Charlson Comorbidity Index is an independent prognostic factor among elderly patients with diffuse large B-cell lymphoma

Purpose

The clinical outcome for elderly patients with diffuse large B-cell lymphoma (DLBCL) has improved. However, the management of elderly patients with cancer is frequently complicated by their coexisting disorders. The aim of this study was to evaluate the correlation between comorbid medical status and clinical outcome among elderly patients with DLBCL.

Methods

We retrospectively analyzed all patients over 65?years old with newly diagnosed DLBCL from 2001 to 2008 in our institution. To assess their comorbid medical status, we calculated Charlson Comorbidity Index (CCI) of each patient without considering primary disease and then divided them into low CCI (0 or 1) or high CCI group (2 or more).

Results

A total of 80 patients from age of 66?C90?years (median 73?years) were analyzed. Seventy-two patients (90%) were treated with cyclophosphamide-, doxorubicin-, vincristine-, and prednisone (CHOP)-based chemotherapy, and 14 patients (18%) were assigned to high CCI. The overall survival (OS) rate at 3?years for all patients was 70%, with significant difference between good and poor risk patients in revised International Prognostic Index (IPI) (90 vs. 45%, P?P?=?0.0045). In addition, high CCI group was significantly inferior to low CCI group for overall response rate (93 vs. 64% P?=?0.0158) and 3-year OS (85 vs. 55% P?=?0.0026), respectively.

Conclusions

Among elderly DLBCL, high CCI was independently associated with worse outcome. Novel discrete strategies for these deteriorated patients are therefore warranted.     

MAGE-A3 expression is an adverse prognostic factor in diffuse large B-cell lymphoma

This study evaluates the prognostic value of MAGE-A3 expression in 28 diffuse large B-cell lymphoma (DLBCL) patients. A significant association was observed between MAGE-A3 expressions, assessed by quantitative real-time RT-polymerase chain reaction (PCR), with advanced stages of disease (P < 0.05). Elevated serum lactate dehydrogenase (LDH) levels and International Prognostic Index (IPI) score were significantly higher in MAGE-A3-positive patients (P = 0.025 and P = 0.004, respectively). Expression of MAGE-A3 was associated with poor response to treatment and a significantly shorter overall survival (P < 0.001). Our data address new information in the association of MAGE-A3 expression and poor prognosis in DLBCL patients.     

Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell‐free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite‐treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03‐55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80‐50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene‐specific methylation data. This analysis shows that global hypomethylation co‐occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.     

Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma

Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.     

Rearrangement of the BCL6 locus at 3q27 is an independent poor prognostic factor in nodal diffuse large B-cell lymphoma

Diffuse large B-cell lymphomas (DLBCL) are a heterogeneous group of tumours, varying in clinical features, immunophenotype and cytogenetics. The aim of this study was to investigate the prognostic significance of BCL6 gene rearrangement at the 3q27 locus in patients with primary nodal disease, and to examine interrelationships with immunophenotype and International Prognostic Index (IPI). We have developed a fluorescent in situ hybridization (FISH)-based technique for the retrospective analysis of the effect of BCL6 gene rearrangements on survival, using nuclei extracted from paraffin-embedded tissue. FISH results were obtained in 111 presentation cases of nodal DLBCL. The IPI was calculated and each case was stained immunocytochemically for BCL6, BCL2 and CD10. 3q27 rearrangements were detected in 25% of cases. BCL2 protein and a germinal centre (GC) phenotype (defined as CD10+, BCL6+) were expressed in 56% and 41% of cases respectively. In multivariate analysis, rearrangement of 3q27 and BCL2 expression and the absence of a GC phenotype were associated with a poor prognosis. These factors can be used in conjunction with the IPI to improve risk stratification in nodal DLBCL.     

Serum albumin retains independent prognostic significance in diffuse large B-cell lymphoma in the post-rituximab era

Serum albumin (SA) has been shown to be a prognostic marker in many hematological malignancies and in diffuse large B-cell lymphoma (DLBCL) prior to chemo-immunotherapy. SA may be a surrogate for age, comorbid status, and disease severity. Here, we aimed to assess whether SA can be an independent prognostic marker in patients with newly diagnosed DLBCL treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP). Patients who presented at the Moffitt Cancer Center from 2007 to 2010 for DLBCL diagnosis or treatment were identified using our institutional database. Clinical and treatment data were recorded, including SA levels at diagnosis. Survival time was estimated using the Kaplan-Meier method, with Cox proportional hazard model used to identify potential risk factors for time-to-event data. From 295 identified patients, 171 were excluded for not having primary treatment at our institution or not having R-CHOP treatment. In 124 included patients (mean age at diagnosis of 58 years, 91 % Caucasian), 25 % were categorized as poor by the revised International Prognostic Index. Overall and progression-free survival at 4 years were 65 % (95 % CI 57–75) and 58 % (95 % CI 0.49–0.69), respectively. Using multivariate analysis, we found that the hazard index of death of patients with SA ≥3.7 g/dL was 26 % (95 % CI 13–53) of the hazard for those patients who had SA <3.7 g/dL when controlling for the revised International Prognostic Index risk and initial lymphocyte count. Our study shows that SA ≥3.7 g/dL is an independent prognostic marker in DLBCL patients treated with R-CHOP.     

