•ABC and GCB subtype sinonasal DLBCL are geno- and phenotypically distinct entities, exhibiting a contrasting disease course and prognosis.•ABC subtype sinonasal DLBCL is part of a superordinate ...family of MCD lymphomas, presenting at immune-privileged and other extranodal sites.
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Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD-L1 expression and copy-number alterations were rare. All lymphomas were Epstein-Barr virus-negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup’s MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B-cell and toll-like receptor signaling therapy.
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.
In this study, we show how the prognostic performance of indices for the survival of diffuse large B‐cell lymphoma can be greatly improved by considering simple models with continuous variables.
The prognostic value of aberrant DNA methylation of cell-free circulating DNA in plasma has not previously been evaluated in diffuse large B cell lymphoma (DLBCL). The aim of this study was to ...investigate if aberrant promoter DNA methylation can be detected in plasma from DLBCL patients and to evaluate this as a prognostic marker. Furthermore, we wanted to follow possible changes in methylation levels during treatment. Seventy-four patients were enrolled in the study, of which 59 received rituximab and CHOP-like chemotherapy. Plasma samples were collected from all patients at the time of diagnosis and from 14 healthy individuals used as controls. In addition, plasma samples were collected during and after treatment for surviving patients. In total, 158 plasma samples were analyzed for DNA methylation in the promoter regions of DAPK (DAPK1), DBC1, MIR34A, and MIR34B/C using pyrosequencing.
Aberrant methylation levels at the time of diagnosis were detected in 19, 16, 8, and 10 % of the DLBCL plasma samples for DAPK1, DBC1, MIR34A, and MIR34B/C, respectively. DAPK1 methylation levels were significantly correlated with DBC1 and MIR34B/C methylation levels (P < 0.001). For the entire cohort, 5-year overall survival (OS) rates were significantly lower in the groups carrying aberrant DAPK1 (P = 0.004) and DBC1 (P = 0.044) methylation, respectively. DAPK1 methylation status were significantly correlated with stage (P = 0.015), as all patients with aberrant DAPK1 methylation were stages III and IV. Multivariate analysis identified DAPK1 as an independent prognostic factor for OS with a hazard ratio of 8.9 (95 % CI 2.7-29.3, P < 0.0007). Patients with DAPK1 methylated cell-free circulating DNA at time of diagnosis, who became long-term survivors, lost the aberrant methylation after treatment initiation. Conversely, patients that maintained or regained aberrant DAPK1 methylation died soon thereafter.
Aberrant promoter methylation of cell-free circulating DNA can be detected in plasma from DLBCL patients and hold promise as an easily accessible marker for evaluating response to treatment and for prognostication. In particular, aberrant DAPK1 methylation in plasma was an independent prognostic marker that may also be used to assess treatment response.
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.
•Early systemic CNS prophylaxis with high-dose methotrexate followed by dose-dense immunochemotherapy is feasible in high-risk DLBCL patients.•Most patients, including those with BCL2/MYC double-hit lymphomas, can achieve durable remissions with a low risk of CNS progression.
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Following intense research efforts, modulation of the immune system has finally proved to be a viable approach for treating malignant disease. Recently, chimeric antigen receptor redirected T cells ...have achieved promising outcomes in patients with B-cell malignancies and they are currently also being investigated in other haematological malignancies, solid tumours and viral infections. Compared with traditional biopharmaceuticals, the properties of genetically modified chimeric antigen receptor redirected T-cell therapies differ in many aspects, thereby posing challenges in terms of post-authorisation data collection and data analysis. We believe that the network of population-based Nordic healthcare databases has some characteristics that can help provide important data on these new types of advanced products. In particular, the possibility of very long follow-up periods with a limited loss to follow-up is an important strength. Given the limited source population and slow access to data, a Nordic chimeric antigen receptor redirected T-cell monitoring project should be seen as complementary to other surveillance initiatives.
