Second primary cancers (SPCs) are a survivorship concern in lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM), but estimates may be influenced by competing mortality and surveillance. We assessed cumulative incidence, relative risk and predictors of SPCs. We studied 521 patients diagnosed with LPL/WM in Region Zealand, Denmark, during 2000-2023. Cancers diagnosed >6 months before or after diagnosis were classified as prior malignancies and SPCs, respectively. Cumulative incidence was estimated with death as a competing event. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) used regional rates. SPC predictors were evaluated using Fine-Gray and Cox models. Median age was 72 years and median follow-up was 8.1 years. Prior malignancy was present in 64 patients (12.3%); 68 (13.1%) developed an SPC. Cumulative incidence was 9.3% at 5 years and 14.6% at 10 years; 166 patients (31.9%) died without a preceding SPC. With 1-year latency, overall cancer risk was not increased (SIR 1.09, 95% confidence interval [CI] 0.84-1.40; AER 21.3 per 10 000 person-years). Haematological cancers showed borderline excess risk, driven by myelodysplastic syndrome. No covariates were associated with SPC risk. SPCs are clinically relevant in LPL/WM, although excess risk appears selective rather than broadly increased. Long-term surveillance should consider myeloid malignancies.

Central nervous system (CNS) involvement in Waldenström macroglobulinemia (WM) is a rare complication that can manifest as Bing-Neel syndrome (BNS) or as histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL). We report data from a single-center cohort of 469 patients consecutively diagnosed with WM between 2000 and 2022. BNS was identified in 1.5

Survival rates for patients with high-risk large B-cell lymphoma (LBCL), particularly those with biological risk factors, remain inadequate. We conducted a biomarker-driven phase II trial involving 123 high-risk patients aged 18-64 with LBCL. Based on their biological risk profiles, patients received either R-CHOEP-14 (without risk factors) or DA-EPOCH-R-based regimens (with risk factors). Biological high-risk factors included C-MYC translocation, C-MYC and BCL2 co-translocation, 17p/TP53 deletion, co-expression of MYC and BCL2, and P53 and/or CD5 immunopositivity. Additionally, we evaluated circulating tumor DNA (ctDNA) kinetics during therapy. Sixty-one patients (50%) were classified into biologically high-risk group. Three-year failure-free survival and overall survival rates for the entire study population were 79% and 88%, respectively. DA-EPOCH-R did not improve survival compared to our previous trial, where patients with the same biological risk factor criteria received R-CHOEP-14-based therapy. High pretreatment ctDNA levels, 17p/TP53 deletion, and TP53 mutations were associated with worse outcomes. In contrast, ctDNA negativity at the end of therapy (EOT) was indicative of a cure and effectively addressed false residual PET positivity. The findings demonstrate promising survival for high-risk LBCL patients, aside from those with TP53 aberrations, high ctDNA levels, and/or EOT ctDNA positivity.

INTRODUCTION:Prognostic models in Waldenström's macroglobulinemia (WM) are typically static, baseline tools applied before treatment initiation and do not account for dynamic post-treatment factors. We evaluated time to next treatment within 24 months (TTNT24), as a prognostic marker in symptomatic patients, and time to lymphoma treatment within 24 months (TTLT24) in initially observed asymptomatic patients. METHODS:In this observational cohort study, patients diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) in Region Zealand from 2000 to 2023 were identified using Danish national registries and health records. TTNT24 was defined as initiation of second-line treatment within 24 months of first-line therapy. TTLT24 was defined as lymphoma-directed treatment initiated within 24 months of diagnosis in initially asymptomatic patients. RESULTS:Among 526 LPL/WM patients, 218 symptomatic patients were evaluated for TTNT24 with 33 (15%) patients receiving second-line treatment within 24 months. TTNT24-positive patients demonstrated inferior overall and lymphoma-related survival compared to TTNT24-negative patients. TTNT24 remained significant in multivariate analysis. Among 310 asymptomatic patients, TTLT24 was significantly associated only with lymphoma-related survival. CONCLUSION:TTNT24 and TTLT24 may serve as dynamic prognostic markers in real-world LPL/WM populations. Their relevance in the era of targeted therapies warrants further investigation.

