Late recurrence of lymphoid malignancies after initial treatment for Hodgkin lymphoma - A study from the Danish Lymphoma Registry.

We analysed a large cohort of Hodgkin lymphoma (HL) patients in order to characterize: (1) the pattern of late recurrence of lymphoid malignancies (LR) after initial treatment for HL over a 35-year period; (2) the clinicopathological parameters influencing the risk of LR; and (3) the outcome of patients experiencing LR. We reviewed data of 3350 HL patients diagnosed in Denmark between 1982 and 2018 and registered in the Danish National Lymphoma Registry (LYFO). LR was defined as a recurrence of lymphoid malignancy at least five years after initial diagnosis. LR occurred in 58 patients, with a cumulative incidence at 10, 15 and 20 years of 2.7%, 4.0% and 5.4% respectively. LR was more frequently observed in patients with nodular lymphocyte-predominant HL (NLPHL) [hazard ratio (HR) 4.5; 95% confidence interval (CI): 2.4-8.4, p < 0.001]. In classical HL (cHL) patients, older age and lymphocytopenia were risk factors for LR with HRs of 1.04 per additional year (95% CI: 1.02-1.06) and 5.6 (95% CI: 2.7-11.5) respectively. Mixed cellularity histological subtype was a risk factor for LR, but only in females, with a HR of 5.4 (95% CI: 1.4-20.4, p = 0.014). In contrast to what was observed in NLPHL, LR in cHL was associated with an almost threefold increased risk of death compared with patients in continuous complete remission. Approximately one fifth (22.4%) of patients with LR experienced a second relapse.

Clinically-suspected cast nephropathy: A retrospective, national, real-world study.

Presentation with severe acute kidney injury due to cast nephropathy (CN) is a medical emergency in multiple myeloma (MM), with high risk of dialysis-dependent renal failure and death. Accrual of patients with CN into interventional studies is difficult, while phase III trials exclude patients with severe renal insufficiency. Real-world data are warranted. We assessed 2252 patients from the population-based Danish Multiple Myeloma Registry (DMMR) who were diagnosed between 2013 and 2017. We identified 204 patients with clinically-suspected CN, defined as serum creatinine concentration >177 µmol/L and serum free light chain (sFLC) concentration >1000 mg/L at the time of diagnosis. The median age was 72 years. Thirty-one percent of patients presented with dialysis-dependent renal failure. Kidney biopsies were performed in 19% of patients and showed CN in 74% of cases. Despite prompt initiation of bortezomib-based therapy in 94% of patients, 33% of patients died in the first year after diagnosis. Compared with the rest of the patients in the DMMR with symptomatic MM, patients with clinically-suspected CN had worse overall survival (OS) irrespective of transplant eligibility. Achievement of renal recovery was associated with deep reductions of involved sFLC. Achievement of very good partial response or better in the first line of therapy and/or deep reduction of involved sFLC at 3 months after initiation of therapy were associated with superior OS. In conclusion, MM patients presenting with clinically-suspected CN have an alarmingly high one-year mortality when treated with current standards of care. Early and deep hematologic response is crucial for survival.

Clinical and treatment-related features determining the risk of late relapse in patients with diffuse large B-cell lymphoma.

It is still unclear whether there are clinically exploitable differences in the biology and behaviour of early versus late relapses in diffuse large B-cell lymphoma (DLBCL). The present study aimed to analyse a large population-based DLBCL cohort in order to identify (i) the frequency of late relapses (LR), (ii) parameters influencing the risk of LR, and (iii) the impact of introducing rituximab on the occurrence of LR. The data of 7247 DLBCL patients was obtained from the Danish Lymphoma Group Registry. Patients with LR had a lower International Prognostic Index and better performance score than early relapse (ER) patients. The use of radiotherapy lowered only the rate of ER while the use of rituximab yielded a lower occurrence of both ER and LR (P < 0·0001 and P < 0·0001, respectively), possibly suggesting a longer-lasting biological effect. Additionally, we found a female overrepresentation among LR patients that had received a rituximab-containing first line treatment. It was found that patients with LR had a significantly better 5-year overall survival compared to ER patients. In conclusion, LR was more frequently associated with low-risk features than ER. Furthermore, we found that the use of modern immunochemotherapy regimens in DLBCL lowers the risk of both ER and LR.

Post-transplant lymphoproliferative disorder following kidney transplantation: a population-based cohort study.

Post-transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long-term post-transplantation follow-up. A retrospective population-based cohort study including all kidney transplant recipients at two Danish centres (1990-2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient-years (95% CI: 4.0-7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9-5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post-transplant patient survival was inferior in patients with PTLD, while death-censored graft survival was not. Using registry data together with extensive pathological review and long follow-up, a rather high incidence of PTLD was found.

Proteomic profiling of pretreatment serum from HIV-infected patients identifies candidate markers predictive of lymphoma development.

