Spanish Ministry of Economy and Competitiveness ‐ Carlos III Institute of Health cofunded by FEDER funds/European Regional Develpment Fund (ERDF) ‐ a way to build Europe. Grant Numbers: PI13/00061 (to Granada), PI13/01162 (to EPIC‐Murcia, Regional Governments of Andalucıa, Asturias, Basque Country, Murcia and Navarra), PI17/01280 and PI14/01219 (to Barcelona). Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP, Spain), Solans, M., Benavente, Y., Saez, M., Agudo, A., Naudin, S., Hosnijeh, F.S., Noh, H., Freisling, H., Ferrari, P., Besson, C., Mahamat-Saleh, Y., Boutron-Ruault, M.-C., Kühn, T., Kaaks, R., Boeing, H., Lasheras, C., Rodríguez-Barranco, M., Amiano, P., Huerta, J.M., Barricarte, A., Schmidt, J.A., Vineis, P., Riboli, E., Trichopoulou, A., Bamia, C., Peppa, E., Masala, G., Agnoli, C., Tumino, R., Sacerdote, C., Panico, S., Skeie, G., Weiderpass, E., Jerkeman, M., Ericson, U., Späth, F., Nilsson, L.M., Dahm, C.C., Overvad, K., Bolvig, A.K., Tjønneland, A., de Sanjose, S., Buckland, G., Vermeulen, R., Nieters, A., Casabonne, D.

Introduction: Patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) who are ineligible for intensive chemotherapy and autologous stem cell transplantation have limited therapeutic options and poor prognosis, and there is an unmet need for new therapeutic alternatives in this situation. Based on gene expression profiling, DLBCL can be divided into the germinal centre B-cell (GCB) and the activated B-cell (ABC) subtype. These subtypes are dependent on different oncogenic pathways and may differ in responsiveness to targeted therapies. Idelalisib is a small-molecule inhibitor of PI3Kδ, currently approved for treatment of follicular lymphoma and CLL. Based on the high response rate of idelalisib in heavily pretreated patients with indolent B-cell lymphomas, among whom many may have undetected transformed disease, we hypothesized that idelalisib may also be active in r/r DLBCL, particularly in the GCB subtype, due to frequent PTEN loss and unregulated activation of PI3K signaling in this subtype. Here, we evaluated the efficacy and safety of idelalisib as a single agent therapy in patients with r/r DLBCL in a multi-centre phase II non-randomized trial. To our knowledge, this is the first prospective study on the use of single agent idelalisib in patients with DLBCL. Methods: Eligibility criteria were: Patients with DLBCL, including transformed low-grade lymphoma, with r/r disease after at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and not candidate for autologous stem cell transplantation. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT for the GCB-DLBCL. Idelalisib 150 mg x 2 p o was given until progression or unacceptable toxicity. Results: In the period 2017-2020, 36 patients were included from six centers in Sweden and Denmark, 18 patients showed a GCB and 16 patients an ABC subtype, two patients could not be classified for subtype. The study was terminated prematurely due to futility in reaching the primary endpoint. The median age was 74 years. Patients had received a median of three previous regimens. In total, 34/36 patients have discontinued treatment (n=24 due to PD, n=7 due to an adverse advent (AE), n=2 due to death, n=1 due to other cause). Median duration of treatment was 8 weeks (range 2-92), see the swimmers plot. Treatment emergent-AEs of grade 3 or higher included elevated liver transaminases (n=6), hematological toxicity (n=4), colitis (n=2), CMV reactivation (n=1), and skin toxicity (n=1). No patient died due to possible treatment-related toxicity. With a median follow up time of 4.9 months, 22 patients were evaluable for efficacy after 8 weeks of treatment, as of May 31, 2020. Fourteen patients had progressive disease before that point of time. The ORR in all patients was 14 % with 3 patients achieving CR (8 %) and 2 patients PR (6 %). In GCB versus ABC subgroups, 2 patients (11 %) compared to 3 patients (19 %) patients reached CR/PR. Among the 9 patients with transformed lymphoma, 3 patients (33 %) reached CR/PR. Among the 5 patients with CR/PR, median duration of response was 67 weeks (95 % CI:19-not reached). Median OS in the GCB subgroup was 15 weeks (95 % CI: 11-56) compared to 23 weeks (95 % CI: 9-not reached) in the ABC subgroup. To date, 2 of the responding patients show ongoing response after 53 respectively 86 weeks of treatment. Conclusions: Single agent idelalisib demonstrated modest activity in patients with r/r DLBCL, but the primary endpoint with higher activity in the GCB subtype was not reached. Instead, a numerically higher response rate was observed in the ABC subgroup. In addition, we noticed a higher number of responding patients among patients with transformed lymphoma compared to patients with primary DLBCL. The results need to be interpreted with caution given the low number of patients. Idelalisib showed a manageable and expected safety profile. Considering the limited treatment options for patients with r/r DLBCL, there is an urgent need for novel therapeutic approaches, especially for patients who are ineligible for autologous stem cell transplantation and chimeric antigen receptor T-cells (CART) therapy. Further exploration of the potential benefit of PI3K inhibitors in selected subgroups of r/r DLBCL is motivated. Translational analyses to reveal potential biomarkers for efficacy of PI3K inhibition in DLBCL will now be performed, in tumor tissue and in circulating tumor DNA from plasma. Figure Disclosures Ekstroem Smedby: Celgene: Other: Advisory Board; Janssen Cilag: Research Funding; Takeda: Research Funding. Larsen:Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Celgene/BMS: Other: Advisory Board; Novartis: Other: Travel grants, Advisory Board. Jørgensen:Gilead: Other: Advisory Board; Novartis: Other: Advisory Board; Roche: Other: Advisory Board. Brown:Gilead: Other: Advisory Board. Jerkeman:Celgene: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. OffLabel Disclosure: Idelalisib is a small-molecule inhibitor of PI3KÃŽÃ'´ currently used for patients with CLL and follicular lymphoma. In this trial, based on the high response rate in heavily pretreated patients with indolent B-cell lymphomas, we hypothesize that this agent may also be active in relapsed/refractory DLBCL.

