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Abstract Background Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. Methods Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. Results Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4–2.3 months). Minimal malignant plasma cells detection limit was 4 × 10–5. Conclusions Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. Trial registration NCT01208766

Abstract: Gene expression profiling (GEP) by microarrays of diffuse large B-cell lymphoma (DLBCL) has enabled the categorization of DLBCL into activated B-cell–like and germinal center B-cell–like subclasses. However, as this does not fully embrace the great diversity of B-cell subtypes, we recently developed a gene expression assay for B-cell–associated gene signature (BAGS) classification. To facilitate quick and easy-to-use BAGS profiling, we developed in this study the NanoString-based BAGS2Clinic assay. Microarray data from 4 different cohorts (n = 970) were used to select genes and train the assay. The locked assay was validated in an independent cohort of 88 sample biopsies. The assay showed good correspondence with the original BAGS classifier, with an overall accuracy of 84% (95% confidence interval, 72% to 93%) and a subtype-specific accuracy ranging between 80% and 99%. BAGS classification has the potential to provide valuable insight into tumor biology as well as differences in resistance to immuno- and chemotherapy that can lead to novel treatment strategies for DLBCL patients. BAGS2Clinic can facilitate this and the implementation of BAGS classification as a routine clinical tool to improve prognosis and treatment guidance for DLBCL patients.

Acute myeloid leukaemia (AML) is characterised by phenotypic heterogeneity, which we hypothesise is a consequence of deregulated differentiation with transcriptional reminiscence of the normal compartment or cell-of-origin. Here, we propose a classification system based on normal myeloid progenitor cell subset-associated gene signatures (MAGS) for individual assignments of AML subtypes. We generated a MAGS classifier including the progenitor compartments CD34+/CD38- for haematopoietic stem cells (HSCs), CD34+/CD38+/CD45RA- for megakaryocyte-erythroid progenitors (MEPs), and CD34+/CD38+/CD45RA+ for granulocytic-monocytic progenitors (GMPs) using regularised multinomial regression with three discrete outcomes and an elastic net penalty. The regularisation parameters were chosen by cross-validation, and MAGS assignment accuracy was validated in an independent data set (N = 38; accuracy = 0.79) of sorted normal myeloid subpopulations. The prognostic value of MAGS assignment was studied in two clinical cohorts (TCGA: N = 171; GSE6891: N = 520) and had a significant prognostic impact. Furthermore, multivariate Cox regression analysis using the MAGS subtype, FAB subtype, cytogenetics, molecular genetics, and age as explanatory variables showed independent prognostic value. Molecular characterisation of subtypes by differential gene expression analysis, gene set enrichment analysis, and mutation patterns indicated reduced proliferation and overrepresentation of RUNX1 and IDH2 mutations in the HSC subtype; increased proliferation and overrepresentation of CEBPA mutations in the MEP subtype; and innate immune activation and overrepresentation of WT1 mutations in the GMP subtype. We present a differentiation-dependent classification system for AML subtypes with distinct pathogenetic and prognostic importance that can help identify candidates poorly responding to combination chemotherapy and potentially guide alternative treatments.

Methods for clustering in unsupervised learning are an important part of the statistical toolbox in numerous scientific disciplines. Tewari, Giering, and Raghunathan (2011) proposed to use so-called Gaussian mixture copula models (GMCM) for general unsupervised learning based on clustering. Li, Brown, Huang, and Bickel (2011) independently discussed a special case of these GMCMs as a novel approach to meta-analysis in highdimensional settings. GMCMs have attractive properties which make them highly flexible and therefore interesting alternatives to other well-established methods. However, parameter estimation is hard because of intrinsic identifiability issues and intractable likelihood functions. Both aforementioned papers discuss similar expectation-maximization-like algorithms as their pseudo maximum likelihood estimation procedure. We present and discuss an improved implementation in R of both classes of GMCMs along with various alternative optimization routines to the EM algorithm. The software is freely available in the R package GMCM. The implementation is fast, general, and optimized for very large numbers of observations. We demonstrate the use of package GMCM through different applications.