OBJECTIVE: HIV-infected individuals have an increased risk of developing lymphoma. We sought to identify markers predictive of lymphoma development by comparing protein expression patterns in serum obtained at the time of HIV diagnosis from patients who later developed malignant lymphoma or benign lymphadenopathy, with samples from patients with no subsequent history of neoplasia. DESIGN: All patients were identified retrospectively from the Danish HIV cohort. METHODS: Serum samples (N = 21), obtained at time of HIV diagnosis, were subjected to high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified by liquid chromatography-tandem mass spectrometry. A tissue microarray, containing diagnostic HIV-lymphoma tissue samples (N = 40), was used to investigate immunohistochemical expression of markers in tumoural lesions. RESULTS: Fourteen differentially expressed protein spots were detected. Using principal components analysis, spots containing immunoglobulin J chain, apolipoprotein A-I, procollagen C-endopeptidase enhancer-1 and complement C4-A were associated with lymphoma development (P < 0.0001). Serum amyloid A-2 was increased almost 10-fold in patients with subsequent lymphoma compared with patients without subsequent lymphoma. In the tissue microarray, amyloid A was widely expressed, and high expression showed a tendency towards inferior outcome (log-rank 0.073). CONCLUSION: We identified several differentially expressed protein spots present already at the time of HIV diagnosis. Analysis of biological differences correlating to lymphoma development at this early stage of a possible malignant transformation may lead to the identification of predictive markers. Further investigation of the potential clinical application of differentially expressed proteins as risk stratification markers for monitoring HIV-positive individuals is warranted.

Occurrence and prognostic relevance of CD30 expression in post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLDs) are potentially fatal, often Epstein-Barr virus (EBV)-driven neoplasias developing in immunocompromised hosts. Initial treatment usually consists of a reduction in immunosuppressive therapy and/or rituximab with or without chemotherapy. However, patients who relapse do poorly, and new treatment options are warranted. With the introduction of the immunoconjugate brentuximab vedotin, the CD30 antigen has become an effectively targetable molecule. Therefore, we investigated the frequency and level of CD30 expression in PTLDs. We identified 108 patients with PTLDs diagnosed during 1994-2011, of whom 62 had adequate paraffin-embedded tissue for tissue microarray construction. Immunohistochemical expression of CD30 was consistently detected in all types of PTLD (overall 85.25%), including the monomorphic subtypes, and was correlated with a more favorable outcome. For diffuse large B-cell lymphoma (DLBCL)-type PTLD this was regardless of EBV status, and remained significant in multivariate analysis. Cell-of-origin had no independent prognostic value in our series of DLBCL PTLD.

HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based Cohort.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a feared complication to organ transplantation, associated with substantial morbidity and inferior survival. Risk factors for PTLD include T cell-depleting induction therapy and primary infection or reactivation of Epstein-Barr virus. Possible associations between certain HLA types and the risk of developing PTLD have been reported by other investigators; however, results are conflicting. METHODS: We conducted a retrospective, population-based study on 4295 Danish solid organ transplant patients from the Scandiatransplant database. Having identified 93 PTLD patients in the cohort, we investigated the association of HLA types with PTLD, Epstein-Barr virus status and time to PTLD onset. The outcomes survival and PTLD were evaluated using Cox regression; mismatching, and the PTLD-specific mortality were evaluated in a competing risk analysis. RESULTS: Risk of PTLD was associated with male sex (odds ratio, 1.70; 95% confidence interval, 1.07-2.71), and, in women, HLA-DR13 conferred an increased risk (odds ratio, 3.22; 95% confidence interval, 1.41-7.31). In multivariate analysis, HLA-B45 and HLA-DR13 remained independent predictive factors of PTLD. Mismatching in the B locus was associated with a reduced risk of PTLD (P < 0.001). Overall survival was poor after a PTLD diagnosis and was significantly worse than that in the remaining transplant cohort (P < 0.001). CONCLUSIONS: Our data indicate risk-modifying HLA associations, which can be clinically useful after transplantation in personalized monitoring schemes. Given the strong linkage disequilibrium in the HLA region, the associations must be interpreted carefully. The large size, virtually complete ascertainment of cases and no loss to follow-up remain important strengths of the study.

Breast implants and anaplastic large-cell lymphoma: a danish population-based cohort study.

BACKGROUND: A potential link between breast implants and anaplastic large-cell lymphoma (ALCL) has been suggested. METHODS: We examined lymphoma occurrence in a nationwide cohort of 19,885 Danish women who underwent breast implant surgery during 1973-2010. Standardized incidence ratios (SIR), with 95% confidence intervals (CI), for ALCL and lymphoma overall associated with breast implantation were calculated. RESULTS: During 179,246 person-years of follow-up, we observed 31 cases of lymphoma among cohort members. No cases of ALCL were identified. SIRs for ALCL and lymphoma overall were zero (95% CI, 0-10.3) and 1.20 (95% CI, 0.82-1.70), respectively. CONCLUSIONS: In our nationwide cohort study, we did not find an increased risk of lymphoma in general, or ALCL in particular, among Danish women who underwent breast implantation. However, our evaluation of ALCL risk was limited by the rarity of the disease. IMPACT: Our results do not support an association between breast implants and ALCL and are consistent with other studies on cancer risk and breast implants.