Prognostic Importance of Comorbidity in a Population-Based Analysis of Patients with Advanced-Stage Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3656-3656
Author(s):  
André Wieringa ◽  
Eric N. van Roon ◽  
Peter Joosten ◽  
Tim Beerden ◽  
Huib Storm ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Lymphoma ◽  
Significant Risk ◽  
B Cell Lymphoma ◽  
Population Based ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Ann Arbor ◽  
Population Based Registry ◽  
Large B Cell

Abstract Abstract 3656 Introduction Diffuse large B-cell lymphoma (DLBCL) is predominantly diagnosed in the elderly and its incidence is therefore rapidly increasing. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the standard treatment for patients with newly diagnosed DLBCL. This is mainly based on data from carefully controlled randomised trials with strict eligibility criteria. Therefore data reflecting the “real world” in the rituximab era are sparse. We conducted an observational prospective cohort study to identify whether comorbidity is an independent risk factor for overall survival (OS) in patients with newly diagnosed DLBCL treated with R-CHOP with curative intent. Methods All patients with newly diagnosed DLBCL in Friesland, a Dutch province, are prospectively registered by their clinicians in a population-based registry (HemoBase®) since January 2005. Patients ≥18 years, CD20 positive, Ann Arbor stage II-IV were included if they received ≥ one cycle of R-CHOP. Clinical variables registered were age, gender, performance status (PS), Ann Arbor stage, presence of B-symptoms, lactate dehydrogenase, bulky disease, number of extranodal sites involved. Comorbidity was scored using the Charlson Comorbidity Index (CCI) [Charlson et. al.; J Chron Dis, 1987]. The score is a summation of the number of comorbidities existing at the time of diagnosis. The group was divided in low CCI (0–1) and high CCI (≥2). The primary endpoint was OS, defined as start of diagnose of DLBCL until death by any cause. Cox Proportional hazards model was used to identify significant risk factors. Variables used to calculate International Prognostic Index (IPI) and CCI were entered into the model. Kaplan-Meier curves were evaluated by log-rank test. Results Over a period of 7 years 302 patients were newly diagnosed with DLBCL after the start of the HemoBase® registry. Of those patients, 76 received no R-CHOP therapy, 9 had unknown Ann Arbor stage and 61 had Ann Arbor stage I. Therefore data from 156 patients could be retrieved from the population-based registry for further analysis. The median age was 69 years (range 23 – 93). The median observation period for the total population was 24 months (range 0 – 83) and for patients still alive 33 months (range 2 – 83). Twenty-five percent of patients had a PS≥2, 39% had IPI≥3. The percentage of patients with 8, 7, 6, 5, 4, 3, 2, or 1 R-CHOP cycle(s) given were 49, 3, 32, 1, 3, 4, 2, 6 respectively. R-CHOP21 was given to 74% and R-CHOP14 to 26%. Dose reduction of 20% or more in doxorubicin, cyclophosphamide or vincristine occurred in 26, 19, and 36% of the patients respectively. In 54% of the patients dose reduction occurred in one or more antineoplastic drugs. Twenty-five patients had a CCI≥2. Most frequently observed comorbidities in the CCI≥2 group were diabetes (36%), peripheral vascular disease (32%), chronic pulmonary disease or second tumor (28%), myocardial infarction (24%), congestive heart failure or cerebrovascular disease (16%). The percentage of patients with a CCI score of 2, 3, 4 or 5 were 64, 28, 4 and 4% respectively. In the CCI≥2 group only 16% of the patients had also a PS≥2. Three year OS in the total study population was 68%: in patients with CCI<2 71% and in CCI≥2 48%. As shown in figure 1, the median overall survival was 18 months in the CCI≥2 group and over 80 months in CCI<2 (p=0.01). From multivariate analysis of CCI and IPI variables only CCI≥2 (p=0.01; HR 2.41 (95%CI 1.20 – 4.87) and PS≥2 (p<0.001; HR 3.77 (95%CI 1.91 – 7.45) were identified as significant risk factors for poor overall survival. Conclusion In this population-based analysis of all patients with advanced-stage DLBCL treated with R-CHOP in a Dutch cohort over a period of 7 years, comorbidity is an important and independent adverse risk factor. Comorbidity data provide important prognostic information on OS, thereby aiding patient consultation in daily practice. Furthermore, our results demonstrate the importance of population-based research. Disclosures: No relevant conflicts of interest to declare.