Next-generation sequencing (NGS) affords comprehensive insights into the genomic landscape of lymphomas. We examined the mutational pattern in patients with Waldenström macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL) as well as the diagnostic and clinical utility of a tailored NGS lymphoma panel. A consecutive series of 45 patients was reviewed and NGS analysis was performed as part of a routine diagnostic setup. The custom designed NGS panel assayed all coding sequences of 59 genes of known clinical significance in lymphoid neoplasms. The most frequently mutated genes were MYD88, CXCR4, BIRC3, CD79B, and ARID1A. Additional somatic mutations were detected in 17 genes with four mutations categorized as pathogenic or likely pathogenic. BIRC3 and TP53 mutations were associated with adverse clinical phenotypes. NGS performance for the MYD88L265P variant was 96% when compared to qPCR. In conclusion, targeted NGS provided important diagnostic and prognostic information in a routine clinical setting.

The clinical and prognostic implications of nodal involvement (NI) in Waldenström macroglobulinaemia (WM) are largely unknown. In this study, we explored the impact of NI on clinical presentation and outcome in a population-based cohort of 469 patients with WM, consecutively diagnosed between 2000 and 2022. NI was detected in 34% of patients and was associated with symptomatic disease, adverse prognostic factors, an increased risk of transformation, and lymphoma-related death. Our findings indicate that NI is of prognostic significance in WM, suggesting a need for enhanced surveillance in these patients.

INTRODUCTION:Extramedullary disease (EMD) is a rare manifestation of Waldenström macroglobulinemia (WM), and its clinical and prognostic implications are poorly understood. METHODS:In this single-center study, we investigated the clinical significance of EMD in a cohort of 469 WM patients. RESULTS:EMD was identified in 30 (6.4%) patients, with the central nervous system, kidneys, and lungs being the most frequently affected sites. The cumulative incidence of EMD was 12.6% at 15 years. Median overall survival rates at 5 and 10 years for patients with EMD were 63% and 37%, respectively. CONCLUSION:Our findings indicate a persistent risk of EMD throughout the disease course, with no significant impact on long-term survival.

Introduction: Survival of patients with high-risk large B-cell lymphoma (LBCL), particularly those with biological risk factors, including chromosomal translocation of BCL2 and MYC oncogenes (double hit; DH) or deletion of 17p/TP53 is suboptimal in response to standard rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) immunochemotherapy. We designed a Nordic Lymphoma Group (NLG-LBC-06) phase II trial to evaluate feasibility and efficacy of a biological risk-adapted treatment strategy in young patients with high-risk aggressive B-cell lymphoma. Methods: Patients aged <65 years with high-risk aggressive B-cell lymphoma (age adjusted International Prognostic Index (aaIPI)≥2 and/or site-specific risk factors for central nervous system (CNS) relapse) were included. All patients received two cycles of R-CHOP-21 with high dose methotrexate (HD) on day 15 and depending on the biological risk factors either four additional courses of biweekly R-CHOP with etoposide (R-CHOEP-14; no biological risk factors) or four courses of dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R; biological risk factors). In addition, one course of R-HD-cytarabine was given to all patients. Biological high-risk was defined as a presence of at least one of the following factors: C-MYC translocation, DH, 17p/TP53 deletion, co-expression of MYC and BCL2 (double protein expression; DPE), P53+ and/or CD5+. Central pathology review was performed by national referral pathologists. Primary end point was 3-year failure free survival (FFS) of the patients with biological risk factors. Results: Between Aug 2017 and Jan 2021, 127 patients were recruited across 14 Nordic centers. At central pathology review, four cases were excluded due to unsuccessful stratification. Median age of the eligible patients was 55 years (range 19-64). Majority of the patients had DLBCL not otherwise specified (n=102; 83%), stage IV disease (n=84; 68%), elevated LDH (n=107; 87%), or B-symptoms (n=72; 59%). C-MYC translocation, DH, 17p/p53 deletion, DPE, P53+ and CD5+ was observed in 20 (17%), 14 (11%), 19 (17%), 39 (32%), 17 (14%) and 8 (7%) of the cases, respectively. Sixty-one patients (50%) were stratified to the biological high-risk group. Most patients (n=112; 91%) received full treatment schedule. In addition, twenty-three patients (19%) received radiotherapy per protocol. Of the 111 patients who underwent response evaluation at the end of immunochemotherapy, 87 (78%) achieved a complete metabolic remission. Treatment failure was recorded in 23 (19%) patients; seven due to adverse event, five due to primary refractory disease and 10 due to lymphoma relapse or progression during follow-up, including two CNS events and one death from other disease. After a median follow up of 37 months (1-63), 3-year FFS, progression free survival (PFS) and overall survival (OS) rates were 79%, 83% and 90%, respectively. Outcome was comparable in biologically high- and low-risk patients (Figure 1, left). Based on a preplanned historical comparison, and after correction for age and aaIPI, FFS of the biological high-risk group (HR, 0,89; 95% CI 0,38-1,71; p=0,58; Figure 1, right) and the entire NLG-LBC-06 study population (HR, 1,03; 95% CI 0,60-1,79; p=0,91) were comparable to FFS of the patients treated in our previous NLG-LBC-05 trial (Leppä et al., 2019). In a multivariate analysis with age and aaIPI, 17p/TP53 deletion remained the only significant biological risk factor for progression and death. Conclusions: Stratification according to biological risk factors is feasible. Safety and efficacy results are encouraging and comparable to our previous study with low number of treatment failures and favorable survival rates. Furthermore, our results indicate that treatment intensification can overcome the adverse impact of biological risk factors, apart from 17p/TP53 deletion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diffuse large B-cell lymphoma is an aggressive disease occurring primarily in elderly patients. Despite high curative rates with doxorubicin-containing treatment, some elderly patients receive less intensive treatments, mainly due to advanced age, comorbidities, and concerns of cardiotoxicity from doxorubicin-containing regimens. We analyzed 1009 patients aged 75 years or older and 10,090 age- and sex-matched comparisons. We aimed to evaluate long-term cardiovascular side effects in elderly patients treated with doxorubicin. Approximately, 64% of patients received doxorubicin-containing treatment. These patients had a persistently increased risk of new-onset heart failure with a hazard ratio of 1.5 and 1.7 when conditioning on survival without heart failure to 6 and 24 months, respectively. Moreover, we observed an increased risk of venous thromboembolism during the first six months following the lymphoma diagnosis. On the contrary, no difference in risk of developing ischemic heart disease or stroke following doxorubicin-containing treatment was observed.

