Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy

BackgroundA recent laboratory study indicated that statins impaired the antitumor effects of rituximab by inducing conformational changes in CD20. Although these findings raised significant concerns about statin use during rituximab treatment, their clinical significance is unclear.Patients and methodsWe conducted a retrospective study investigating the effects of statins on the prognosis of diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Newly diagnosed DLBCL patients were analyzed (n = 256), including 35 patients taking statins.ResultsThe 3-year progression-free survival rates were 84% and 73% (P = 0.38), while the overall survival rates were 89% and 78% (P = 0.28) for those patients treated with and without statins, respectively. After adjusting for the International Prognostic Index and serum cholesterol level, statin use was not associated with prognosis.ConclusionsThese results indicate that statins do not influence the clinical prognosis of DLBCL treated with RCHOP. Further studies with larger numbers of patients are warranted to confirm the prognostic significance of statins for patients with DLBCL receiving rituximab-containing chemotherapy.     

Soluble interleukin-2 receptor retains prognostic value in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP (RCHOP) therapy

Background: Soluble interleukin-2 receptor (SIL-2R) is knownto be a prognostic parameter in patients with diffuse largeB-cell lymphoma (DLBCL) receiving cyclophosphamide, doxorubicin,vincristine and prednisone (CHOP) therapy. However, its prognosticvalue has not been well known since the introduction of rituximab. Patients and methods: We retrospectively evaluated the prognosticimpact of SIL-2R in 228 DLBCL patients, comparing 141 rituximab-combinedCHOP (RCHOP)-treated patients with 87 CHOP-treated patientsas a historical control. Results: Patients with high serum SIL-2R showed significantlypoorer event-free survival (EFS) and overall survival (OS) thanpatients with low SIL-2R in both the RCHOP group (2-year EFS,66% versus 92%, P < 0.001; OS, 82% versus 95%, P = 0.005)and the CHOP group (2-year EFS, 40% versus 82%; OS, 61% versus90%, both P < 0.001). Multivariate analysis including thefive parameters of International Prognostic Index (IPI) andtwo-categorized IPI revealed that SIL-2R was an independentprognostic factor for EFS and OS in the RCHOP group as wellas in the CHOP group. Conclusions: Our results demonstrate that SIL-2R retains itsprognostic value in the rituximab era. The prognostic valueof SIL-2R in DLBCL patients receiving rituximab-combined chemotherapyshould be reassessed on a larger scale and by long-term follow-up. Key words: diffuse large B-cell lymphoma, rituximab, soluble interleukin-2 receptor Received for publication July 5, 2008. Revision received September 11, 2008. Accepted for publication September 16, 2008.     

Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia.

PURPOSE: For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC). METHODS: We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with "B" symptoms or bulky [> 10 cm] disease) DLBCL. RESULTS: A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P = .002) and overall survival (risk ratio, 0.40; 95% CI, 0.27 to 0.61, P < .0001) were significantly improved in the postrituximab group. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of progression-free survival (risk ratio, 0.59; 95% CI, 0.41 to 0.85; P = .005) and overall survival (risk ratio, 0.43; 95% CI, 0.29 to 0.66; P < .001). The benefit of treatment in the postrituximab era was present regardless of age. CONCLUSION: The addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL patients of all ages in the province of BC.     

美罗华联合CHOP方案与CHOP方案治疗初治弥漫性大B细胞淋巴瘤的临床对比研究

背景与目的:CHOP方案是治疗弥漫性大B细胞淋巴瘤的标准方案。美罗华是一种抗CD20单克隆抗体,对弥漫性大B细胞淋巴瘤有效。本研究中比较美罗华联合CHOP方案和单用CHOP方案治疗初治的弥漫性大B细胞淋巴瘤的疗效和不良反应。方法:采用同期非随机对照的前瞻性研究方法,将72例初治的弥漫性大B细胞淋巴瘤患者分为联合组和CHOP组。联合组34例,采用CHOP方案(环磷酰胺加阿霉素加长春新碱加强的松)加美罗华(375mg/m2,于每周期化疗前2天静脉滴注1次)治疗;CHOP组38例,单用CHOP方案化疗。两组均每3周为一个循环周期,6个周期后比较两组的疗效及不良反应。结果:联合组完全缓解23例,部分缓解7例,总有效率为93.8%(30/32);CHOP组完全缓解19例,部分缓解8例,总有效率为75.0%(27/36),两组疗效差异有显著性(P<0.05);联合组和CHOP组1年的无进展生存率分别为81.2%和52.8%,总生存率为93.8%和75.0%,联合组均显著优于CHOP组(P<0.05)。联合组的不良反应主要为发热等输注相关的不良反应,以及骨髓抑制等化疗相关的血液学不良反应,其中输注相关的不良反应轻微,患者均可耐受,而骨髓抑制情况与CHOP组类似。结论:美罗华联合CHOP方案能够提高CHOP方案治疗初治弥漫性大B细胞淋巴瘤的疗效,而毒性反应类似,可作为该病的一线治疗方案。     

Addition of rituximab to reduced-dose CHOP chemotherapy is feasible for elderly patients with diffuse large B-cell lymphoma

Purpose  

The aim of this study was to evaluate the efficacy and toxicity of reduced-dose (RD) RCHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy for elderly patients with diffuse large B-cell lymphoma (DLBCL).     