Outcome of Diffuse Large B Cell Lymphoma in the VA System: The Rituximab Era.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4729-4729
Author(s):  
Rami S. Komrokji ◽  
Sanjay Maraboyina ◽  
Rami Y. Haddad ◽  
Zeina A. Nahleh ◽  
Malek M. Safa
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Population Based ◽  
Wilcoxon Test ◽  
P Value ◽  
Medical Centers ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: Addition of rituximab to chemotherapy in patients with diffuse large B cell Lymphoma (DLBCL) has been shown to improve survival in several recent clinical studies. A study from British Columbia confirmed those results in a population-based cohort. No similar population based studies were conducted in the USA. Our study aims to address outcome of DLBCL in the era of rituximab in the VA health system. Methods: This was a retrospective analysis. The VA Central Cancer Registry (VACCR) database was used to identify patients with DLBCL diagnosed between 1995 and 2005. There are approximately 120 VA medical centers diagnosing and/or treating patients with cancer. The VACCR aggregates the data collected by the medical centers’ cancer registries. Data were extrapolated and analyzed using bio-statistical software SPSS. Variables included age, sex, stage of disease, histology subtype, date of diagnosis, date of last contact, date of relapse, vital status, whether patients received chemotherapy and or radiation. Use of rituximab was not specifically recorded in the registry. Due to that we divided the patients into two groups, patients diagnosed with DLBCL before 2001 (pre rituximab era group) and patients diagnosed after 2001 (rituximab era group). The initial results of rituximab in DLBCL were presented in 2000 and published in January 2002. Independent t test was used for comparing continuous variables and chi square test for categorical variables. Wilcoxon test was used to compare survival among the two groups. Results: There were 2792 patients with DLBCL at the VACCR between 1995 and 2005, 1772 patients in pre rituximab era and 1020 patients in the rituximab era. The mean age at diagnosis was to 64 in pre rituximab group and 66 in rituximab group (P-value 0.015). Race distribution was similar between the two groups. More patients were diagnosed at advanced stage (stage III and IV) 61 % in rituximab group compared to 57% in pre rituximab group (P-value &lt;0.005), IPI score data were not available. More patients in pre rituximab era did not receive multi-agent chemotherapy 28% versus 22% (P-value &lt; 0.005). More patients received radiation 21 % in pre rituximab group compared to 16% in rituximab era group (P-value &lt; 0.005). The 5-year overall survival was 26% in pre rituximab era and 36% after rituximab (P-value 0.0025). Using Cox regression multivariable analysis age, use of mutli-agent chemotherapy, radiation and whether patients were diagnosed and treated before or after 2001 were statistically significant independent variables affecting survival. Conclusions: Overall survival of DLBCL in VA patients had improved in the rituximab era. The magnitude of improvement observed in this study is similar to what was described in previous studies. Other factors contributing to improvement in outcomes such as supportive care could not be differentiated in this study. This is a population-based study suggesting improvement in survival in DLBCL in the rituximab era.

