Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era

Central nervous system (CNS) events, including CNS relapse and progression to CNS, are known to be serious complications in the clinical course of patients with lymphoma. This study aimed to evaluate the risk of CNS events in patients with diffuse large B-cell lymphoma in the rituximab era. We performed a retrospective survey of Japanese patients diagnosed with diffuse large B-cell lymphoma who underwent primary therapy with R-CHOP chemoimmunotherapy between September 2003 and December 2006. Patients who had received any prophylactic CNS treatment were excluded. Clinical data from 1221 patients were collected from 47 institutions. The median age of patients was 64 years (range, 15-91 years). We noted 82 CNS events (6.7%) and the cumulative 5-year probability of CNS events was 8.4%. Patients with a CNS event demonstrated significantly worse overall survival (P < 0.001). The 2-year overall survival rate after a CNS event was 27.1%. In a multivariate analysis, involvement of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were identified as independent risk factors for CNS events. We conclude that patients with these risk factors, in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events in the rituximab era. The efficacy and manner of CNS prophylaxis in patients for each involvement site should be evaluated further.     

R-CHOP-14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy

Treatment of diffuse large B-cell lymphoma (DLBCL) with CHOP-21 (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg for 5 days every 21 days) results in long-term remission in approximately 45% of patients. Recent phase III trials have demonstrated improved survival by modifying CHOP either through adding rituximab or shortening the time between cycles to 14 days. These studies prompted our institution to treat newly diagnosed patients with DLBCL refusing or not eligible for protocol-based therapy with R-CHOP-14. In this single-institution retrospective analysis, we report our results with this regimen. Forty-nine patients with newly diagnosed DLBCL and ineligible or refusing protocol-based therapy were retrospectively identified. Patients were treated with 6-8 cycles of R-CHOP-14 given with filgrastim and prophylactic antibiotics. The main toxicities with R-CHOP-14 were hematological and neurological and were not unexpected. There were no treatment-related deaths. Patients received 90% of planned cytotoxic drug density. The complete remission/complete remission uncertain (CR/CRu) rate was 82.2%. At a median follow-up of 24 months, the event-free survival was 80% and overall survival 90%. These results demonstrate R-CHOP-14 can be given to patients safely and short-term results regarding survival are promising. Whether adding rituximab and increasing dose intensity improves survival over either alone will require randomized studies.     

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial

BackgroundThere is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19–88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up.Patients and methodsSix hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials.ResultsElderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65–73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22–3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18–4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors.ConclusionsOur data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches.Trial numbersISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).     

Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database

BACKGROUND:

Little is known about the utility of central nervous system (CNS) prophylaxis for diffuse large B‐cell lymphoma (DLBCL) in the rituximab era. The objective of this study was to characterize patterns of CNS prophylaxis for patients who received combined rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) chemotherapy using the National Comprehensive Cancer Network Non‐Hodgkin Lymphoma Outcomes Database, a prospective cohort study that collects clinical and outcomes data for patients at 7 participating centers.

METHODS:

Patients who were eligible for this analysis presented with newly diagnosed DLBCL between January 2001 and July 2008, had no evidence of baseline CNS disease, and had received R‐CHOP within 180 days of diagnosis. The authors assessed incidence and covariates of prophylaxis, prophylaxis modality, and, using propensity score analysis, outcomes such as overall survival.

RESULTS:

Of 989 eligible patients, 117 received CNS prophylaxis (11.8%), most intrathecally (71.8%). Involvement of bone marrow, other high‐risk site, >1 extranodal site, higher International Prognostic Index score, and higher stage were associated individually with the receipt of prophylaxis (all P < .0001). At a median follow‐up of 2.5 years, there were 20 CNS recurrences (2% [95% confidence interval, 1.1%‐2.9%]) among all patients, and overall survival was not affected by prophylaxis.

CONCLUSIONS:

Given the overall low rate of CNS recurrence and lack of prophylaxis‐associated survival benefit, the current data called into question the practice of CNS prophylaxis in the rituximab era. Cancer 2011. © 2011 American Cancer Society.     