Diagnostic and prognostic evaluation of chronic lymphocytic leukemia (CLL) involves blood cell counts, immunophenotyping, IgVH mutation status, and cytogenetic analyses. We generated B-cell associated gene-signatures (BAGS) based on six naturally occurring B-cell subsets within normal bone marrow. Our hypothesis is that by segregating CLL according to BAGS, we can identify subtypes with prognostic implications in support of pathogenetic value of BAGS. Microarray-based gene-expression samples from eight independent CLL cohorts (1,024 untreated patients) were BAGS-stratified into pre-BI, pre-BII, immature, naïve, memory, or plasma cell subtypes; the majority falling within the memory (24.5-45.8%) or naïve (14.5-32.3%) categories. For a subset of CLL patients (n = 296), time to treatment (TTT) was shorter amongst early differentiation subtypes (pre-BI/pre-BII/immature) compared to late subtypes (memory/plasma cell, HR: 0.53 [0.35-0.78]). Particularly, pre-BII subtype patients had the shortest TTT among all subtypes. Correlates derived for BAGS subtype and IgVH mutation (n = 405) revealed an elevated mutation frequency in late vs. early subtypes (71% vs. 45%, P < .001). Predictions for BAGS subtype resistance towards rituximab and cyclophosphamide varied for rituximab, whereas all subtypes were sensitive to cyclophosphamide. This study supports our hypothesis that BAGS-subtyping may be of tangible prognostic and pathogenetic value for CLL patients.

BACKGROUND:Radiation-therapy (RT) induces mucositis, a clinically challenging condition with limited prophylactic interventions and no predictive tests. In this pilot study, we applied global gene-expression analysis on serial human oral mucosa tissue and blood cells from patients with tonsil squamous cell cancer (TSCC) to identify genes involved in mucositis pathogenesis. METHODS AND FINDINGS:Eight patients with TSCC each provided consecutive buccal biopsies and blood cells before, after 7 days of RT treatment, and 20 days following RT. We monitored clinical mucositis and performed gene-expression analysis on tissue samples. We obtained control tissue from nine healthy individuals. After RT, expression was upregulated in apoptosis inducer and inhibitor genes, EDA2R and MDM2, and in POLH, a DNA-repair polymerase. Expression was downregulated in six members of the histone cluster family, e.g., HIST1H3B. Gene expression related to proliferation and differentiation was altered, including MKI67 (downregulated), which encodes the Ki-67-proliferation marker, and KRT16 (upregulated), which encodes keratin16. These alterations were not associated with the clinical mucositis grade. However, the expression of LY6G6C, which encodes a surface immunoregulatory protein, was upregulated before treatment in three cases of clinical none/mild mucositis, but not in four cases of ulcerative mucositis. CONCLUSION:RT caused molecular changes related to apoptosis, DNA-damage, DNA-repair, and proliferation without a correlation to the severity of clinical mucositis. LY6G6C may be a potential protective biomarker for ulcerative mucositis. Based on these results, our study model of consecutive human biopsies will be useful in designing a prospective clinical validation trial to characterize molecular mucositis and identify predictive biomarkers.

BACKGROUND:Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. METHODS AND FINDINGS:Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5-6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. CONCLUSIONS:Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity.

The concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational studies. By the classical approach, a CD19−/CD45low/−/CD38high/CD138+ malignant plasma cell, but not the CD19+/CD38low/− memory B cell compartment, is enriched for tumorigenic cells that initiate myeloma in xenografted immunodeficient mice, supporting that myeloma stem cells are present in the malignant PC compartment. Using a new approach, analysis of c-DNA libraries from CD19+/CD27+/CD38− single cells has identified clonotypic memory B cell, suggested to be the cell of origin. This is consistent with multiple myeloma being a multistep hierarchical process before or during clinical presentation. We anticipate that further characterization will require single cell geno- and phenotyping combined with clonogenic assays. To implement such technologies, we propose a revision of the concept of a myeloma stem cell by including operational in vitro assays to describe the cellular components of origin, initiation, maintenance, and evolution of multiple myeloma. These terms are in accordance with recent (2012) consensus statements on the definitions, assays, and nomenclature of cancer stem cells, which is technically precise without completely abolishing established terminology. We expect that this operational model will be useful for future reporting of parameters used to identify and characterize the multiple myeloma stem cells. We strongly recommend that these parameters include validated standard technologies, reproducible assays, and, most importantly, supervised prospective sampling of selected biomaterial which reflects clinical stages, disease spectrum, and therapeutic outcome. This framework is key to the characterization of the cellular architecture of multiple myeloma and its use in precision medicine.