利妥昔单抗联合CHOP与单用CHOP方案治疗初治弥漫大B细胞型淋巴瘤的对比研究

目的:比较利妥昔单抗(商品名:美罗华)联合CHOP(环磷酰胺,阿霉素,长春新碱和泼尼松)与单用CHOP方案化疗治疗弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)的临床疗效。方法:根据患者的意愿,49例DLBCL患者分别接受6疗程CHOP方案或CHOP加利妥昔单抗方案化疗,每3周1疗程,共6个疗程。结果:R-CHOP组的CR率高于CHOP组,但差异无统计学意义(82.6%VS 65.4%,P=0.173)。中位随访时间为35月(4-66月),R-CHOP组及CHOP组的3年OS分别为75.0%±19.6%,54.9%±20.4%,P=0.043;而3年EFS分别为69.7%±20.9%,45.8%±20.6%,P=0.029。R-CHOP组的3年OS及EFS优于CHOP组,差异有统计学意义。两组患者的不良反应无明显差别。结论:与单用CHOP方案相比,利妥昔单抗联合CHOP方案明显提高DLBCL患者的EFS及OS,而不良反应无明显增加。     

利妥昔单抗联合CHOP与单用CHOP方案治疗初治弥漫大B细胞型淋巴瘤的对比研究

目的：比较利妥昔单抗（商品名：美罗华）联合CHOP（环磷酰胺,阿霉素,长春新碱和泼尼松）与单用CHOP方案化疗治疗弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma,DLBCL）的临床疗效。方法：根据患者的意愿,49例DLBCL患者分别接受6疗程CHOP方案或CHOP加利妥昔单抗方案化疗,每3周1疗程,共6个疗程。结果：R-CHOP组的CR率高于CHOP组,但差异无统计学意义（82.6%VS 65.4%,P=0.173）。中位随访时间为35月（4-66月）,R-CHOP组及CHOP组的3年OS分别为75.0%±19.6%,54.9%±20.4%,P=0.043;而3年EFS分别为69.7%±20.9%,45.8%±20.6%,P=0.029。R-CHOP组的3年OS及EFS优于CHOP组,差异有统计学意义。两组患者的不良反应无明显差别。结论：与单用CHOP方案相比,利妥昔单抗联合CHOP方案明显提高DLBCL患者的EFS及OS,而不良反应无明显增加。     

Addition of rituximab is not associated with survival benefit compared with CHOP alone for patients with stage I diffuse large B-cell lymphoma

Background

The role of rituximab in combination with CHOP regimen in patients with stage I diffuse large B-cell lymphoma (DLBCL) remains to be defined. We aimed to compare CHOP plus rituximab (R-CHOP) with CHOP alone and determine the value of radiotherapy in these patients.

Methods

Between 2003 and 2009, 140 untreated patients with stage I DLBCL were retrospectively analyzed in this study.

Results

Seventy-eight patients were treated in R-CHOP group and 62 in CHOP group. Ninety-one patients received additional radiotherapy at the end of chemotherapy. The different treatment groups were well-balanced with respect to baseline characteristics. Complete response (CR) rate was 77% both in R-CHOP and CHOP groups (P=0.945). After a median follow-up period of 56 months, patients received R-CHOP regimen had similar 5-year progression-free survival (PFS) (76% vs. 85%; log-rank P=0.215) and 5-year overall survival (OS) (90% vs. 96%; log-rank P=0.175) compared with those with CHOP alone. Patients with radiotherapy had significantly increased 5-year PFS compared with those who had chemotherapy alone (86% vs. 71%; log-rank P=0.005). At multivariate analysis, patients who had CR (P=0.008) and received radiotherapy (P=0.003) were significantly associated with superior PFS.

Conclusions

CHOP alone could be as effective as R-CHOP regimen and additional radiotherapy would be necessary for stage I or stage I non-bulky DLBCL patients.     

