Nervous System Relapse In Patients Research Articles

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.

The Role of Prophylactic Chemotherapy for the Prevention of Central Nervous System Relapse in Patients with Large B Cell Lymphoma: A Meta-Analysis

Introduction: Central nervous system (CNS) relapse in large B cell lymphoma (LBCL) is a rare, but catastrophic event associated with poor prognosis without an effective standard prophylactic strategy. Intravenous and/or intrathecal chemotherapy have been proposed for patients at high risk for CNS relapse (i.e., CNS-IPI of 4 or greater) with mixed results due to the lack of prospective trials comparing different approaches. Large retrospective cohort studies have challenged the value of CNS prophylaxis. We performed a systematic review and meta-analysis (MA) assessing the role of chemoprophylaxis in preventing CNS relapse for LBCL patients treated with chemoimmunotherapy. Methods: A systematic literature review was conducted using the major online databases, including English language studies published from 2011 until 2022. Data were pooled from the studies with a comparator group using the random effects model to report odds ratio (OR) and 95% confidence intervals (95% CI). Data from single-arm studies were pooled using the random effects model to report the pooled proportion with 95% CIs. Results: There were 16 studies included in the MA (12 retrospective and 4 prospective) assessing the role of CNS prophylaxis in a total of 11,530 patients. The incidence of CNS relapse appeared to be higher among patients who received CNS chemoprophylaxis (n=2108) compared with patients without chemoprophylaxis(n=9422) (OR 1.70, 95% CI 1.10-2.61) (figure 1). Among the single-arm studies, the pooled proportion of the incidence of CNS relapse, isolated CNS relapse and secondary CNS relapse was 5% (95% CI 4%-7%), 5% (95% CI 4%-7%), and 1% (95% CI 0%-2%), respectively. Results are confounded by the retrospective design of most studies, different types of chemoprophylaxis and heterogeneous patient population. Discussion: This systematic review and MA demonstrated consistent rates of CNS relapse as seen in prior large cohorts, and did not show evidence for the use of chemoprophylaxis in patients with LBCL to prevent CNS relapse. Given the scarcity of high quality data due to the absence of prospective trials and the lack of motivation by multiple stakeholders to develop these type of studies, the totality of evidence grouped in this MA constitutes one of the most robust datasets arguing against chemoprophylaxis for prevention of CNS relapse in patients with LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: Incidence and Risk Factors in the Rituximab Era