BACKGROUND:Dozens of omics based cancer classification systems have been introduced with prognostic, diagnostic, and predictive capabilities. However, they often employ complex algorithms and are only applicable on whole cohorts of patients, making them difficult to apply in a personalized clinical setting. RESULTS:This prompted us to create hemaClass.org, an online web application providing an easy interface to one-by-one RMA normalization of microarrays and subsequent risk classifications of diffuse large B-cell lymphoma (DLBCL) into cell-of-origin and chemotherapeutic sensitivity classes. Classification results for one-by-one array pre-processing with and without a laboratory specific RMA reference dataset were compared to cohort based classifiers in 4 publicly available datasets. Classifications showed high agreement between one-by-one and whole cohort pre-processsed data when a laboratory specific reference set was supplied. The website is essentially the R-package hemaClass accompanied by a Shiny web application. The well-documented package can be used to run the website locally or to use the developed methods programmatically. CONCLUSIONS:The website and R-package is relevant for biological and clinical lymphoma researchers using affymetrix U-133 Plus 2 arrays, as it provides reliable and swift methods for calculation of disease subclasses. The proposed one-by-one pre-processing method is relevant for all researchers using microarrays.

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin

BackgroundInternational collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases.Methods and findingsWe used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (>90% of publications) was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013.Conclusion and perspectiveMultiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care.

BackgroundMalignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment.MethodsWe investigated 50 inflammatory response gene polymorphisms in 355 B-cell non-Hodgkin's lymphoma (B-NHL) samples encompassing 216 diffuse large B cell lymphoma (DLBCL) and 139 follicular lymphoma (FL) and 307 controls. The effect of single genes and haplotypes were investigated and gene-expression analysis was applied for selected genes. Since interaction between risk genes can have a large impact on phenotype, two-way gene-gene interaction analysis was included.ResultsWe found inherited SNPs in genes critical for inflammatory pathways; TLR9, IL4, TAP2, IL2RA, FCGR2A, TNFA, IL10RB, GALNT12, IL12A and IL1B were significantly associated with disease risk and SELE, IL1RN, TNFA, TAP2, MBL2, IL5, CX3CR1, CHI3L1 and IL12A were, associated with overall survival (OS) in specific diagnostic entities of B-NHL. We discovered noteworthy interactions between DLBCL risk alleles on IL10 and IL4RA and FL risk alleles on IL4RA and IL4. In relation to OS, a highly significant interaction was observed in DLBCL for IL4RA (rs1805010) * IL10 (rs1800890) (HR = 0.11 (0.02-0.50)). Finally, we explored the expression of risk genes from the gene-gene interaction analysis in normal B-cell subtypes showing a different expression of IL4RA, IL10, IL10RB genes supporting a pathogenetic effect of these interactions in the germinal center.ConclusionsThe present findings support the importance of inflammatory genes in B-cell lymphomas. We found association between polymorphic sites in inflammatory response genes and risk as well as outcome in B-NHL and suggest an effect of gene-gene interactions during the stepwise oncogenesis.

Long noncoding RNAs (lncRNAs) have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7), and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6), respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as "guilt by association". By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations.

Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström’s macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance.

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

Background The value of performing post-therapy routine surveillance imaging in patients with Hodgkin lymphoma is controversial. This study evaluates the utility of positron emission tomography/computed tomography using 2-[18F]fluoro-2-deoxyglucose for this purpose and in situations with suspected lymphoma relapse.Design and Methods We conducted a multicenter retrospective study. Patients with newly diagnosed Hodgkin lymphoma achieving at least a partial remission on first-line therapy were eligible if they received positron emission tomography/computed tomography surveillance during follow-up. Two types of imaging surveillance were analyzed: “routine” when patients showed no signs of relapse at referral to positron emission tomography/computed tomography, and “clinically indicated” when recurrence was suspected.Results A total of 211 routine and 88 clinically indicated positron emission tomography/computed tomography studies were performed in 161 patients. In ten of 22 patients with recurrence of Hodgkin lymphoma, routine imaging surveillance was the primary tool for the diagnosis of the relapse. Extranodal disease, interim positron emission tomography-positive lesions and positron emission tomography activity at response evaluation were all associated with a positron emission tomography/computed tomography-diagnosed preclinical relapse. The true positive rates of routine and clinically indicated imaging were 5% and 13%, respectively (P=0.02). The overall positive predictive value and negative predictive value of positron emission tomography/computed tomography were 28% and 100%, respectively. The estimated cost per routine imaging diagnosed relapse was US$ 50,778.Conclusions Negative positron emission tomography/computed tomography reliably rules out a relapse. The high false positive rate is, however, an important limitation and a confirmatory biopsy is mandatory for the diagnosis of a relapse. With no proven survival benefit for patients with a pre-clinically diagnosed relapse, the high costs and low positive predictive value make positron emission tomography/computed tomography unsuitable for routine surveillance of patients with Hodgkin lymphoma.