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL) over the last 10-15 years, this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is an active agent in R/R MCL, but with a limited duration of response. For patients refractory to this agent, there are few treatment options. Other active agents in R/R MCL are venetoclax, and the combination of lenalidomide and rituximab (R2). In this multi-centre open-label phase Ib-II trial, we evaluated safety and efficacy of this triplet combination in R/R MCL; previously exposed to ibrutinib and ibrutinib naive. Another objective of this trial was to test the feasibility of stopping treatment in patients achieving molecular remission. The objective of the phase Ib portion of the trial was to establish the recommended phase 2 dose (RP2D) of venetoclax and lenalidomide. Methods: Main eligibility criteria: patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease. The primary endpoint was overall response rate (ORR) at 6 months. Minimal residual disease (MRD) monitoring by patient specific RQ-PCR was performed every 3 months during follow-up, according to EuroMRD criteria. Treatment schedule (cycle length 28 days): Cohort A: Lenalidomide 15 mg p o daily, days 1-21, Venetoclax 400 mg p o days 1-28 (after ramp-up). Cohort B: Lenalidomide 20 mg p o daily, days 1-21, Venetoclax 400 mg p o days 1-28 (after ramp-up). Cohort C: Lenalidomide 20 mg p o daily, days 1-21, Venetoclax 800 mg p o days 1-28 (after ramp-up). Cohort Y: Lenalidomide 15 mg p o daily, days 1-21, Venetoclax 600 mg p o days 1-28 (after ramp-up). In all cohorts: Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. The phase 1 portion of the study followed a sequential dose escalation, '3 + 3' design. The MTD was defined as the highest dose studied for which the incidence of DLT was less than two out of six subjects during the first 8 weeks of treatment. For both the phase I and II part of the trial, when MRD-negative in blood, treatment continue for another 3 months, when a new evaluation of MRD in blood and bone marrow is performed. If MRD negativity is confirmed, treatment is stopped and the patient will be followed with MRD and CT. Patients without molecular marker are followed by PET-CT. Results: Three patients each in Cohorts A, B and C were enrolled from 31-MAY-2018, at 5 centres in Sweden and Norway. No patient in Cohorts A+B experienced any DLT, but in Cohort C, 2/3 patients had grade 3-4 infection (DLT). A fourth cohort, named Y, was started, intermediate between B and C, without DLT, and the RP2D was established as Venetoclax 600 mg, and Lenalidomide 15 mg. Since then, an additional 8 pts have been recruited in the phase 2 portion (total 21). The median age is 71 years. Patients had received a median of 2 previous regimens (range: 1-7), and 3 had progressed after ibrutinib. Hematological toxicity was the most frequent AE, with 19/20 pts with G3-4 neutropenia, requiring G-CSF support, and 6/20 pts with G3-4 thrombocytopenia. Three events of G3-4 infection were recorded. Single patients each reported G-3-4 rash, renal failure, atrial flutter or melaena. No event of tumor lysis syndrome was reported. With a median follow up time of 5 months, 16 patients were evaluable for efficacy as of June 30, 2020. ORR is 56% with 5 CR and 4 PR. Median duration of response and PFS have not been reached. 4 pts (20%) have stopped treatment in CR and molecular remission, 6 are on treatment, 2 pts have undergone allo-SCT in remission, 1 pt stopped treatment due to toxicity, and 8 have progressed, out which 4 have died. One of two evaluable patients previously treated with ibrutinib responded with a PR. Of the 6 patients evaluable for MRD at 6 months, 6/6 patients have achieved molecular remission in blood and 5/6 in bone marrow. Conclusions: At a target dose of venetoclax of 600 mg, and lenalidomide 15 mg, this combination is tolerable and shows efficacy in R/R MCL, although associated with a high degree of neutropenia. Interestingly, a response adapted treatment strategy, by stopping treatment in molecular remission, appears to be feasible, although follow-up is still short. Figure Disclosures Jerkeman: Abbvie: Research Funding; Roche: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Hutchings:Daiichi: Research Funding; Sankyo: Research Funding; Roche: Consultancy; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Genmab: Honoraria; Takeda: Honoraria; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Genmab: Consultancy.

