Outcome data of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) beyond the second line are scarce outside of clinical trials. Novel therapies in the R/R setting have ...been approved based on single-arm trials, but results need to be contextualized by real-world outcomes. Medical records from 3753 Danish adults diagnosed with DLBCL were reviewed. Patients previously treated with rituximab and anthracycline-based chemotherapy who received the third or later line (3 L+) of treatment after 1 January 2015, were included. Only 189 patients with a median age of 71 years were eligible. The median time since the last line of therapy was 6 months. Patients were treated with either best supportive care (22%), platinum-based salvage therapy (13%), low-intensity chemotherapy (22%), in clinical trial (14%) or various combination treatments (32%). The 2-year OS-/PFS estimates were 25% and 12% for all patients and 49% and 17% for those treated with platinum-based salvage therapy. Age ≥70, CNS involvement, elevated LDH and ECOG ≥2 predicted poor outcomes, and patients with 0-1 of these risk factors had a 2-year OS estimate of 65%. Only a very small fraction of DLBCL patients received third-line treatment and were eligible for inclusion. Outcomes were generally poor, but better in intensively treated, fit young patients with limited disease.
Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have poor outcomes following first-line cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP). Evidence shows ...chemotherapy and immune checkpoint blockade can increase antitumor efficacy. This study investigated durvalumab, a programmed death-ligand 1 inhibitor, combined with R-CHOP or lenalidomide + R-CHOP (R
2
-CHOP) in newly diagnosed high-risk DLBCL. Patients received durvalumab 1125 mg every 21 days for 2–8 cycles + R-CHOP (non-activated B-cell ABC subtype) or R
2
-CHOP (ABC), then durvalumab consolidation (1500 mg every 28 days). Of 46 patients, 43 received R-CHOP and three R
2
-CHOP. All patients had the high-risk disease; 14 (30.4%) and eight (17.4%) had double- or triple-hit DLBCL, respectively. Following induction, 20/37 (54.1%) patients receiving durvalumab + R-CHOP achieved complete response (CR), and seven (18.9%) partial response (PR); 25 (67.6% 95% CI 50.2–82.0) continued to consolidation and were progression-free at 12 months. Among efficacy-evaluable patients with double- or triple-hit DLBCL (
n
= 12), five achieved CR and five PR. Adverse events were generally consistent with R-CHOP. Correlative analyses did not identify conclusive biomarkers of response. Durvalumab + R-CHOP is feasible in DLBCL with no new safety signals, but the combination provided no greater benefit than R-CHOP.
The tumor microenvironment (TME) and limited immune surveillance
play important roles in lymphoma pathogenesis. Here we
aimed to characterize immunological profiles of diffuse large B-cell
lymphoma ...(DLBCL) and predict the outcome in response to
immunochemotherapy. We profiled the expression of 730 immune-related
genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring
platform, and used multiplex immunohistochemistry to characterize T-cell
phenotypes, including cytotoxic T cells (CD8, Granzyme B, OX40, Ki67),
T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as
regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188
patients. We observed a high degree of heterogeneity at the transcriptome
level. Correlation matrix analysis identified gene expression signatures
with highly correlating genes, the main cluster containing genes for cytolytic
factors, immune checkpoint molecules, T cells and macrophages, together
named a TME immune cell signature. Immunophenotyping of the distinct
cell subsets revealed that a high proportion of immune checkpoint positive
T cells translated to unfavorable survival. Together, our results demonstrate
that the immunological profile of DLBCL TME is heterogeneous and clinically
meaningful. This highlights the potential impact of T-cell immune
checkpoint in regulating survival and resistance to immunochemotherapy.
(Registered at clinicaltrials.gov identifiers: NCT01502982 and NCT01325194.)