The burden of late effects among Hodgkin lymphoma (HL) survivors treated according to contemporary protocols remains poorly characterized. We used nation‐wide registers to assess number of inpatient ...bed‐days and specialist outpatient visits among 1048 HL‐patients (<25 years, diagnosed 1990‐2010) and 5175 country‐, sex‐, and age‐matched comparators. We followed them for up to 24 years, with time‐dependent assessment of relapse status. International Classification of Diseases (ICD‐10) chapter‐specific hazard ratios (HRs) were assessed in Cox regression analyses, and nonparametric statistics described patterns of health‐care‐use. Relative to comparators, relapse‐free survivors were at increased risk of infections, diseases of the blood, endocrine, circulatory and respiratory systems, and unspecific symptoms, HRs ranging from 1.86 to 3.05. Relative to comparators, relapsed survivors had at statistically significantly increased risk of diseases reflecting practically all investigated disease‐chapters, HRs ranging from 1.60 to 18.7. Among relapse‐free survivors, 10% of the patients accounted for 80% of all hospital bed days, and 55% were never hospitalized during follow‐up. Among relapsed‐survivors, 10% of the patients accounted for 50% of the bed days, and only 24% were never hospitalized during follow‐up. In contrast, 10% of the comparators accounted for 90% of hospital bed days and 75% were never hospitalized. These findings challenge the impression of a uniformly distributed long‐term morbidity among all HL survivors and emphasize the need for early identification and attention to patients particularly susceptible to late effects, such as relapsed survivors.
The distribution of health‐care use among young Hodgkin lymphoma (HL) survivors was markedly uneven. Only 25% of matched‐comparators experienced hospitalization during follow‐up, while 45% of relapse‐free patients and 76% of relapsed HL survivors required one or more hospitalizations more than 1 year after primary‐ or relapse‐diagnosis. The hospitalizations reflected a broad disease spectrum (infectious, blood, endocrine, circulatory, respiratory, digestive, genitourinary, skin, musculoskeletal disorders, and even injuries). This emphasizes targeted preventive measures especially for ever‐relapsed survivors.
Abstract Background After completing treatment for cancer, survivors may experience late effects: consequences of treatment that persist or arise after a latent period. Purpose To identify and ...describe all models that predict the risk of late effects and could be used in clinical practice. Data sources We searched Medline through April 2014. Study selection Studies describing models that (1) predicted the absolute risk of a late effect present at least 1 year post-treatment, and (2) could be used in a clinical setting. Data extraction Three authors independently extracted data pertaining to patient characteristics, late effects, the prediction model and model evaluation. Data synthesis Across 14 studies identified for review, nine late effects were predicted: erectile dysfunction and urinary incontinence after prostate cancer; arm lymphoedema, psychological morbidity, cardiomyopathy or heart failure and cardiac event after breast cancer; swallowing dysfunction after head and neck cancer; breast cancer after Hodgkin lymphoma and thyroid cancer after childhood cancer. Of these, four late effects are persistent effects of treatment and five appear after a latent period. Two studies were externally validated. Six studies were designed to inform decisions about treatment rather than survivorship care. Nomograms were the most common clinical output. Conclusion Despite the call among survivorship experts for risk stratification, few published models are useful for risk-stratifying prevention, early detection or management of late effects. Few models address serious, modifiable late effects, limiting their utility. Cancer survivors would benefit from models focused on long-term, modifiable and serious late effects to inform the management of survivorship care.
UNFOLDER (Unfavorable Young Low‐Risk Densification of R‐Chemo Regimens) is an international phase‐3 trial in patients 18–60 years with aggressive B‐cell lymphoma and intermediate prognosis defined by ...age‐adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R‐CHOP‐14 or 6× R‐CHOP‐21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and predisolone) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F‐18 fluordesoxyglucose positron emission tomography/computed tomography (FDG‐PET). Primary endpoint was event‐free survival (EFS). A total of 695 of 700 patients were eligible for the intention‐to‐treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R‐CHOP‐21: 155; R‐CHOP‐14: 150) and 162 to observation (R‐CHOP‐21: 81, R‐CHOP‐14: 81). Two hundred twenty‐eight patients not qualifying for radiotherapy were randomized for R‐CHOP‐14 versus R‐CHOP‐21. After a median observation of 66 months 3‐year EFS was superior in the radiotherapy‐arm versus observation‐arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression‐free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R‐CHOP‐14 and R‐CHOP‐21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005‐005218‐19).
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