Lenalidomide plus bendamustine-rituximab does not overcome the adverse impact of TP53 mutations in mantle cell lymphoma

Introduction: The incidence of most lymphomas increase with age. Comorbidities, frailty and old age per se largely preclude inclusion of the very elderly in clinical trials. Thus, optimal treatment strategies and patient characteristics for elderly patients are less well defined and there is a lack of knowledge of how the oldest lymphoma patients are treated and fare. Lymphomas have a heterogeneous biology and even milder treatment may sometimes result in remission, survival benefits, and good palliation. With the rise in incidence and prevalence of lymphoma in an increasingly ageing population, improved knowledge regarding disease course, treatment and prognosis of lymphoma subtypes among the very elderly lymphoma population is warranted. Therefore, we aimed to characterise the cohort of very elderly (aged ≥85) patients with lymphoma with regard to distribution of lymphoma subtypes, choice of active treatment and overall survival (OS). Methods: The study population was identified via the Swedish lymphoma register (SLR, >95% national coverage). Data regarding stage, prognostic factors, treatment and survival among all patients aged ≥85 diagnosed with malignant lymphomas (any histology) 2007-2013 was retrieved. Diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas, Hodgkin lymphoma and mantle cell lymphoma were grouped as aggressive lymphomas. Follicular lymphoma, marginal zone lymphoma and Mb Waldenström were grouped as indolent lymphomas. Overall survival (OS) proportions were computed and illustrated using the Kaplan-Meier method. Multivariate cox regression analysis was used to investigate associations of active treatment, age, Ann Arbor stage, performance status (PS) and elevated lactate dehydrogenase (LDH) with survival. Results: During the time period 1191 patients aged ≥85 were identified through the SLR. Of these, 298 (25%) were aged ≥90. The most commonly occurring lymphoma subtype was DLBCL (n=458, 38%). The number and proportion of patients with other subtypes are presented in Table 1. Among all patients, 36% presented with elevated LDH, 39% with PS score >2, 49% with Ann Arbor stage III-IV, 11% with bulky disease and 25% presented with B-symptoms. All these factors were associated with inferior outcome, as expected. Data regarding administration of active treatment was available for 75% (n= 887) of patients. Among patients with aggressive lymphoma subtypes, 389 patients (72%) received active treatment, of which 44% was specified as administered with curative intent. The most common type of treatment in this group was dose reduced R-CHOP. Among patients with indolent subtypes 124 patients (49%) received active treatment (most commonly chlorambucil, bendamustine or trofosfamide). Two-year OS for patients with aggressive and indolent lymphomas was 27.5% and 58.7%, respectively. OS rates for specific subtypes are presented in table 1 and figure 1. The increase in OS associated with administration of active treatment was more prominent among patients with aggressive lymphomas. Here, patients who received active treatment had a 2-year OS rate of 36.2%, compared to 11.3% for those who did not (adjusted hazard ratio (HR): 0.47 (0.35-0.63) p= Conclusion: We demonstrate relatively encouraging overall survival data for very elderly patients from a real-world setting. Our data indicate that active treatment may be feasible also for some of the very elderly patients with lymphoma, especially among patients with aggressive lymphomas such as DLBCL. This study represents the largest cohort of its kind and this type of population based data may be useful to inform and improve clinical lymphoma management in this age group. Updated data including relative survival, comorbidity and addition of patients aged ≥85 from the Danish lymphoma register will be available and presented by the time of the ASH meeting. Disclosures Smedby: Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals.