Incidence and risk factors for central nervous system relapse in patients with primary mediastinal large B-cell lymphoma in the rituximab era

Central nervous system (CNS) involvement is rare in primary mediastinal large B-cell lymphoma (PMLBCL). We aimed to evaluate the incidence of CNS relapse as first treatment failure event and the effect of the induction chemotherapy regimen, central nervous system - international prognostic index (CNS-IPI) and other clinical and laboratory variables on the risk of CNS relapse in 564 PMLBCL patients treated with immunochemotherapy. Only 17 patients (3.0%) received CNS prophylaxis. During a 55-month median follow-up only 8 patients experienced CNS relapse as first event, always isolated. The 2-year cumulative incidence of CNS relapse (CI-CNSR) was 1.47% and remained unchanged thereafter. The CI-CNSR was not affected by the chemotherapy regimen (R-CHOP or R-da-EPOCH). None of the established International Prognostic Index factors for aggressive lymphomas predicted CNS relapse in PMLBCL. The 2-year CI-CNSR in patients with versus without kidney involvement was 13.3% versus 0.96% (p < 0.001); 14.3% versus 1.13% with versus without adrenal involvement (p < 0.001); and 10.2% versus 0.97% with versus without either kidney or adrenal involvement. CNS-IPI was also predictive (2-year CI-CNSR in high-risk vs. intermediate/low-risk: 10.37% vs. 0.84%, p < 0.001). However, this association may be driven mainly by kidney and/or adrenal involvement. In conclusion, in PMLBCL, CNS relapse is rare and appears to be strongly associated with kidney and/or adrenal involvement.     

Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era

BACKGROUND:

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

METHODS:

The authors retrospectively analyzed 1221 patients treated uniformly with standard R‐CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL such as intravascular lymphoma, primary effusion lymphoma, pyothorax‐associated lymphoma, primary central nervous system lymphoma, and intraocular lymphoma were also excluded. The authors evaluated 26 extranodal sites of involvement with respect to prognostic impact. The median age was 64 years (range, 15‐91 years).

RESULTS:

Univariate analysis revealed that patients with involvement of specific extranodal sites had significantly worse overall survival (OS) than did patients without such involvement; these sites included nasal cavity, paranasal sinus, lung, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testis, bone, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with the involvement of the pleura (P < .001), small intestine (P = .015), peritoneum (P = .002), adrenal gland (P < .001), testis (P = .005), bone marrow (P < .001), and peripheral blood (P = .002) had significantly worse OS, whereas those with Waldeyer ring involvement had significantly better OS (P = .038). Subgroup analysis with the nodal and/or Waldeyer patient group also showed prognostic impact of Waldeyer ring by multivariate analysis (relative risk, 0.3; P = .04).

CONCLUSIONS:

Extranodal involvement affects the prognosis of patients undergoing R‐CHOP therapy for DLBCL. Cancer 2012. © 2011 American Cancer Society.     

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)     

Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story

BackgroundImproved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers.Design and methodsTo evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL.ResultsOur results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival.ConclusionsA new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.     

R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study

Several studies have shown that adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or reducing the interval between chemotherapy cycles from 3 weeks to 2 weeks improves survival in patients with diffuse large B-cell lymphoma (DLBCL). These studies prompted our group (GOTEL) to evaluate prospectively in a pilot study the feasibility and efficacy of R-CHOP-14 in patients with DLBCL. Patients (<70 years) with stage II bulky or stage III or IV DLBCL and no significant comorbidities were included in the study. Rituximab was administered on day 1 before chemotherapy. R-CHOP was given every 14 days. All patients received filgrastim (5 microg/kg) from days 4 to 10. From May 2002 to August 2004, 80 patients were recruited. Median age was 53 years and 58 patients were <60 years. According to the age-adjusted international prognostic index (aaIPI), 13 patients (16%) had low-risk disease, 31 (39%) low-to-intermediate risk, 27 (34%) high-to-intermediate risk and 9 (11%) high-risk disease. Grade 3-4 neutropenia was observed in 15 patients (17.5%) and grade 3-4 infections in 13 patients (16%). After therapy, 58 patients (73%) achieved CR-CRu (95% CI: 55-90%). With a median follow-up of 26 months, progression-free survival (PFS) and overall survival (OS) at 30 months were 72% and 86%, respectively. Administration of R-CHOP-14 is feasible and effective in patients <70 years.     