Genetic Polymorphisms In Genes Involved In R-CHOP Metabolism and Event-Free and Overall Survival In Diffuse Large B-Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 996-996 ◽  
Author(s):  
James R Cerhan ◽  
Thomas M Habermann ◽  
Matthew J Maurer ◽  
James E Wooldridge ◽  
Stephen M Ansell ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Variant Allele ◽  
Newly Diagnosed ◽  
Enzyme Expression ◽  
Large B Cell Lymphoma ◽  
Individual Snps ◽  
Large B Cell

Abstract Abstract 996 Background: Treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has improved survival in diffuse large B-cell lymphoma (DLBCL) lymphoma, although a significant percentage of patients do not achieve a remission or they relapse. One potential explanation for this observation is that host pharmacogenetic background may impact metabolism, detoxification and transport of R-CHOP. However, there are few prospectively collected data that address pharmacogenetics in DLBCL, particularly for event-free and overall survival in the rituximab era. We therefore tested the hypothesis that functional candidate single nucleotide polymorphisms (SNPs) from genes involved in the metabolism of CHOP (CYP2C19, CYP3A5, ABCB1, ABCC2, ABCG2, RAC2, CYBA, NR3C1, GSTA1, GSTP1, TP53) and rituximab (FCGR2A, FCGR3A) influence prognosis in DLBCL. Methods: We genotyped 19 SNPs from 13 genes in a prospective cohort of newly diagnosed DLBCL patients with germline DNA enrolled at the Mayo Clinic and University of Iowa from 2002–2008 as part of the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. All patients were systematically followed through 2009 for overall survival (OS) and event-free survival (EFS), defined as disease progression, retreatment or death due to any cause. All SNPs were genotyped on the Illumina Golden-Gate platform. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with OS and EFS. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group. An ordinal test was used to assess the trend across genotypes, and a p<0.05 was considered statistically significant. All Cox models adjusted for International Prognostic Index (IPI) and treatment. Results: The median age at diagnosis of the 439 DLBCL patients was 62 years (range 18–92). The IPI was distributed as follows: 0–1 (34%), 2 (26%), 3 (24%) and 4–5 (16%). All patients were treated with chemotherapy, and 91% received R-CHOP. Through 2009, there were 171 events (39%) and 122 (28%) deaths, with a median follow-up for living patients of 49 months (range 1–98). The SNP rs1045642 in the ATP-binding cassette (ABC) protein gene ABCB1 was associated with OS (p=0.012). The variant T allele for ABCB1 rs1045642 (minor allele frequency (MAF)=0.47) is associated with a silent I→I substitution, and the T allele predicts low enzyme expression. Compared to CC homozygotes, patients with CT (HR=0.66, 95% CI 0.44–0.99) or TT (HR=0.53, 95% CI 0.31–0.90) genotypes had superior OS. We also observed an association of the GSTP1 SNP rs1695 with OS (p-trend=0.018). The variant G allele (MAF of 0.31) is associated with an A→V substitution, and this change predicts low enzyme expression. Compared to AA homozygotes, patients with the AG (HR=0.78, 95% CI 0.54–1.14) or GG (HR=0.39, 95% CI 0.17–0.90) genotypes had superior OS. Nearly identical associations for these two SNPS were observed with EFS. There were no significant associations with any of the other SNPs that we evaluated. Conclusions: In a large series of newly diagnosed DLBCL patients treated in the rituximab era, we found evidence that genetic variation in ABCB1 and GSTP1 is associated with improved OS and EFS after adjusting for IPI and treatment. The variant allele for ABCB1 is associated with slower enzyme activity, favorably impacting doxorubicin and vincristine pharmacodynamics, and the variant allele for GSTP1 is associated with slower detoxification of doxorubicin and vincristine, increasing bioavailability of these drugs. A comprehensive evaluation of the role of pharmacogenetics in DLBCL is warranted. Support: P50 CA97274, R01 CA129539. Disclosures: No relevant conflicts of interest to declare.

