Search

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. [ABSTRACT FROM AUTHOR]

Infections during first-line therapy for DLBCL are often associated with chemotherapy dose reductions and increased mortality. Systemic infections have also been suggested as beneficial promotors of immunological responses. However, whether there is an association between the timing of an infectious episode and outcome during treatment has not yet been clarified. We investigated how the occurrence and timing of infectious episodes during the first line of treatment for "de novo" DLBCL influenced patient outcome. We used data on DLBCL patients from the Danish Lymphoma Registry, the Danish National Patient Registry, and the Danish National Pathology Registry. Infections were categorized according to type (ICD-10) and time of occurrence after treatment start. "Early" infections were defined as occurring between days 7 and 42 and "late" infections between days 100 and 150 from treatment start. Patients experiencing both "early and late" infections were categorized separately. We used multivariable Cox regression and Kaplan-Meier estimates to assess the association between infections and survival adjusting for NCCN-IPI, sex, comorbidity, and rituximab treatment. We identified 3546 patients, median age 65 years (IQR 56,73). Infectious episodes occurred in 1171 (33%) patients, of which 666 had "early," 303 "late," and 202 both "early and late" events. Patients without registered infections had a 5-year overall survival (OS) rates of 74%. Those with "early," "late," or "early+late" had 5-year OS of 65%, 62%, and 53%, respectively. Compared with patients without any registered infections, hazard rate ratios (HR) were 1.24 (95% CI 1.05-1.47), 1.32 (95% CI 1.06-1.63), and 1.59 (95% CI 1.27-2.00), respectively, in the multivariable model. We observed that infectious episodes during first-line treatment for "de novo" DLBCL occurred in 44% of the patients. Irrespective of timing, patients with infectious episodes had an inferior outcome compared to those without. Outcome patterns were similar for patients registered with sepsis. [ABSTRACT FROM AUTHOR]

Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Approximately, 2–10% of patients with CLL develop RT, most often as diffuse large B-cell lymphoma. To assess the incidence of RT, we examined risk factors for RT and death among patients with RT in a nationwide CLL cohort (from 2008 to 2016). Among 3772 patients, 113 had biopsy-proven RT. With a median follow-up of 4.3 years, the 5-year cumulative incidence of RT was 2.8%. Advanced Binet stage (B/C) (p<.001), unmutated IGHV (p<.001), and del(17p) (p<.001) were independently associated with risk of developing RT. Half of the patients with RT (49%) were treatment-naïve prior to transformation and demonstrated longer survival after RT compared to patients previously treated for CLL (6.1 vs. 2.8 years, p=.03). Whether this finding could be explained by a higher proportion of clonally unrelated RT among treatment-naïve patients, remain to be addressed. [ABSTRACT FROM AUTHOR]

Background: Hemoglobin (Hgb) concentration at diagnosis is associated with outcome in cancer. In a recently reported simplified 3-factor prognostic score in Hodgkin lymphoma, Hgb, along with age and clinical stage, outperformed the classical International Prognostic Score with seven parameters. Methods: In the present study, we investigated if pretherapeutic Hgb concentration added prognostic information to the NCCN-IPI in diffuse large B-cell lymphoma. We included patients from the Danish Lymphoma Registry (LYFO; N = 3499) and from the Molecular Epidemiology Resource (MER; N = 1225), Mayo Clinic and University of Iowa. Four sex-specific Hgb groups were defined: below transfusion threshold, from transfusion threshold to below lower limit of normal, from lower limit of normal to the population mean, and above the mean. We used multivariable Cox regression to estimate the hazard rate ratios (HR) and 95% CIs for overall survival (OS) and event-free survival (EFS), adjusting for sex, NCCN-IPI, comorbidity, and rituximab treatment. Results: Approximately half of the patients had Hgb levels below the lower limit of normal. Compared to patients with Hgb levels above the mean, an inferior OS was directly correlated with lower pretreatment Hgb within the predefined groups (HR=1.23, HR=1.51, and HR=2.05, respectively). These findings were validated in the MER. Conclusion: Based on multivariable analysis, lower pretreatment Hgb, even within the normal range but below the mean, added prognostic information to established indices such as the NCCN-IPI and the Charlson comorbidity index. [ABSTRACT FROM AUTHOR]

We investigated if survival was predicted by nadir neutrophil counts after the first cycle of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Neutrophil counts (109/L) were categorized in four grades in the nadir time frame. Prognostic indices and comorbidity levels were calculated and used to adjust the Cox regression model. Kaplan–Meier and Cox regression methods were used to estimate and compare survival. We identified 965 patients. Grade 4 neutropenia was present in 432 (45%). Grade 0 patients had a 5-year overall survival of 67%, grade 1–2: 78%, grade 3: 64%, and grade 4: 57%. Compared with grade 0 adjusted hazard ratios (HR) for death were: 0.77 (95% CI 0.49–1.21) for grade 1–2, 1.18 (95% CI 0.82–1.71) for grade 3, and 1.33 (95% CI 1.02–1.73) for grade 4. Grade 4 neutropenia after the 1st cycle of chemotherapy predicted inferior outcome compared with grade 0 and 1–2. Grade 1–2 neutropenia seemed to have superior outcome. [ABSTRACT FROM AUTHOR]

Involvement of the internal female reproductive organs by diffuse large B-cell lymphoma ( DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab-containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus ( n = 14), ovaries ( n = 10) or both ( n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression-free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system ( CNS) involvement ( SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09-39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL. [ABSTRACT FROM AUTHOR]

AbstractUp to 50% of diffuse large B-cell lymphoma (DLBCL) patients are ineligible for participation in clinical trials. Ineligible patients have inferior outcomes, but less is known about the impact of commonly used organ-function-based inclusion criteria on drug efficacy estimates. Data on DLBCL patients treated with CHOP+/-rituximab were retrieved from the Danish Lymphoma Registry. Trial inclusion criteria were extracted from four international DLBCL trials (REMoDL-B, GOYA, POLARIX, and HOVON-84). Differences in overall survival (OS) and 5-year restricted mean survival differences (5 y-RMSDs) between trial eligible and ineligible patients were computed. The effectiveness of adding rituximab to CHOP was quantified by the 5 y-RMSD between CHOP and R-CHOP-treated patients and the impact of individual trial criteria on estimated effectiveness was quantified by Shapley-values. In total, 4,083 R-CHOP-treated and 890 CHOP-treated DLBCL patients were included. Across the trials, 18.6-29.3% of the included R-CHOP-treated patients were deemed ineligible for trial based on organ function and performance status alone. Ineligible patients had significantly worse survival, with adjusted absolute differences in 5-year OS of 9-15%. The impact of individual criteria on the estimated effectiveness of adding rituximab to CHOP was small (Shapley-value range, −2.74-0.31). Using a smaller set of criteria derived from a data-driven approach, the number of eligible patients increased by 16-38% and the 5 y-RMSD increased by 0.7-3.1 months. In conclusion, OS among trial ineligible DLBCL patients is inferior as expected, but relaxing trial criteria would have increased the number of trial participants without making major changes in estimated efficacy for a hypothetical CHOP versus R-CHOP trial. This does not necessarily imply that trial findings based on selected patients are unreliable, as the estimated effectiveness of adding rituximab to CHOP was only slightly affected by omitting selected inclusion criteria. [ABSTRACT FROM AUTHOR]

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed. [ABSTRACT FROM AUTHOR]

Purpose Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown. Methods We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS. Results Of 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2–21.2%) compared with 2.6% (95% CI 1.7–3.5) among those with ≤2 sites ( P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values. Conclusions Patients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication. [ABSTRACT FROM AUTHOR]