Cyclin B1 expression is an independent prognostic marker for poor outcome in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin's lymphoma in the Western world; it is characterized by marked genetic, morphological and clinical heterogeneity. The identification of prognostic markers could help to develop risk-adapted treatment strategies. As proliferation of cells is essential for tumour growth, analysis of the cell cycle and its individual phases might give additional information on tumour progression and clinical behaviour. To investigate the prognostic value of proteins specifically related to the cell cycle phases S, G2 and M in DLBCL, the expression of cyclin A as a marker of S phase and cyclin B1 as a G2/M phase marker were analysed in combination with other clinicopathological parameters in a large cohort of patients. Expression of cyclin B1 and cyclin A were determined by immunohistochemistry using tissue microarray methodology. Immunoreactivity for cyclin B1 and cyclin A was correlated with clinical data using a two-sided Fisher's exact test. Impact on overall survival was analysed by the Kaplan-Meier method. A negative prognostic impact was found for expression of cyclin B1. Nuclear and/or cytoplasmic staining in > or = 1% of tumour cells was significantly associated with shorter overall survival in the multivariate analysis (p=0.008). Furthermore, the prognostic impact of cyclin B1 expression was independent of the tumour stage. No prognostic significance was found for expression of cyclin A. In conclusion, this study demonstrates the independent prognostic value of an expression of cyclin B1 in DLBCL and proposes its evaluation as a prognostic marker in the assessment of this entity which is easily applicable in daily routine practice.     

利妥昔单抗联合CHOP方案对弥漫型大B细胞淋巴瘤的疗效及影响因素

目的探讨利妥昔单抗联合CHOP方案对弥漫型大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)的疗效,观察影响化疗疗效的相关因素。方法本组选择我院2006年1月至2011年1月收入的DLBCL患者17例,患者给予利妥昔单抗联合CHOP方案治疗。观察化疗后疗效及淋巴结亚群改变情况,收集患者的性别、年龄、PS评分、Ann Arbor分期、结外浸润情况、LDH水平、体力状态(PS)评分、B症状、血红蛋白及T细胞浸润等相关情况,观察其对化疗的相关影响。结果本组所有17例患者完成治疗,治疗后疗效评估显示CR7例,PR6例,SD3例,PD1例,治疗有效率为76.4%(13/17)。影响化疗疗效相关因素分析中显示,血清LDH水平、PS评分、AnnArbor分期为影响患者化疗疗效的相关因素,P0.05。结论利妥昔单抗联合CHOP对弥漫型大B细胞淋巴瘤疗效显著,其中PS评分低、Ann Arbor分期低、血清LDH水平正常的患者化疗疗效相对较好。     

Prognostic impact of immunohistochemical biomarkers in diffuse large B-cell lymphoma in the rituximab era

We evaluated the usefulness of prognostic markers in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) ± rituximab (R-CHOP) in Japan. We studied 730 patients with DLBCL; 451 received CHOP and 279 R-CHOP. We analyzed biopsy samples immunohistochemically for markers of germinal center B cells (CD10, Bcl-6), postgerminal center B cells (Multiple myeloma-1), and apoptosis (Bcl-2). The median follow-up period for surviving patients was 56.4 months for the CHOP group and 25.2 months for the R-CHOP group. DLBCL were categorized as germinal center B (GCB) subtype (352/730; 48.2%) or non-GCB subtype (378/730; 51.8%). In the CHOP group, the high expression of CD10 ( P  = 0.022) or Bcl-6 ( P  = 0.021), or GCB subtype ( P  = 0.05) was associated with better overall survival, whereas the high expression of Bcl-2 ( P  = 0.001) or MUM1 ( P  = 0.011), or non-GCB subtype ( P  = 0.05) was associated with worse overall survival. In the R-CHOP group, however, these biomarkers except Bcl-6 were not significant prognostic factors. The patients with non-GCB subtype showed improved survival in the R-CHOP group ( P  = 0.756). The International Prognostic Index was a useful clinical marker of survival in the CHOP group ( P  < 0.001) and also in the R-CHOP group ( P  < 0.001). Results of improved survival with rituximab addition indicate that the relevance of previously recognized prognostic factors should be re-evaluated. ( Cancer Sci  2009; 100: 1842–1847)     

Reactivation of hepatitis B virus due to rituximab plus CHOP after preemptive lamivudine administration in a patient with diffuse large B-cell lymphoma

A 59-year-old woman received eight cycles of R-CHOP for diffuse large B-cell lymphoma from July, 2004. Pretreatment HBV serological tests were positive, however, the transaminases were within normal limits, and she remained asymptomatic. Lamivudine (LAM) was administered orally from the start of R-CHOP. HBV-DNA levels gradually decreased and were not detected until December, 2004. LAM was administered until 3 months after the end of chemotherapy, with the entire treatment lasting less than 1 year. Two months after the cessation of treatment, she was re-admitted for general malaise. A liver function test revealed severe abnormalities, and HBVDNA levels were increased. Clinically, she was experiencing acute hepatitis due to HBV reactivation. She was then treated with LAM and interferon-beta immediately. Her HBV-DNA levels soon decreased, and liver function improved.     