Psychological distress following cancer diagnosis may lead to mental health complications including depression and anxiety. Non‐Hodgkin lymphomas (NHLs) include indolent and aggressive subtypes for ...which treatment and prognosis differ widely. Incident use of psychotropic drugs (PDs—antidepressants, antipsychotics, and anxiolytics) and its correlation to lymphoma types can give insights into the psychological distress these patients endure. In this prospective matched cohort study, we used nationwide population‐based registries to investigate the cumulative risk of PD use in NHL patients compared to a sex‐ and age‐matched cohort from the Danish background population. In addition, contact patterns to psychiatric departments and incident intentional self‐harm or completed suicide were explored. In total, 8750 NHL patients and 43 750 matched comparators were included (median age 68; male:female ratio 1.6). Median follow‐up was 7.1 years. Two‐year cumulative risk of PD use was higher in NHL patients (16.4%) as compared to the matched comparators (5.1%, p < .01); patients with aggressive NHL subtypes had the highest incidence. Prescription rates were higher in the first years after diagnosis but approached the rate of the matched population 5 years into survivorship in aggressive NHLs, whereas patients with indolent subtypes continued to be at higher risk. NHL patients had a slightly higher two‐year risk of suicide/intentional self‐harm (0.3%) as compared to the matched comparators (0.2%, p = .01). These results demonstrate that mental health complications among NHL patients are frequent. Routine assessment for symptoms of depression and anxiety should be consider as part of standard follow‐up of NHL patients.
SET domain and mariner transposase fusion gene (SETMAR), also known as Metnase, has previously been shown to suppress the formation of chromosomal translocation in mouse fibroblasts. Despite the fact ...that hematologic malignancies are often characterized by chromosomal rearrangements, no studies have hitherto investigated the expression pattern of the gene in these disorders. We hypothesized that a high expression of SETMAR protected the cells from chromosomal rearrangements; thus, we examined the mRNA expression of SETMAR transcript variants in hematologic patients. We identified six transcript variants (var1, var2, var5, varA, varB, varC), of which three had not been reported previously. Expression levels were quantified by transcript-specific quantitative polymerase chain reaction in 15 healthy individuals, 70 acute myeloid leukemia (AML) patients (translocation positive, n = 30 AMLTPos , translocation negative, n = 40 AMLTNeg ), seven patients with mantle cell lymphoma (t 11,14 positive), and 13 patients with chronic myeloid leukemia (t 9,22 positive). All variants were significantly overexpressed in both subgroups of AML compared with healthy individuals (var1 and var2: p < 0.00001 for both AML subgroups, varA and varB: p = 0.0002, var5: p = 0.0008, and varC: p = 0.0001 for AMLTNeg ; varA: p = 0.0048, varB and var5: p = 0.0001, varC: p = 0.0017). When comparing the expression in AMLTNeg and AMLTPos , we found a significantly increased expression of the full length SETMAR in AMLTNeg (var1: p = 0.047), suggesting a protective effect of high SETMAR expression on formation of chromosomal translocations. In conclusion, we have found known and novel SETMAR splice variants to be significantly increased in AML. To our knowledge, this is the first study that describes an expression profile of SETMAR in subgroups of hematologic malignancies, which can be linked to the incidence of chromosomal rearrangements.
The use of locked nucleic acid (LNA) probes and primers potentially improves sensitivity and specificity of quantitative PCR (qPCR) assays. One area of application is that of minimal residual cancer ...where PCR techniques have proved to be highly relevant tools in patient follow-up. We present here sensitive and specific consensus qPCR assays for quantification of the malignant lymphoma translocations, t(11;14) and t(14;18), by taking advantage of the thermodynamic properties of LNA. The assays were applied to genomic DNA from patients diagnosed with mantle cell lymphoma (MCL) and follicular lymphoma (FL), respectively. Two consensus forward primers targeting the BCL1 and BCL2 genes were designed together with a common consensus reverse primer and hydrolysis probe, the latter consisting exclusively of LNA, both targeting the J segments of the immunoglobulin heavy chain (IgH) gene. The quantitative range of both assays was 1×100 to 5×10−5, and the sensitivity was 10−5, without the need for patient-specific primers. Peripheral blood (PB) and bone marrow (BM) samples from 36 patients diagnosed with MCL and nine patients diagnosed with FL were analysed using this novel qPCR approach. The level of minimal residual disease (MRD) using t(11;14) and t(14;18) as genetic targets reflected the clinical status of the patients: low levels of MRD at clinical remission, and increasing levels at disease progression. The present assays could prove as useful tools in lymphoma therapy.