Background: Central nervous system relapses (CNSR) are uncommon in primary mediastinal large B-cell lymphoma (PMLBCL) with a reported incidence of 2.3-3.8% in the Rituximab era. Clinical risk factors for CNSR have been recognized in diffuse large B-cell lymphoma (DLBCL), but may not be applicable in PMLBCL, a pathobiologically distinct entity with constitutive activation of NFκB and JAK-STAT pathways and Programmed Death (PD) Ligand 1 and 2 overexpression. Aim: To evaluate the incidence of first CNSR events without prior systemic progression and explore prognostic associations with baseline characteristics, CNS-IPI, and induction immunochemotherapy. Methods: This is a retrospective study of a multinational cohort of 596 adult PMLBCL patients treated with R-CHOP or DA-EPOCH-R immunochemotherapy with or without radiotherapy between 2000 and early 2022. The cumulative incidence of first CNSR (CI-CNSR) was estimated considering the competing risks of death from any cause or prior systemic disease relapse/progression. Results: Baseline characteristics are shown in Table 1. Only 17 patients (2.9%) received CNS prophylaxis [high-dose methotrexate (HD-MTX) 9, intrathecal MTX±other 7, both 1]. Kidney and/ or adrenal involvement at diagnosis was highly correlated with advanced stage, ≥2extranodal sites and high CNS-IPI (4-6) (p<0.001), with the vast majority of the latter also having kidney and/or adrenal involvement. With a 55-month median follow-up [interquartile range (IQR) 32-97 months], all 10 first CNSR events(9 isolated and 1 associated with systemic relapse) were recorded within 2 years of diagnosis [median time7.5 months, IQR 6-8, range 5-13 months], for a 2-year CI-CNSR of 1.78% (95% CI 0.9-3.2%). Two of 10 CNSR cases had received CNS prophylaxis with HD-MTX. All CNSR were parenchymal and only 2/8 were successfully salvaged (2 still under treatment). Four patients with CNSR had kidney involvement (plus adrenal in 2/4). Two of seven patients with both kidney and adrenal involvement and 2/ 17 with kidney infiltration only relapsed in the CNS. Kidney [subhazard ratio (SHR) 15.4, p<0.001], adrenal (SHR 13.6, p=0.001), any kidney or adrenal involvement (SHR 12.5, p<0.001), and high CNS-IPI (4-6, SHR 13.0, p<0.001) were associated with CNSR in univariate analysis. All 4 patients with high CNS-IPI who experienced CNSR (out of 35), had also kidney and/or adrenal involvement. Looser but significant associations were observed with high IPI (2-5; SHR 6.3, p=0.009), advanced stage (III/IV; SHR 5.5, p=0.007), impaired performance status (≥2; SHR 6.6, p=0.005), and ≥2 extranodal sites (SHR 5.4, p=0.009) but not chemotherapy backbone (R-CHOP or DA-EPOCH-R), CNS prophylactic therapy, age, gender, B-symptoms, LDH elevations or other baseline labs, serositis or PMLBCL-specific prognostic indices (stage IV/ extranodal plus bulky or high LDH≥2x). Conclusion: In PMLBCL, CNSR is rare and appears to be primarily associated with kidney and/or adrenal involvement. CNS-IPI is also strongly prognostic but highly correlated with kidney and/or adrenal involvement. No late (>2 years) occurrences were seen and 9/10 relapses were isolated in the CNS. No inferences regarding the value of primary CNS prophylaxis can be made. Even in this very large series multivariate is not reliable due to the small number of events. A larger multinational effort is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Limited efficacy of high-dose methotrexate to prevent the central nervous system relapse in patients with IVLBCL

To evaluate the efficacy of high-dose methotrexate (HD-MTX, ≥1 g/m2) for the prevention of central nervous system (CNS) recurrence in patients with intravascular large B-cell lymphoma (IVLBCL), we reviewed 51 patients with pathologically diagnosed untreated IVLBCL. In total, there were five cases of CNS relapse (9.8%), and the 12-month CNS relapse rate was 9.2%. No statistical difference in CNS relapse rate (p = 0.86) was observed between patients with and without HD-MTX (n = 20 and 31, respectively). Furthermore, the composite endpoint defined as either CNS and/or neurolymphomatosis relapse was not significant in terms of the administration of HD-MTX (p = 0.25). No significant predictor of CNS relapse was found. In conclusion, patients with IVLBCL are at high risk of CNS recurrence; however, HD-MTX administration may not be effective for CNS recurrence prophylaxis. Key points The administration of HD-MTX for patients with untreated IVLBCL may not be effective for preventing CNS relapse.