Background In Denmark, fine needle aspiration is the standardized tool for obtaining tissue samples from lymph nodes (LN) of the neck. However, because of a low specificity toward lymphomas, LNs suspicious for this disease are often surgically removed and examined. International studies have implied that a core needle biopsy (CNB) is sufficient for detecting lymphomas, thereby potentially avoiding surgery. However, all studies have been conducted retrospectively and the goal of this prospective study was to find the true sensitivity of CNB. Material and Methods Fifty-seven patients were enrolled in the study, one was excluded due to lack of CNB material. LNs suspected for lymphoma were surgically removed from the neck, whereafter a CNB was obtained from the removed LN. The CNB and the remaining part of the LN were sent to the Department of Pathology for further processing and the samples were blinded and examined by two pathologists separately. A consensus diagnosis was reached in cases with divergent diagnostic proposals. Sensitivity of the CNB method in comparison to whole tissue sections for lymphoma diagnosis was calculated. Results The CNB method gave the correct diagnosis in 66% of lymphoma cases, was inconclusive in 14% and gave an incorrect lymphoma subtype in 18%. In 2% the CNB wrongly resulted in a benign diagnosis. CNB was correct in all the non-lymphoma cases; thereby retaining a specificity of 100%. Conclusion This prospective study found a sensitivity of 66% for diagnosing lymphoma with a CNB. As the CNB in this study was obtained under optimal conditions, unlike in clinical practice, we conclude that CNB cannot be recommended as a standard tool for diagnosing lymphomas.

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.