Rituximab Does Not Improve Progression Free (PFS) or Overall Survival (OS) in Patients with Limited Stage Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3755-3755
Author(s):  
Ephraim P. Hochberg ◽  
Nicole Birrer ◽  
Christiana E. Toomey ◽  
Jeffrey A. Barnes ◽  
Alfred Ian Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Logrank Test ◽  
Limited Stage ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Abstract 3755 Poster Board III-691 Introduction Diffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy accounting for approximately 33% of all newly diagnosed NHLs. Three randomized trials and multiple retrospective analyses have demonstrated both progression-free (PFS) and overall survival (OS) benefit to the addition of the anti-CD20 monoclonal antibody rituximab to anthracycline-containing chemotherapy in older advanced-stage patients, and in young low-risk patients with DLBCL. Approximately half of newly diagnosed patients with DLBCL present in limited stage and the benefit of rituximab containing chemotherapy regimens for these patients remains uncertain. Methods We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, Dana Farber Cancer Institute and Brigham and Women's Hospital, to identify all patients 18 years or older diagnosed with limited stage DLBCL between 2000 and 2006. We included all patients treated with 3 or more cycles of anthracycline containing chemotherapy with curative intent. We excluded primary DLBCL of the CNS. We determined the impact of the use of rituximab on OS and PFS. PFS and OS were calculated from the date of initial diagnosis. Results A total of 138 patients met eligibility criteria and are included in the analysis. Median age was 51 years (range 18-89 years). 30% of patients were above 60 years of age, and less than 3% had an IPI score of 3 or higher. One hundred and six patients received CHOP + rituximab (RCHOP) and 32 received CHOP alone. Of the 106 patients receiving RCHOP, 48 were irradiated and 58 were not. Of the 32 patients receiving CHOP, 20 received radiation and 12 did not. At a median follow-up of 35 months (range 3-109 months), PFS and OS for the entire cohort are 86.2% and 90.6%, respectively. On univariate analysis of outcome, the addition of rituximab to CHOP did not improve PFS (81.3% vs. 87.7%,p=0.817, Logrank Test) or OS (84.4% vs. 92.5%, p=0.411, Logrank Test). Conclusion The outcome of an unselected series of patients with limited stage DLBCL is excellent. In this retrospective cohort of patients with limited stage DLBCL, the use of rituximab in conjunction with standard chemotherapy did not improve PFS or OS. The results we obtained are very similar to those reported by SWOG (Persky et al. JCO 2008). The overlapping confidence intervals for PFS and OS between SWOG 0014 and 8736 patients and our data suggest that a large multicenter trial will be needed to show a benefit of rituxan in this extremely good prognosis population. Disclosures: Hochberg: Genentech: Speakers Bureau; Biogen-Idec: Speakers Bureau; Enzon: Speakers Bureau; Amgen: Speakers Bureau.

Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients Treated with Immunochemotherapy Who Are Alive and Progression Free 12 Months After Diagnosis Have a Subsequent Overall Survival Similar to That of the General Population

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1540-1540 ◽  
Author(s):  
Matthew J Maurer ◽  
Herve Ghesquieres ◽  
Thomas E. Witzig ◽  
Carrie A. Thompson ◽  
Ivana N. Micallef ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
General Population ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Age And Sex