Clinicopathologic characteristics and treatment outcome of the addition of rituximab to chemotherapy for CD5-positive in comparison with CD5-negative diffuse large B-cell lymphoma

Background: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) comprises ∼10% of DLBCLs, and it is associated with poor prognosis. The clinicopathologic characteristics and prognosis of CD5-negative (CD5-) DLBCL and CD5+ DLBCL were compared.Patients and methods: The subjects were 607 DLBCL patients in whom cell surface markers could be analyzed, among 930 consecutive patients registered in the Adult Lymphoma Treatment Study Group between 1998 and 2008.Results: In all, 102 patients (16.8%) had CD5+ DLBCL. Compared with CD5- DLBCL, CD5+ DLBCL was more closely associated with elevated serum lactate dehydrogenase level, advanced stage, poor performance status, extranodal sites, CD10-, BCL-2+, MUM1+, and nongerminal center B-cell type. The 5-year overall survival (OS) rates of CD5+ DLBCL (n = 102) and CD5- DLBCL (n = 505) were 55% and 65%, respectively (P = 0.032), with 5-year progression-free survival (PFS) rates of 52% and 61%, respectively (P = 0.041). In the CD5+ DLBCL patients, the addition of rituximab to chemotherapy significantly improved PFS (4-year PFS, 47.4% versus 62.5%), but not OS (4-year OS, 57.8% versus 63.5%).Conclusions: For CD5+ DLBCL, the addition of rituximab to chemotherapy significantly improved the PFS, but not OS. Therefore, it is thought that a new treatment strategy is necessary for CD5+ DLBCL.     

VNCOP-B plus rituximab in the treatment of diffuse large B-cell lymphoma in the elderly

The conventional treatment included CHOP and several age-adapted regimens, from first to third generation, designed and tested for their feasibility and efficacy in elderly patients. Recently, some trials demonstrated that CHOP-rituximab was superior to CHOP alone. Between February 2003 and November 2005, 24 untreated patients 60 years and older with DLBCL were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B) plus four rituximab administrations. Nineteen of the 24 patients (80%) obtained a CR, four achieved a PR, and the remaining patient had a disease progression. The overall response rate was 96%. Sixteen of the 19 complete responders remain in continuous CR at a median of 24 months (range 12 - 42). Three CRs relapsed within 12 months from the completion of treatment. Clinical and hematological toxicity was moderate. This regimen was effective in inducing a good remission rate with moderate toxic effects in elderly DLBCL patients.     

High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. Although the International Prognostic Index (IPI) provides a clinical model for risk stratification of patients with DLBCL, notable variability in outcome is still observed within the same IPI category. Tumor-infiltrating macrophages (also called Tumor-associated macrophages) are the major component in the microenvironment of DLBCL. Their correlation with the prognosis of DLBCL remains controversial. Using a CD68 antibody in immunohistochemical analysis, we studied the expression of CD68 in 112 Chinese patients with DLBCL, with 65 patients (58%) categorized as low CD68 expression and 47 patients (42%) as high CD68 expression. The complete response (CR) rate of patients with low CD68 expression was higher than that with high CD68 expression (66.1% vs. 51.6%), but there was no statistical significance (P?=?0.060). The median survival time of patients with low CD68 expression was not achieved and that of high expression was 41?months (P?=?0.029). The results suggest that higher expression of CD68 tended to yield poor treatment outcome of DLBCL.     

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab

BackgroundCD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era.Patients and methodsWe analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab.ResultsNo significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease.ConclusionsOur results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.     

Serum soluble CD27 level is associated with outcome in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone

Since the introduction of rituximab (R), the prognosis for diffuse large B-cell lymphoma (DLBCL) has markedly improved. We evaluated the prognostic significance of serum soluble CD27 (sCD27) in 143 patients with DLBCL treated with cyclophosphamide, doxorubicin, vincristine and prednisolone plus rituximab (R-CHOP). Five-year overall survival rates for patients with sCD27≥213 U/mL or <213 U/mL were 38.7% and 76.8%, respectively (p =0.0005). Multivariate analysis revealed that serum sCD27 was significantly correlated with OS (p =0.047). Immunohistochemical staining for CD27 in lymphoma tissues revealed positive lymphoma cells in 22 cases (18.5%) and positive microenvironment T-cells in 62 cases (52.1%) and was negative in the remaining patients. In these three subgroups, median sCD27 levels were 336 U/mL, 242.6 U/mL and 109.9 U/mL, respectively (p =0.004). Thus, serum sCD27 level is associated with CD27 expression on lymphoma cells, and may be a powerful prognostic factor for DLBCL.