Impact of Double Hit Lymphoma and Cell of Origin in the Risk of Central Nervous System Relapse in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Introduction: Central nervous system (CNS) relapse is an uncommon but devastating complication occurring in about 2-10% of patients with diffuse large B-cell lymphoma (DLBCL). The CNS-IPI is a validated prognostic tool used to identify patients at high risk of CNS relapse. MYC and BCL2/BCL6 rearrangements (double-hit lymphoma- DHL) and non-GCB (NGCB) cell of origin may be at higher risk of CNS relapse. However, the ability of these molecular data to refine CNS-IPI risk prediction has not been assessed. In this study, we aimed to describe the impact of DHL and NGCB cell of origin in the incidence of CNS relapse in patients with newly diagnosed DLBCL.Methods: A retrospective review was conducted to identify patients with newly diagnosed DLBCL from 01/01/2002 - 06/30/2015 using the University of Iowa/Mayo Clinic Lymphoma Molecular Epidemiology Resource database. Patients with primary CNS lymphoma or with CNS involvement at diagnosis were excluded. All patients received chemoimmunotherapy. Clinical, biological, laboratory and radiological data were abstracted including the occurrence of CNS relapse. CNS IPI risk score categories were defined as low- (≤1) intermediate- (2-3) and high-risk (≥4) as originally described (Schmitz et al, JCO 2016). Cell of origin (COO) classification into GCB and non-GCB subtypes was performed using Hans algorithm and/or NanoString data. Characteristics between groups were compared using Kruskal-Wallis or Chi-squared test as appropriate. Survival analysis was performed using Cox proportional hazards model and the Kaplan Meier method. Statistical analysis was performed using SAS version 9.4M5 and R version 4.0.3.Results: We identified a total of 1,360 patients with newly diagnosed DLBCL. Patients had a median age of 62 years (range 18-93 years), were predominantly male (56%), had a performance status <2 (84%), had stage III/IV disease (61%) and an elevated LDH (56%) at diagnosis. Fluorescent in situ hybridization data was present for 65% of patients. Among patients with available data, DHL and NGCG COO represented 2.8% and 36% of the cohort, respectively. CNS IPI high- and intermediate-risk categories were present in 12.4% and 52% of the patients, respectively. R-CHOP was the most common upfront chemotherapy (n=980, 72%).The median follow-up for the entire cohort was 84.9 months (IQR: 58.9-120.9). Overall, 50 patients (3.6%) had a CNS relapse during the study period. Lymphoma relapsed in the CNS in 3.0% (95% CI:2.1-4.4), 4.7% (95% CI: 3.4-6.3) and 4.9% (95% CI: 3.7-6.6)% of patients with CNS-IPI score of intermediate/high risk at 1, 3 and 5 years following the diagnosis of DLBCL. In patients with low risk CNS-IPI, 1.1% (95% CI: 0.4-2.5), 1.7% (95% CI: 0.9-3.4) and 1.7% (95% CI: 0.9-3.4) had a CNS relapse at 1, 3 and 5 years following DLBC diagnosis. Patients with CNS relapse were more likely to have elevated LDH (76% vs 56%, p=0.008), advanced stage (78% vs 61%, p=0.01), adrenal involvement (8% vs 2.4%, p=0.014) and have a CNS IPI intermediate risk (68% vs 51%), and high risk (16% vs 12.3%, p=0.014) at the time of initial diagnosis compared to patients without CNS relapse. Patients with CNS relapse had similar rates of DHL (4% vs 2.7%, p=0.17) and NGCB cell of origin (42% vs 36.2%, p=0.52) compared to patients without CNS relapse.In the multivariable analysis, the strongest predictors for CNS relapse were CNS IPI high risk (Hazard Ratio [HR]= 3.6, 95%CI= 1.4-9.7) and CNS IPI intermediate risk (HR= 3.15, 95%CI= 1.46-6.81). DHL and NGCB cell of origin were not associated with a significantly higher risk of CNS relapse (HR= 1.79, [95%CI=0.42-7.59] and HR= 1.26, [95%CI=0.62-2.57], respectively).Conclusion: CNS relapse was an uncommon occurrence in patients with DLBCL who were treated with chemoimmunotherapy. CNS IPI intermediate- and high-risk scores remain the strongest predictors of CNS relapse in patients with DLBCL after adjusting to biological high-risk variables including DHL and NGCB cell of origin. Larger studies are required to validate our findings due to the low incidence of CNS relapse in our cohort. [Display omitted] DisclosuresFarooq: Kite, a Gilead Company: Honoraria. Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Novak: Celgene/BMS: Research Funding.

Prediction and prevention of central nervous system relapse in patients with extranodal natural killer/T-cell lymphoma

AbstractBecause non–anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline–based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.