Mucormycosis is a life threatening infection in patients with haematological disease. We introduced a Mucorales-PCR and an aggressive, multidisciplinary management approach for mucormycosis during 2016–2017 and evaluated patient outcomes in 13 patients diagnosed and treated in 2012–2019. Management principle: repeated surgical debridement until biopsies from the resection margins were clean as defined by negative Blankophor microscopy, Mucorales-PCR (both reported within 24 h), and cultures. Cultured isolates underwent EUCAST E.Def 9.3.1 susceptibility testing. Antifungal therapy (AFT) (mono/combination) combined with topical AFT (when possible) was given according to the minimal inhibitory concentration (MIC), severity of the infection, and for azoles, specifically, it was guided by therapeutic drug monitoring. The outcome was evaluated by case record review. All patients underwent surgery guided by diagnostic biopsies from tissue and resection margins (195 samples in total). Comparing 2012–2015 and 2016–2019, the median number of patients of surgical debridements was 3 and 2.5 and of diagnostic samples: microscopy/culture/PCR was 3/3/6 and 10.5/10/10.5, respectively. The sensitivity of microscopy (76%) and Mucorales-PCR (70%) were similar and microscopy was superior to that of culture (53%; p = 0.039). Initial systemic AFT was liposomal amphotericin B (n = 12) or posaconazole (n = 1) given as monotherapy (n = 4) or in combination with isavuconazole/posaconazole (n = 3/6) and terbinafine (n = 3). Nine patients received topical amphotericin B. All received isavuconazole or posaconazole consolidation therapy (n = 13). Mucormycosis related six month mortality was 3/5 in 2012–2015 and 0/7 patients in 2016–2019 (one patient was lost for follow-up). Implementation of combination therapy (systemic+topical AFT/combination systemic AFT) and aggressive surgical debridement guided by optimised diagnostic tests may improve the outcome of mucormycosis in haematologic patients.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

Introduction: 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 aimed to assess, whether a dose-dense immunochemotherapy approachwith early systemic CNS prophylaxis improves outcome and reduces the incidence of CNS events. Methods: We conducted a Nordic Lymphoma Group phase II (NLG-LBC-05) trial during 2011-2014 in patients aged 18–64 years with untreated DLBCL including BCL-2/MYC double hit lymphomas, and an age-adjusted international prognostic index (aaIPI) 2-3 or site specific risk factors for CNS recurrence. Treatment consisted of two courses of high-dose methotrexate (HD-Mtx) in combination with biweekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP-14), followed by four courses of R-CHOP-14 with etoposide (R-CHOEP-14) and one course of high dose cytarabine with R (R-HD-AraC). In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. Our co-primary endpoints were failure free survival and CNS progression rates. Results: Of 143 enrolled patients, 139 patients were eligible with a median age of 56 (range 20-64). The majority of the patients had advanced stage (92%), elevated LDH (91%), more than one extranodal site, (67%) and B-symptoms (63%). Four (2.9%) patients developed AML/MDS. Treatment related death occurred in five (3.6%) patients. Of the 119 patients who underwent PET-CT, 91 (77%) achieved a metabolic CR, and 19 of 35 patients (21%) with CT-based CRu/PR were in metabolic CR according to PET-CT. Only one out of 15 biopsies (9%) from the PET+ lesions contained vital lymphoma. At five years of median follow-up, failure free survival (FFS), overall survival (OS) and CNS progression rates were 74%, 84% and 2.3%, respectively. Deauville score 5, but not 4 at the end of treatment was associated with increased risk of progression and death. Treatment reduced the risk of progression compared to our previous NLG-LBC-04 trial, where systemic CNS prophylaxis was given after six courses of biweekly R-CHOEP (HR=0.493; 95% CI 0.312-0.780, p=0.003), and overcame the adverse impact of aaIPI3 and BCL-2/MYC double hit lymphomas on survival. Conclusion: The results are encouraging with favorable survival rates, low toxic death rate and low number of CNS events. Keywords: “double-hit” lymphomas; CNS prophylaxis; diffuse large B-cell lymphoma (DLBCL). Disclosures: Leppä, S: Research Funding: Mundipharma, Amgen.

Background: Optimal treatment strategy for the oldest patients with diffuse large B-cell lymphoma (DLBCL) remains controversial, as this group often is precluded from clinical trials, and population-based studies are limited. Methods: All Danish DLBCL-patients >= 75 years diagnosed from 2003 to 2012 were identified, using the Danish National Lymphoma Registry (LYFO). Information regarding baseline characteristics, treatment, comorbidities and outcomes was retrieved from LYFO, the Danish National health registries and medical records. Patients were stratified by age (75e79; 80-84 and 85 + years), comorbidity score and treatment modality (standard treatment [R-CHOP/CHOP-like], less intensive regimens or palliative treatment). Findings: A total of 1011 patients were included. Standard treatment was initiated in 64%, ranging from 83% among patients aged 75-79 years to 32% among patient aged 85 + years. With standard treatment, median overall survival (OS) estimates were 4.6, 2.6, and 1.9 years for the age groups 75-79, 80-84 and 85 + years. Among patient aged 75-79 and 80-84 years, OS was superior with standard treatment, although high comorbidity scores attenuated this association. Among patients aged 85+ years, survival was not influenced by treatment intensity. Patients >= 80 years had similar OS regardless of intended (R-)CHOP dosing, whereas patients of 75-79 years scheduled for full dose had higher OS. Standard treatment was not associated with increased hospitalisation. Interpretation: Standard treatment is feasible with good outcomes in a large proportion of elderly DLBCL-patients. Planned dose reduction in patients aged >= 80 years had no negative impact on OS. (C) 2018 Elsevier Ltd. All rights reserved.