Prevention of CNS relapse in diffuse large B-cell lymphoma

CNS relapse occurs in about 5% of patients during the course of diffuse large B-cell lymphoma and entails a dismal prognosis. This consideration has led to the adoption of CNS prophylaxis, although known risk factors do not allow for an accurate prediction of CNS recurrences because they have insufficient sensitivity and specificity. Here, we review the reports of CNS events in major studies of diffuse large B-cell lymphoma before and after the introduction of rituximab, and probe the evidence that underlies prophylactic strategies such as intrathecal or high-dose intravenous chemotherapy. Now that rituximab is available, CNS prophylaxis relies on little—if any—evidence and should not be routinely administered. Nonetheless, several patient subgroups probably have a high risk of systemic and CNS relapses, and how to manage their treatment is a challenge. These subgroups include patients with testicular lymphoma or those who have more than one extranodal site involved plus at least one additional risk factor. For such patients, we recommend against prophylactic intrathecal chemotherapy because of the rare occurrence of isolated leptomeningeal relapses, the absence of evidence-based efficacy, and the potential harmful side-effects that are associated with this procedure. Because many CNS events are a result of primary resistance to treatment or accompany systemic relapses, high-dose intravenous methotrexate has been suggested as an alternative approach that needs to be validated in prospective controlled trials.     

Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy

Background: The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the risk of central nervous system (CNS) relapse in the R-CHOP in a population-based cohort of patients with DLBCL.Methods: Patients with DLBCL diagnosed from 1 September 1999 to 14 January 2005 at the British Columbia Cancer Agency (BCCA) were identified. Patients were included if they were ≥16 years old with advanced stage or any stage with testicular involvement and were treated with CHOP (1999–2001) or R-CHOP (2001–2005) with curative intent.Results: Four hundred and thirty-five patients were identified; 126 (29%) were treated with CHOP and 309 (71%) with R-CHOP. With a median follow-up of 5.7 years, there were 31 CNS relapses in total with a trend to a reduced likelihood of CNS relapse in R-CHOP-treated patients (3-year risk 9.7% versus 6.4, P = 0.085). In multivariate analysis, the use of rituximab significantly reduced the risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]; this benefit was more striking in patients who achieved a complete response (HR 0.18, P = 0.005).Conclusion: The use of R-CHOP appears to reduce the overall risk of CNS relapse in patients with DLBCL particularly in patients who achieve a complete response.     

原发性中枢神经系统弥漫大B细胞淋巴瘤临床病理学观察

目的：观察原发性中枢系统弥漫大B细胞淋巴瘤（PCNS-DLBCL）临床病理学、影像学特点,探讨其免疫组化、基因重排检测及microRNA表达特征。方法：收集确诊的PCNS -DLBCL 25例,观察并分析影像学、病理组织学、免疫组化标记特点,并进行重链和轻链基因重排检测。对其中10例典型PCNS-DLBCL、10例颅外生发中心来源的弥漫大B细胞淋巴瘤（GC-DLBCL）和10例颅外非生发中心来源的弥漫大B细胞淋巴瘤（NGC-DLBCL）的石蜡包埋组织块微切割提取microRNA,进行芯片杂交,对三者间的差异性进行比较。结果：PCNS-DLBCL多累及两个或两个以上脑叶（10/25例）,其中额叶受累最为常见（6/25例）。所有病例均可见中心母细胞样的大淋巴细胞围绕血管呈靶环样生长。免疫组化染色结果显示,25/25例均弥漫强阳性表达CD20、CD79a,不表达CD3、CD5、CD23、CyclinD1,Ki-67阳性率在50％-90％（平均80％）,仅有3例表达CD10（占12％）,19例表达Bcl-6（占76％）,22例表达Mum-1（88％）。基因重排检测显示24/25例呈B细胞单克隆性（96％）。microRNA芯片杂交显示,与NGC-DLBCL比较,升高2倍及以上者788个microRNA或片段,下降0．5倍以下者401个microRNA或片段;与GC-DLBCL比较,升高2倍及以上者611个microR-NA或片段,下降0．5倍以下者229个microRNA或片段。结论：PCNS-DLBCL以老年男性好发,常累及多个部位,免疫组化显示大部分为活化B细胞来源,基因重排检测B细胞单克隆性高,microRNA芯片杂交显示, PCNS-DLBCL microRNA表达明显不同于颅外NGC-DLBCL和GC-DLBCL,可能存在microRNA诊断性标志物。从microRNA表达差异的数量看,PCNS-DLBCL与颅外GC-DLBCL差异较小,此与二者的预后接近相关。     

A nomogram prognostic index for risk-stratification in diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study