The Predictors and Prevention of the Central Nervous System Relapse in Patients with Extranodal NK/T Cell Lymphoma, Nasal Type

Background: The incidence of central nervous system (CNS) involvement is rare ranging from 0 to 6% in patients with extranodal NK/T cell lymphoma, nasal type. A few studies have suggested that CNS prophylaxis should be considered in the high PINK group, but it is unclear because of relatively small numbers of patients. However, non-anthracycline-based chemotherapy with L-asparaginase improved the survival outcome, and the frequency of CNS relapse is expected to increase. Therefore, we aimed to identify the incidence and risk factors for CNS relapse and to evaluate the need for CNS prophylaxis with high-dose methotrexate (HD MTX) regimens. Patients and methods: We retrospectively reviewed 399 patients who had diagnosed with extranodal NK/T-cell lymphoma, nasal type, and received non-anthracycline based chemotherapy from January 2000 to January 2019 at multicenter in Korea. The CNS relapse was defined as a brain parenchymal or leptomeningeal involvement confirmed either by MRI or CSF study during chemotherapy or follow-up period. For subgroup analysis, we used the prognostic index of natural killer lymphoma (PINK), and the prognostic index of natural killer lymphoma with Epstein-Barr virus DNA (PINK-E), which includes age, Ann Arbor stage, lymph node involvement, and EBV DNA. Patients were divided into two groups, according to whether the chemotherapy regimen included HD-MTX. Results: Twenty-seven patients (6.8%, 27/399) experienced CNS relapse during chemotherapy or follow-up period. The median overall survival of all patients was 93.7 months [95% confidence interval (CI) 72.53-114.95], and the median time to CNS relapse of 27 patients was 10.1 months (range 0.0-42.0). The clinical variables associated with CNS relapse were BM involvement (HR 4.026, p=0.002), extranodal involvement≥2 (HR 8.198, p&lt;0.001), EBV DNA (HR 3.90, p=0.013), Ann Arbor stage III/IV (HR 9.397, p&lt;0.001), PINK [intermediate (HR 4.700, p=0.009), high (HR 9.554, p&lt;0.001)], and PINK-E [intermediate (HR 6.032, p=0.001), high (HR 6.775, p&lt;0.001)]. In multivariate analysis, PINK was the powerful predictor of CNS relapse (HR 3.486, p=0.019). The cumulative incidence of CNS relapse was significantly different between groups of Ann Arbor stage (p&lt;0.001), PINK (p=0.004), or PINK-E (p=0.002). The incidence of CNS relapse in patients with/without HD-MTX regimens was six patients (6/101, 5.9%) and 21 patients (21/298, 7.0%). Although there was no significant difference between both treatment groups in all patients, the patients who received chemotherapy with HD MTX regimens had a lower incidence of CNS relapse than those who received other regimens in Ann Arbor stage III/IV (p=0.033). Conclusions: We demonstrate the strong predictability of PINK and PINK-E for CNS relapse in patients with extranodal NK/T-cell lymphoma, nasal type. HD MTX regimens reduced the incidence of CNS relapse in Ann Arbor stage III/IV groups, and CNS prophylaxis should be considered for these patients. Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