Clinical characteristics and prognostic analysis of Chinese patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults. As it is a highly heterogenous disease, many studies have focused on finding useful prognostic factors to help guide therapy. In this report, we examine several biological markers in 83 patients with DLBCL enrolled in our hospital, including cell origin, serum lactate dehydrogenase (LDH) levels, and international prognostic index (IPI), in order to find the best combination of prognostic factors. We also examined whether DLBCL has a significant geographic difference, since several studies have suggested that the prevalence and potential etiological factors of lymphomas in China may be different from those in other countries. Our results demonstrate that: (1) patients in China have higher extranodal tissue involvement and different extranodal organ distribution than patients reported from other countries; (2) Chinese patients have higher rates of germinal center (GC) cell origin; and (3) among nine prognostic variables, lower IPI scores, GC cell origin determined by immunohistochemical staining, and no more than 1.5 times of normal levels of LDH are statistically significant good prognostic factors in Chinese patients with DLBCL, whereas age at the time of diagnosis, clinical stage, β₂-microglobulin levels, extranodal tissue involvement, and expression levels of Bcl-6 protein were not useful in determining prognosis.     

Male gender is an adverse prognostic factor in B-cell lymphoma patients treated with immunochemotherapy

Male gender is an adverse prognostic factor in Hodgkin's lymphoma, but no such association has yet been established in non-Hodgkin lymphomas. Here, we have evaluated whether gender has prognostic impact on the survival of patients with B-cell non-Hodgkin lymphoma in the postrituximab era of lymphoma therapies. The study populations consisted of 217 diffuse large B-cell lymphoma (DLBCL) and 110 follicular lymphoma (FL) patients treated with immunochemotherapy. Hundred and sixty chemotherapy-treated DLBCL patients served as a control group. According to Kaplan-Meier analyses, female patients had a significantly better progression-free survival than men both in DLBCL (4 yr PFS 75% vs. 60%; P= 0.013) and in FL (4 yr PFS 68% vs. 52%, P=0.036) patients treated with immunochemotherapy. In chemotherapy-treated DLBCL patients, no difference in survival between the genders was found. The results support the idea that women seem to respond better to rituximab.     

Late relapse in patients with diffuse large B-cell lymphoma

The outcomes for 162 patients with diffuse large B-cell lymphoma treated with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like regimen who obtained a complete remission and who subsequently relapsed after ≥5 years of remission (late relapse, N=30), or <5 years of remission (early relapse, N=132), were compared. The late relapsing patients had better prognostic characteristics at diagnosis, such as stage I/II disease (73% vs. 49%, P=0·04), a normal lactic dehydrogenase (77% vs. 48%, P=0·01), and a Karnofsky performance score of ≥80 (100% vs. 86%, P=0·01). The 3-year survival after relapse was better in late relapsing patients (48% vs. 25%, P=0·03), but the survival at 5 years (32% vs. 20%) and 10 years (13% vs. 14%) after relapse was not different. A multivariate analysis of factors predicting survival after relapse found age (P<0·0001) and presence of B-symptoms (P=0·03) to predict survival, but not early versus late relapse. A small percentage of the late relapsing patients can have a prolonged second remission. However, the overall survival from the time of relapse was not different between early and late relapsing patients with most succumbing to lymphoma.     

Comparison of prognostic models for patients with diffuse large B-cell lymphoma in the rituximab era

Several revisions of International Prognostic Index (IPI) have been proposed for patients with diffuse large B-cell lymphoma (DLBCL) after the introduction of rituximab. Expanding evidence suggests that baseline absolute lymphocyte count (ALC) is also an independent factor for outcome prediction. We investigated the optimal prognostic model for these patients in the rituximab era. The study enrolled 274 consecutive patients with DLBCL receiving first-line cyclophosphamide, doxorubicin, vincristine, and prednisone based chemotherapy with rituximab between 2003 and 2009. Five factors within IPI and ALC were entered for Cox regression analysis. Overall survival (OS) and progression-free survival were calculated for different risk groups of models. Efficacy of models was compared by the value of Akaike information criterion (AIC). Revised IPI (R-IPI) and ALC/R-IPI, but not IPI, were informative to discriminate between different risk groups. In multivariate analysis for individual factors of the prognostic models, performance status >1 [odds ratio (OR) 3.59], Ann Arbor stage III or IV (OR 2.24), and ALC <1?×?10⁹/L (OR, 2.75) remained significant. Another modified score based on the three factors divided patients into four risk groups and the 3-year OS rate was 93, 77, 39, and 13 %, respectively. By comparing AIC values in the Cox proportional hazards model, the modified three-factor model was the superior prognostic model followed by established ALC/R-IPI, R-IPI, and standard IPI. In conclusion, the addition of the novel factor, ALC, interacts with other established factors in outcome prediction for DLBCL. Development of a new score is needed for a better risk stratification in the rituximab era and would be helpful in the design of future clinical trials. The proposed three-factor model should be validated in large-scale studies.     

Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4–8) and advanced stage (III–IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P?<?0.001) and OS (P?<?0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR?=?1.90, 95% CI: 1.15–3.16 for PFS, P?=?0.013; HR?=?2.65, 95% CI: 1.46–4.79 for OS, P?=?0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P?=?0.0194 for PFS, P?=?0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.     

CD21S antigen expression in tumour cells of diffuse large B-cell lymphomas is an independent prognostic factor indicating better overall survival

To evaluate the clinical significance of CD21S expression of diffuse large B-cell lymphoma (DLBCL) tumour cells, we compared their clinical features, immunophenotype, response to therapy and outcome in relation to CD21S expression. Between 1987 and 1999, frozen sections from 240 DLBCL cases were examined for CD21S expression by immunohistochemical methods. CD21S expression was detected on the tumour cells of 87 (36%) cases. The median age of the CD21S(+) DLBCL cases was 65 years (range: 17-84 years), the male-female ratio was 42:45, and they showed the following clinical features: Eastern Cooperative Oncology Group score >1 in 14%, lactate dehydrogenase greater than normal levels in 38%, extranodal sites >1 in 14%, stages III/IV disease at diagnosis in 29%, B symptoms in 17%, and a high/high-intermediate International Prognostic Index (IPI) in 23%. They also showed a better overall survival (P = 0.00001, log-rank test) and a better complete remission rate (P = 0.00004, chi-square test) than CD21S(-) DLBCL. Moreover, CD21S(+) DLBCL showed a better survival than CD21S(-) DLBCL for both low/low-intermediate and high/high-intermediate risk categories of IPI (P = 0.045 and P = 0.0016 respectively). Multivariate analysis identified CD21S expression as an independent factor for survival when compared with the five IPI factors. These findings indicate that CD21S expression of DLBCL tumour cells is a useful prognostic factor for survival.     

The derived neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with angioimmunoblastic T-cell lymphoma

To determine whether inflammatory markers, derived neutrophil-to-lymphocyte ratio (dNLR), haemoglobin/platelet ratio (HPR) or platelet/lymphocyte ratio (PLR) are predictive for prognosis in angioimmunoblastic T-cell lymphoma (AITL), we derived dNLR, HPR and PLR values for 110 AITL patients and appropriate cut-off point values to define overall survival (OS) and progression-free survival (PFS). dNLR ≥ 2·2, HPR ≥ 0·4 or PLR < 100 were significant factors for shorter OS and PFS. On univariate analysis, these three parameters were significantly associated with worse OS and PFS. On multivariate analysis, only dNLR remained a significant, independent prognostic factor for both OS and PFS.     

A prognostic score for AIDS-related diffuse large B-cell lymphoma in Brazil

The aim of this study was to evaluate a prognostic score for aids-related lymphoma (ARL). A retrospective study of 104 patients with ARL treated between January 1999 and December 2007 was conducted. Diffuse large B-cell lymphoma (DLBC) was the most observed histological type (79.8%). The median CD4 lymphocyte count at lymphoma diagnosis was 125 cells per microliter. Treatment response could be evaluated in 83 (79.8%) patients, and 38 (45.8%) reached complete remission (CR); overall response rate was 51.8% (95 CI = 38.5–65.1%). After a median follow-up of 48 months, the 4-year overall survival (OS) rate among all patients was 35.8%, with a median survival time of 9.7 months (95% CI = 5.5–13.9 months). The survival risk factors observed in multivariate analysis (previous AIDS and high-intermediate/high international prognostic index (IPI)) were combined to construct a risk score, which divided the whole patient population in three distinct groups as low, intermediate, and high risk. When this score was applied to DLBC patients, a clear distinction in response rates and in OS could be demonstrated. Median disease-free survival (DFS) for patients that achieved CR was not reached, and DFS in 4 years was 83.0%. Our results show that the reduced OS observed could be explained by poor immune status with advanced stage of disease seen in our population of HIV-positive patients. Further studies will be needed to clarify the role of different treatment approaches for ARL in the setting of marked immunosuppression and to identify a group of patients to whom intensive therapy could be performed with a curative intent.