Background We aimed to establish a predictive prognostic risk-stratification model for diffuse large B-cell lymphoma (DLBCL) in the rituximab era.Methods The data of 1406 primary DLBCL patients from the Sun Yat-Sen University Cancer Center were analysed to establish a nomogram prognostic index (NPI) model for predicting overall survival (OS) based on pre-treatment indicators. An independent cohort of 954 DLBCL patients from three other hospitals was used for external validation.Results Age, performance status, stage, lactate dehydrogenase, number of extranodal sites, BCL2, CD5 expression, B symptoms and absolute lymphocyte and monocyte count were the main factors of the NPI model and could stratify the patients into four distinct categories based on their predicted OS. The calibration curve demonstrated satisfactory agreement between the predicted and actual 5-year OS of the patients. The concordance index of the NPI model (0.794) was higher than the IPI (0.759) and NCCN-IPI (0.750), and similar results were obtained upon external validation. For CD5 + DLBCL patients, systemic treatment with high-dose methotrexate was associated with superior OS compared to R-CHOP-based immunochemotherapy alone.Conclusions We established and validated an accurate prediction model, which performed better than IPI and NCCN-IPI for prognostic stratification of DLBCL patients.Subject terms: B-cell lymphoma, Cancer models     

利妥昔单抗时代弥漫大B细胞淋巴瘤的预后影响因素

目的 弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是非霍奇金淋巴瘤中最常见的一种类型,临床表现、免疫表型、分子遗传学特征和预后均具有显著的异质性,近年来靶向药物利妥昔单抗联合常规化疗的运用,改善了DLBCL患者的预后.本研究总结在利妥昔单抗使用背景下DLBCL预后影响因素的研究进展.方法 应用PubMed及万方数据库检索系统,以“利妥昔单抗、弥漫大B细胞淋巴瘤和预后因素”作为关键词,检索2007-2016年相关文献,检索到英文文献322篇,中文文献38篇.纳入标准:(1) DLBCL的研究内容;(2)利妥昔单抗时代DLBCL预后影响因素.剔除标准:(1)无原始数据的综述;(2)个例报道;(3)重复内容的文章.根据纳入标准和剔除标准,符合分析文献37篇.结果 DLBCL是非霍奇金淋巴瘤中最常见的一大类型,临床表现、免疫表型、分子遗传学特征及预后均具有显著的异质性,利妥昔单抗前时代,常规化疗能使约40％的患者获得长期缓解,近年来靶向CD20药物利妥昔单抗的运用使DLBCL患者的缓解率明显提高,预后显著改善,同时也改变了一些指标在预后评估系统中的地位.结论 重新评估DLBCL预后影响因素,以及建立更为完善的预后评估体系,将有助于更准确的对DLBCL患者行危险度分层,并给与相应治疗,以进一步改善患者的疗效和生存.     

Clinical outcome in diffuse large B-cell lymphoma with hepatitis C virus infection in the rituximab era: a single center experience

Clinical outcome of diffuse large B-cell lymphoma (DLBCL) patients with hepatitis C virus (HCV) infection in the rituximab era remains unclear. The aim of the present study was to compare the clinical outcome, treatment response and hepatotoxicity in DLBCL patients who received rituximab containing immunochemotherapy that had HCV infection and those that did not have HCV infection between January 2004 and October 2011. Of the 272 consecutive histopathologically diagnosed DLBCL patients in our department, a total of 248 were retrospectively analyzed in the present study. There were 28 DLBCL patients with HCV infection (the HCV group) and 220 DLBCL patients without HCV infection (the control group). We compared overall survival (OS), progression-free survival (PFS), treatment response and hepatotoxicity according to HCV infection. In terms of OS (P=0.525) and PFS (P=0.759), there were no significant differences between the HCV group and the control group. Objective response rates were 92.9% (26/28) in the HCV group and 95.9% (211/220) in the control group (P=0.619). In the HCV group, seven patients (25.0%) developed hepatotoxicity during immunochemotherapy. In the control group, 35 patients (15.9%) developed hepatotoxicity during chemotherapy. No patient required discontinuation of immunochemotherapy owing to hepatotoxicity in either group. In terms of hepatotoxicity, there was no significant difference between these two groups (P=0.281). In conclusion, our study results suggested that HCV infection might not influence the clinical course in DLBCL patients who receive rituximab-containing immunochemotherapy.     

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.