Background: 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 investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two completed Nordic trials including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these studies to compare clinical outcome and prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) vs at the end (CRY-04) of therapy. Patients and Methods: Inclusion criteria were age 18-65 years, primary DLBCL or grade 3 follicular lymphoma without signs of CNS involvement, WHO performance score 0-3, age-adjusted International Prognostic Index (aaIPI 2-3) and/or involvement of anatomical sites associated with an increased risk for CNS recurrence (e.g. testis, facial sinuses, orbita). In CRY-04, six courses of R-CHOEP14 were followed by HD-Mtx and HD-Ara-C. In CHIC, treatment consisted of two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP14 and one course of R-HD-AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. Primary end points were failure free survival (FFS; disease progression, discontinuation of protocolled therapy due to toxicity, death from any cause) at 3 years and CNS progression rate at 1.5 years. Secondary end points included progression-free survival (PFS; disease progression or death from any cause) and overall survival (OS) at 3 years. Results: Among 303 patients enrolled in the trials (CRY-04, n = 160 and CHIC, n = 143), 295 (CRY-04, n = 154 and CHIC, n = 139) met inclusion criteria and were evaluable for baseline characteristics and primary end points. Median age (54 and 56 years, p = 0.222), male/female ratio, stage and aaIPI scores were comparable in the two cohorts. Three-year FFS was 63% in CRY-04 and 77% in CHIC (p = 0.018) after a median follow-up of 5 and 3 years, respectively. Cumulative incidence rates of CNS progression were 5.0% and 2.4% (p = 0.22), and 3-year OS 80% and 86% (p = 0.508), respectively. Treatment in the CHIC reduced the risk of systemic progression (aaIPI adjusted RR = 0.484, 95%CI 0.300-0.782, p = 0.003). PFS benefit with CHIC vs CRY-04 was observed across pre-specified subgroups, and particularly in patients <60 years old (p = 0.007), with low proliferation index (Ki67 expression <75%, p = 0.029), and BCL2 positivity (p = 0.006). In the subsets of patients with available PET data, Deauville score 5 at the end of treatment was associated with increased rate of progression and death in both trials (p = 0.012). Only one out of 17 biopsies from PET positive lesions (DS 3-5) contained vital lymphoma tissue. Conclusions: Our results derived from trial data with homogenous treatment support the use of HD-Mtx in the beginning rather than at the end of therapy. Superior outcome seems to be primarily due to better systemic control of the disease. In addition, number of CNS recurrences is reduced. Keywords: CNS prophylaxis; diffuse large B-cell lymphoma (DLBCL); immunochemotherapy

Cell surface molecules of the B7/CD28 family play an important role in T-cell activation and tolerance. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied whereas PD-L2 has received less attention. However, recently the expression of PD-L2 was described to be independently associated with clinical response in anti-PD1-treated cancer patients. Here, we investigated whether PD-L2 might represent a natural target that induces specific T cells. We identified spontaneous specific T-cell reactivity against two epitopes located in the signal peptide of PD-L2 from samples from patients with cancer as well as healthy individuals ex vivo. We characterized both CD8+ and CD4+ PD-L2-specific T cells. Interestingly, the epitope in PD-L2 that elicited the strongest response was equivalent to a potent HLA-A2-restricted epitope in PD-L1. Importantly, PD-L1-specific and PD-L2-specific T cells did not cross-react; therefore, they represent different T-cell antigens. Moreover, PD-L2-specific T cells reacted to autologous target cells depending on PD-L2 expression. These results suggested that activating PD-L2 specific T cells (e.g., by vaccination) might be an attractive strategy for anti-cancer immunotherapy. Accordingly, PD-L2 specific T cells can directly support anti-cancer immunity by killing of target cells, as well as, indirectly, by releasing pro-inflammatory cytokines at the microenvironment in response to PD-L2-expressing immune supressive cells.