Background: Comorbidity impacts overall survival amongst patients with diffuse large B-cell lymphoma (DLBCL). However, associations of comorbidity with lymphoma characteristics, treatment selection and lymphoma-specific mortality are less well known. Objective: To examine the impact of comorbidity on DLBCL characteristics, treatment intent and cause of death. Methods: We identified 3905 adult patients diagnosed with DLBCL 2007–2013 through the Swedish Lymphoma Register. We assessed comorbid disease history according to the Charlson comorbidity index (CCI). Comorbidity data and causes of death were collected through register linkage. Associations were estimated using multinomial regression and flexible parametric survival models. Results: Overall, 45% of the patients (n = 1737) had a history of at least one comorbidity at DLBCL diagnosis (cardiovascular disease, diabetes and solid cancer were most frequent), and 997 (26%) had a CCI score of ≥2. The relative probability of presenting with poor performance status (PS > 2) was higher amongst comorbid patients [Relative Risk Ratio (RRR)PS >2: 2.02, 95% CI: 1.63–2.51]. Comorbid patients had a substantially lower relative probability of receiving curative treatment (RRR: 0.48, 95% CI: 0.38–0.61). Amongst all patients, CCI ≥ 1 was associated with a significantly increased risk of all-cause and lymphoma-specific death after adjustments. Amongst patients selected for curative treatment, comorbidity was associated with an increased risk of all-cause death (HRCCI >1: 1.54, 95% CI: 1.32–1.80), but not with lymphoma-specific death (HRCCI >1: 1.05, 95% CI: 0.86–1.28). Conclusion: Comorbidity is associated with inferior DLBCL outcome, mainly due to a lower likelihood of receiving treatment with curative intent. Possibly, more comorbid DLBCL patients could be treated with curative intent if comorbid conditions were optimized in parallel.

Survival has improved among patients with diffuse large B-cell lymphoma (DLBCL) with the addition of anti-CD20 antibody therapy. We aimed to quantify trends and remaining loss in expectation of life (LEL) due to DLBCL at a national population-based level. Patients diagnosed with DLBCL 2000-2013 (N = 7114) were identified through the Swedish Lymphoma Registry and classified according to the age-adjusted International Prognostic Index (aaIPI). The novel measure LEL is the difference between remaining life years among patients and the general population and was predicted using flexible parametric models from diagnosis and among 2-year survivors, by age and sex. Median age at DLBCL-diagnosis was 70 (18-105) years and 54.8% presented with stage III-IV disease. On average, LEL due to DLBCL decreased from 8.0 (95% CI: 7.7-8.3) to 4.6 (95% CI: 4.5-4.6) years over the study period. By risk group, LEL was most reduced among patients with aaIPI ≥2 aged 50-60 years. However, these patients were still estimated to lose >8 years in 2013 (eg, LELmales50years 8.6 years (95% CI: 5.0-12.3)). Among 2-year survivors, LEL was reduced from 6.1 years (95% CI: 5.6-6.5) (aaIPI ≥ 2) and 3.8 years (95% CI: 3.6-4.1) (aaIPI < 2) to 1.1 (95% CI: 1.1-1.2) and 1.0 year (95% CI: 0.8-1.1), respectively. The reduction was observed across all ages. Results for females were similar. By using LEL we illustrate the improvement of DLBCL survival over time. Despite adequate immunochemotherapy, substantial LEL among patients with IPI ≥ 2 points to remaining unmet medical needs. We speculate that observed reduced losses among 2-year survivors indicate a reduction of late relapses.

The aims of the present study were to establish the maximally tolerated dose (MTD) of the histone deacetylase inhibitor valproate together with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). A phase 1 dose escalation study of valproate together with R-CHOP followed by a dose expansion study using the established MTD of valproate was performed. MTD of valproate together with R-CHOP was established at 60 mg/kg per day, as higher doses resulted in auditory adverse events (AEs). In the study population, 2-year progression-free survival was 84.7% (95% confidence interval [CI], 73.2%-98%). The 2-year overall survival (OS) was 96.8% (n = 31; 95% CI, 90.8%-100%). These data were compared with 2 risk-factor matched populations of R-CHOP-treated patients from the Swedish Lymphoma Registry (cohort A, n = 330 and B, n = 165). As compared with the matched cohorts, we observed a statistically significant (P = .034 and 0.028, respectively) beneficial effect of the addition of valproate to R-CHOP on the OS in the studied population. In conclusion, addition of valproate to R-CHOP is a feasible strategy in first-line treatment of DLBCL. The proposed phase 2 dose is 60 mg/kg per day together with prednisone. Auditory AEs were unexpected and warrant close monitoring. Our findings suggest that drugs that target histone deacetylation may add benefit and are tolerable when combined with standard R-CHOP in DLBCL. The phase 1 trial was registered at www.clinicaltrials.gov as #NCT01622439.