Many patients diagnosed with lymphoma are of working age. Cancer patients are known to have a higher risk of sick leave and disability pension, but this has only been delineated for certain subtypes ...of lymphoma. Therefore, this study aimed at investigating the overall risk of disability pension for all lymphoma subtypes and at quantifying return to work for patients with lymphoma in work before diagnosis.
Patients aged 18-60 years with lymphoma in complete remission (CR) diagnosed between 2000 and 2019 were included in the study. Using national registers, each patient was matched with five comparators from the general population with same sex, birth year, and level of Charlson Comorbidity Index. Risk of disability pension was calculated from 90 days after CR or end of treatment with competing events (death, retirement pension, early retirement pension, relapse for patients, or lymphoma diagnosis for comparators). Return to work for patients was calculated annually until 5 years after diagnosis for patients employed before diagnosis.
In total, 4072 patients and 20,360 comparators were included. There was a significant increased risk of disability pension for patients with all types of lymphoma compared to the general population (5-year risk difference: 5.3 (95% confidence interval (CI): 4.4;6.2)). Patients with non-Hodgkin lymphoma were more likely to get disability pension than patients with Hodgkin lymphoma (sex- and age-adjusted 10-year risk difference: 2.9 (95% CI: 0.3;5.5)). One year after diagnosis, 24.5% of the relapse-free patients were on sick leave. Return to work was highest 2 years after diagnosis (82.1%).
Patients with lymphoma across all subtypes have a significantly higher risk of disability pension. Return to work peaks at 2 years after diagnosis.
For most patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), R-CHOP immunochemotherapy leads to complete remission and 60-70% of patients remain progression-free after 5 years. Given ...a median age of 65, it is relevant to disentangle how DLBCL and DLBCL therapy influence health care use among the survivors. In this nationwide study, the health care use among Danish DLBCL patients diagnosed in 2007-2015, who achieved complete remission after R-CHOP(-like) therapy, was explored and compared to matched comparators from the Danish general population. The post-remission 5-year risk of hospitalization was significantly higher among DLBCL survivors (55%) compared to matched comparators (49%, P < 0.001). DLBCL survivors had on average 10.3 (9.3-11.3) inpatient bed days within 5 years of response evaluation, whereas matched comparators had 8.4 (7.9-8.8). The rate of outpatient visits was also significantly higher(excluding routine follow-up visits, incidence rate ratio, 1.3, P < 0.001), but translated into only a very small absolute difference of <1 outpatient visits within 5 years between DLBCL survivors (4.2 visits, 95% CI, 4.0-4.4) and matched comparators (3.8 visits, 95% CI, 3.7-3.9). In conclusion, DLBCL survivors have an increased incidence of hospital visits due to a wide range of conditions, but in absolute terms the excess use of health care services in DLBCL survivors was small.
Abstract Overall survival (OS) for patients with a hematological cancer may differ between immigrant and Danish-born patients due to disparities in socioeconomic status, health literacy, and language ...proficiency. This cohort study aimed to investigate survival and hospitalization according to immigrant status while controlling for confounders. Patients with newly diagnosed hematological cancer in 2000–2020 were identified in the Danish nationwide hematological registers and stratified into Danish-born, Western, and non-Western patients. Patients were followed from diagnosis until death, 31st December 2021, or emigration, whichever came first. Crude OS, standardized OS, and 5-years OS differences were computed using flexible parametric models and hazard ratios using Cox regression. Number of hospitalization days in the year before and after diagnosis, respectively, were calculated using Poisson regression. A total of 2,241 immigrants and 41,519 Danish-born patients with a hematological cancer were included. Standardized 5-years OS was similar between groups with 58% (95% confidence interval 57–58%) for Danish-born patients, 57% (55–60%) for Western, and 56% (53–58%) for non-Western immigrant patients. Subgroup analyses identified OS differences in selected subgroups. Non-Western immigrant patients had 1.3 (0.5–2.1) more hospitalization days in the year before diagnosis and an adjusted incidence rate ratio of hospitalization days of 1.14 (1.13–1.15) in the year after diagnosis compared with Danish-born patients. In conclusion, there were no overall differences in survival when comparing immigrant patients to Danish-born patients after controlling for relevant confounders. Healthcare utilization was slightly higher among non-Western immigrant patients before and after diagnosis, but differences were small on an individual patient level.
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