Introduction: The optimal treatment strategy for elderly patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Comorbidities and frailty often preclude enrollment in clinical trials and very few population-based studies have addressed outcome of elderly patients in detail. This population-based study investigated treatment strategies and outcomes for DLBCL patients older than 75 years. Methods: DLBCL patients aged 75 and over diagnosed between 2003 and 2012 were identified using the Danish National Lymphoma Registry (LYFO). Information regarding lymphoma characteristics, treatment, comorbidity and outcome were obtained from LYFO, the Danish National health registries and medical records. Patients were stratified by age (75-79; 80-84 and ≥85 years), comorbidity score, and treatment modality (standard treatment (CHOP or CHOP-like) with or without rituximab, less intensive regimens and palliative treatment). Results: 1,011 patients were included. Standard treatment was initiated in 64%, ranging from 83% among the 75-79 year olds to 32% among the 85+ year olds. With standard treatment, 5-year overall survival (OS) estimates were 47%, 38% and 26% for the age groups 75-79; 80-84 and ≥85, respectively. Among the 75-79 year olds, OS was superior with standard treatment regardless of comorbidity, although OS benefit associated with standard treatment diminished in patients with high comorbidity scores. Among 85+ year olds OS was equal with standard treatment and less intensive regimens, also in patients with low comorbidity scores. Patients above 80 years had similar OS regardless of intended (R-)CHOP dosing, whereas OS was higher in the 75-79 year olds scheduled for full dose. Patients receiving standard treatment were not hospitalized more than patients receiving less intensive chemotherapy. Conclusion: Standard treatment is feasible with good outcomes in a large proportion of elderly DLBCL-patients, also outside clinical trials. Candidates for standard treatment must be carefully selected among patients above 80 years, and particular caution is necessary in patients older than 85 years, where even patients without comorbidity might not benefit from standard treatment. Planned dose reduction seems beneficial in patients older than 80 years. Table 1. Baseline characteristics for 1,011 patients with diffuse large b-cell lymphoma (DLBCL) aged 75-79, 80-84, or ≥85 years. Data are population-based and the cohort comprises all Danish patients older than 74 years with DLBCL diagnosed 2003-2012. * N = 3 patients are categorized as None due to missing observations in the Danish National Patient Registry. Figure 1: Overall survival for 1,011 patients with diffuse large b-cell lymphoma (DLBCL) aged 75-79, 80-84, or ≥85 years with either none, moderate or high Charlson Comorbidity Index (CCI) score, stratified by treatment modality. Data are population-based and the cohort comprises all Danish patients older than 74 years with DLBCL diagnosed 2003-2012. Keywords: diffuse large B-cell lymphoma (DLBCL); elderly; R-CHOP.

Introduction: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of early central nervous system (CNS) progression is high. Here we present the final results from a Nordic phase II study, where dose-dense chemoimmunotherapy including early systemic CNS prophylaxis with high dose methotrexate (HD-Mtx), further intensified by intrathecally (IT) administered liposomal cytosine arabinoside (AraC), was given.

Aggressive NK-cell leukemia is a rare malignancy mostly seen in younger Asians with a rapid clinical course and poor prognosis. Here, we describe a 69 years old Caucasian woman presenting with massive leukemization of neoplastic NK-cells. The cells were abnormal in morphology and surface marker expression and this clearly distinguished them from their normal counterpart. They were large and variable in shapes with irregular folding of the nuclei. By flow cytometry, their light scatter characteristics resembled normal monocytes. They showed bright expression of CD56 and CD2 but markedly decreased expression of CD7. They also expressed CD25. The patient presented with general malaise, including high fever, abdominal pain, signs and haemophagocytosis, and she quickly deteriorated and died 11 days after hospitalization. The origin of the leukemic cells of aggressive NK-cell leukemia is most likely the relatively scarce population of CD56(bright) NK-cells, primarily residing lymph nodes and tonsils. The immunophenotype of the case presented here support this, adding CD25 expression which is not earlier addressed in this entity.