Purpose The general outlook for patients with diffuse large B-cell lymphoma (DLBCL) in first remission is important information for patients and for planning post-treatment follow-up. The purpose of this study was to evaluate the survival of patients with DLBCL in remission compared with a matched general population. Methods A total of 1,621 patients from the Danish Lymphoma Registry who were newly diagnosed with DLBCL between 2003 and 2011 were included in this study. All patients were ≥ 16 years of age at diagnosis and had achieved complete remission or complete remission unconfirmed after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like therapy. Results The 5-year post-treatment DLBCL survival was inferior to survival in the matched general population (78%; 95% CI, 76 to 80; v 87%; standardized mortality ratio, 1.75; P < .001). Excess mortality was present but reduced for patients achieving post-treatment event-free survival for 24 months (pEFS24; standardized mortality ratio, 1.27; P < .001). In age-stratified analyses, the survival of patients < 50 years of age was normalized to the general population after achieving pEFS24 ( P = .99). During the first 8 years after pEFS24, the average loss of lifetime was 0.31 mo/y (95% CI, 0.11 to 0.50 mo/y). Excess mortality diminished when analyzing death from lymphoma as competing event to death from other causes, suggesting that early and late relapse is responsible for increased mortality in patients with DLBCL. Conclusion Although this population-based study does not support complete normalization of survival for patients with DLBCL achieving pEFS24, the estimated loss of residual lifetime was low for patients in continuous remission 2 years after ending treatment. Therefore, pEFS24 is an appealing and relevant milestone for patient counseling and could be a surrogate end point in clinical trials.

Purpose: Routine imaging for diffuse large B-cell lymphoma (DLBCL) in first complete remission (CR) is controversial and plays a limited role in detecting relapse. This population-based study compared the survival of Danish and Swedish patients with DLBCL for whom traditions for routine imaging have been different., Patients and Methods: Patients from the Danish and Swedish lymphoma registries were included according to the following criteria: newly diagnosed DLBCL from 2007 to 2012, age 18 to 65 years, and CR after R-CHOP/CHOEP. Follow-up for Swedish patients included symptom assessment, clinical examinations, and blood tests at 3- to 4-month intervals for 2 years, with longer intervals later in follow-up. Imaging was only recommended when relapse was clinically suspected. Follow-up for Danish patients was similar but included routine imaging (usually computed tomography every 6 months for 2 years)., Results: Danish (n = 525) and Swedish (n = 696) patients with DLBCL had comparable baseline characteristics. Cumulative 2-year progression rate after CR was 6% (95% CI, 4 to 9) for International Prognostic Index (IPI) ≤ 2 versus 21% (95% CI, 13 to 28) for IPI > 2. Age > 60 years (hazard ratio [HR], 2.3; 95% CI, 1.6 to 3.4), elevated lactate dehydrogenase (HR, 2.3; 95% CI, 1.4 to 3.8), B symptoms (HR, 1.7; 95% CI, 1.1 to 2.5), and Eastern Cooperative Oncology Group performance status ≥ 2 (HR, 1.8; 95% CI, 1.0 to 3.0) were associated with worse post-CR survival. Imaging-based follow-up strategy had no impact on survival, neither for all patients nor for IPI-specific subgroups., Conclusion: DLBCL relapse after first CR is infrequent, and the widespread use of routine imaging in Denmark did not translate into better survival. This favors follow-up without routine imaging and, more generally, a shift of focus from relapse detection to improved survivorship., (© 2015 by American Society of Clinical Oncology.)