Abstract Abstract 1540 Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma in the western world. Outcomes have improved with the standard initial therapy of rituximab and anthracyline based chemotherapy (immunochemotherapy). However, 20–40% of patients will either fail to achieve remission or relapse following initial immunochemotherapy. Most relapses occur early, and long-term outcome of relapsed/refractory patients is generally poor despite salvage regimens and stem cell transplant. Traditionally, studies for DLBCL have been evaluated using progression-free and/or overall survival. However, the event rate in DLBCL slows significantly approximately 12–18 months after diagnosis, and late events are often due to competing (non-DLBCL related) risks, especially in older patients. Here we examine outcome of DLBCL patients based on their event status at 12 months. Methods: Newly diagnosed DLBCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER). Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for events (progression, re-treatment, or death due to any cause) and overall survival (OS). Event-free status at 12 months after diagnosis (EFS12) was assessed as a dichotomous variable. Cause of death was determined by medical record and death certificate review using prospectively determined definitions. Expected survival was based on age and sex matched survival using the Minnesota population death rates. Confirmation cohorts were from a Lyon, France hospital based registry and NCCTG clinical trial N0489. Results: 680 patients with newly diagnosed DLBCL and treated with rituximab + anthracycline based chemotherapy were enrolled in the MER from 2002 to 2009. The median age was 62 years (range 18–92). 53% were male. At a median follow-up of 59 months (range 8–116), 266 patients (39%) had an event and 188 patients (28%) died. 162 patients (24%) had an event in the first 12 months after diagnosis, comprising 60% of all events. Patients with an event in the first 12 months had poor survival with death almost exclusively due to disease (Figures 1a, 2a). In contrast, patients who were event-free at 12 months had comparable survival to the age and sex matched general population (Figure 2b) and were more likely to die of other causes than DLBCL (Figure 1b). Overall survival rates by EFS12 status were validated in patients from a French hospital-based registry (N=265) and the NCCTG N0489 clinical trial (N=87) with additional replication studies underway. Conclusions: DLBCL patients who are event-free at 12 months after diagnosis have an excellent prognosis with an overall survival similar to that of an age- and sex- matched general population and are more likely to die of other causes than DLBCL. This finding has implications for clinical management, new clinical trials, and follow-up testing in this patient population. In contrast, patients with an event within the first 12 months after diagnosis have a poor prognosis with almost all deaths secondary to DLBCL. EFS status at 12 months identifies patients with poor outcomes due to disease. This can be utilized as an endpoint in biologic studies and clinical trials to address early treatment failures. EFS status at 12 months should be incorporated into prognostic models to identify high risk patients in newly diagnosed DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Poor outcome in patients with diffuse large B-cell lymphoma is associated with high percentage of bcl-2 and Ki 67-positive tumor cells

2009 ◽  
Vol 66 (9) ◽  
pp. 738-743 ◽  
Author(s):  
Maja Perunicic-Jovanovic ◽  
Ljubomir Jakovic ◽  
Andrija Bogdanovic ◽  
Olivera Markovic ◽  
Vesna Cemerikic-Martinovic ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
High Risk ◽  
Prognostic Value ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Newly Diagnosed ◽  
Ki 67 ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Background/Aim. Newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) tretaed with immunochemotherapy have durable remission and improved overall survival. It is important to identify high risk patients who may benefit from even more effective therapies. Methods. In a group of 50 newly diagnosed patients with DLBCL, treated with CHOP/R-CHOP (cyclophosphemide doxorubicine, vincristine, prednisone with or without rituximab) regimen, we analyzed the prognostic value of the expression of Ki67 and bcl-2 at diagnosis as well as other standard clinical parameters: International Prognostic Index (IPI), bulky disease, extranodal distribution and lactat dehydrogenase (LDH). Significance was tested according to response rate and overall survival. Results. Univariate survival analysis showed that high IPI had a statistically significant negative influence on overall and event free survival time (log rank, p < 0.01). The log rank test analysis signified that patients with a high proliferative fraction (Ki-67 > 60%) had a worse overall survival rate (OS5y) of 40% compared to those with low proliferation (Ki-67 < 60%) with OS5y of 80% (p < 0.01). There was a clear difference between bcl-2 positivity (treshold 50%) and the achievement of complete remission (66% vs 86% in patients with bcl-2 high and low levels respectively, p < 0.05). In survival analysis, patients with low bcl-2 expression had significantly higher OS5y - 68% compared to those with high bcl-2+ with OS5y 37% (p < 0.05). Multivariate analysis performed by Cox model revealed that IPI > 3, high Ki-67+, bcl-2 positivity had a significant independent prognostic value concerning overall survival (p < 0.05). Conclusion. An initial high IPI score associated with high Ki-67+ and bcl2+ could represent possible predictive factors of poor prognosis, which would help to identify a high risk subgroup of newly diagnosed DLBCL.

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