Background: Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone. Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0–3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m2) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1–21. The primary endpoint was overall response assessed in the intention-to-treat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276. Findings: Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17·8 months (IQR 14·7–20·9), 38 (76%, 95% CI 63–86) patients had an overall response, including 28 (56%, 42–69) patients who had a complete response and ten (20%, 11–33) who had a partial response. The most common grade 3–4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke. Interpretation: Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial. Funding: Janssen and Celgene.

The international prognostic index (IPI) and similar models form the cornerstone of clinical assessment in newly diagnosed diffuse large B-cell lymphoma (DLBCL). While being simple and convenient to use, their inadequate use of the available clinical data is a major weakness. In this study, we compared performance of the International Prognostic Index (IPI) and its variations (R-IPI and NCCN-IPI) to a Cox proportional hazards (CPH) model using the same covariates in nondichotomized form. All models were tested in 4863 newly diagnosed DLBCL patients from population-based Nordic registers. The CPH model led to a substantial increase in predictive accuracy as compared to conventional prognostic scores when evaluated by the area under the curve and other relevant tests. Furthermore, the generation of patient-specific survival curves rather than assigning patients to one of few predefined risk groups is a relevant step toward personalized management and treatment. A test-version is available on lymphomapredictor.org.

Six cycles of R-CHOP-21 are not inferior to eight cycles for treatment of diffuse large B-cell lymphoma : a Nordic Lymphoma Group Population-based Study

Trends in Hodgkin lymphoma (HL) survival among patients treated outside of clinical trials provide real-world benchmark estimates of prognosis and help identify patient subgroups for targeted trials. In a Swedish population-based cohort of 1947 HL patients diagnosed 1992-2009 at ages 18-59 years, we estimated relative survival (RS), cure proportions (CP) and median survival times using flexible parametric cure models. Overall, the CP was 89% (95%CI:0.87-0.91) and median survival of the uncured was 4.6 years (95%CI:3.0-6.3). For patients aged 18-50 years diagnosed after the year 2000, CP was high and stable, whereas for patients 50-59 years cure was not reached. The survival of relapse-free patients was similar to that of the general population (RS5-year :0.99; 95%CI:0.98-0.99, RS15-year :0.95; 95%CI:0.92-0.97). The excess mortality of relapsing patients was 19 times (95%CI:12-31) that of relapse-free patients. Despite modern treatments, patients with adverse prognostic factors (e.g., advanced stage) still had markedly worse outcomes [CPstage:IIIB 0.82 (95%CI:0.73-0.89); CPstage:IVB 0.72, (95%CI:0.60-0.81)] and patients with international prognostic score (IPS) ≥3 had 2.7 times higher excess mortality (95%CI:1.0-7.0, p=0.04) than patients with IPS

No randomised study in the rituximab era has been performed specifically to evaluate addition of etoposide to treatment of diffuse large B-cell lymphoma (DLBCL). The aim of this study was to compare the outcome with three chemotherapy regimens (R-CHOP-21, R-CHOP-14 and R-CHOEP-14) in a population-based cohort in terms of overall survival, adjusted for clinical prognostic factors. Through the Swedish Lymphoma Registry, 3443 patients with DLBCL were identified 2007-2012. Among all patients, there was no evidence of a difference between the regimens, after adjustment for prognostic factors. However, when restricted to patients aged up to 65, R-CHOEP-14 was associated with superior outcome compared to both R-CHOP-21 (hazard ratio: 0.49, 95% confidence interval: 0.3-0.9, p = 0.028) and R-CHOP-14 (hazard ratio: 0.64, 95% confidence interval: 0.4-1.0, p = 0.06), when adjusted for prognostic factors. Results were consistent in an additional stratified analysis with patients grouped according to age and IPI-score. In conclusion, we could show that R-CHOEP-14 was associated with superior overall survival in patients with DLBCL aged up to 65 years, indicating that this may be a valid treatment option for this patient population. To further investigate which patient groups that may benefit the most from treatment intensification, R-CHOEP-14 should be compared to R-CHOP-21 in a randomised setting. Copyright © 2015 John Wiley & Sons, Ltd.