Central Nervous System Relapse in Patients with Peripheral T-Cell Lymphoma

Introduction: Central nervous system (CNS) relapse or progression in peripheral T-cell lymphoma (PTCL) is a rare event. Due to its rarity, little is known about the incidence, risk factors and the clinical course after CNS relapse in PTCL.Methods: A total of 301 patients with PTCL were included in this study. All patients were diagnosed between 2003.1 and 2016.6 in Asan Medical Center, Seoul, Korea. Patients with CNS involvement at diagnosis and cutaneous anaplastic large-cell lymphoma were excluded.Histologic subtypes included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) (n=151, 50.2%), anaplastic large-cell lymphoma (ALCL) (n=75, 24.9%, including ALK positive/negative/unknown, n=39/33/3 each), angioimmunoblastic T-cell lymphoma (AITL) (n=54, 17.9%), enteropathy-associated T-cell lymphoma (EATL) (n=21, 7%).Disease progression or relapse with CNS involvement was confirmed by pathology or MRI of the affected organ. Risk factors at diagnosis for subsequent CNS progression were analyzed with cox regression method. P value <.05 was considered as statistically significant.Results: Out of 301 patients enrolled, 197 patients were male and 104 patients were female. Median age at diagnosis was 57 (range: 15-86). During 75.1 months of median follow-up, 10 patients developed CNS relapse or progression (3.3%).Among those 10 patients with CNS involvement, 4 patients had PTCL-NOS, 4 patients had ALCL (3 ALK positive, 1 ALK negative) and 2 patients had EATL. Leptomeningeal involvement of lymphoma was found in 6 out of 10 patients. Brain or spinal parenchymal involvement was found in 1 patient. Three patients had both leptomeningeal and parenchymal involvement.Median time from initial diagnosis to CNS involvement was 3.6 months (95% confidence interval (CI): 1.1-6.2). All patients with CNS relapse or progression died, and their median overall survival (OS) from CNS involvement was 1.4 months (0.2-2.6). Median OS from diagnosis was 5.1 months (2.9-7.3) in these patients. On the other hand, median OS of patients without CNS relapse was 10.3 months (7.8-12.9) (p=0.002).Univariate analysis showed 2 risk factors associated with occurrence of CNS relapse or progression as follows; subcutaneous tissue or muscle involvement (hazard ratio (HR) 8.9 [95% CI: 2.5-31.5], p=0.001) and Ki-67 labeling index≥80% (HR 11.9 [1.5-94.8], p=0.02). Due to the small number of CNS events, multivariate analysis was not available. No association was found with age, sex, international prognostic index, histologic type, serum lactate dehydrogenase level, stage of the disease and number of involved extranodal sites.Conclusions: Our study demonstrated that although CNS relapse or progression in PTCL was rare (3.3%), it showed dismal prognosis with median OS of 1.4 months. Since CNS involvement occurred in the early course of the disease, we suggest that evaluation for CNS disease should be considered in highly selected patients. DisclosuresNo relevant conflicts of interest to declare.

Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study.

Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4–29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.

New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma: a retrospective study.

BackgroundIn patients with diffuse large B-cell lymphoma (DLBCL), central nervous system (CNS) relapse is uncommon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the efficacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction.MethodsA total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat-sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathecal chemotherapy prophylaxis (methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R-CHOP set in particular, the Kaplan–Meier method coupled with the log-rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Differences were evaluated using a two-tailed test, and P < 0.05 was considered significant.ResultsAt a median follow-up of 46 months, 25 (4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3-year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R-CHOP group (P = 0.045). Intrathecal chemotherapy prophylaxis did not confer much benefit in terms of preventing CNS relapse. Bone involvement [hazard ratio (HR) = 4.21, 95% confidence interval (CI) 1.38–12.77], renal involvement (HR = 3.85, 95% CI 1.05–14.19), alkaline phosphatase (ALP) >110 U/L (HR = 3.59, 95% CI 1.25–10.34), serum albumin (ALB) <35 g/L (HR = 3.63, 95% CI 1.25–10.51), treatment with rituximab (HR = 0.34, 95% CI 0.12–0.96), and a time to complete remission ≤ 108 days (HR = 0.22, 95% CI 0.06–0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement (HR = 4.44, 95% CI 1.08–18.35), bone marrow involvement (HR = 11.70, 95% CI 2.24–60.99), and renal involvement (HR = 10.83, 95% CI 2.27–51.65) were independent risk factors for CNS relapse in the R-CHOP set.ConclusionsIn the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemotherapy prophylaxis alone was not sufficient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R-CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.

Central nervous system relapse in patients with diffuse large B cell lymphoma: analysis of the risk factors and proposal of a new prognostic model.

Central nervous system (CNS) relapse in patients with diffuse large B cell lymphoma (DLBCL) is an uncommon event, and the outcome of patients with CNS relapse is poor. However, no reliable prediction models for CNS relapse have been developed. We retrospectively analyzed consecutive de novo DLBCL patients referred to our department between September 2004 and August 2015 and treated with R-CHOP or R-CHOP-like regimens. Of 413 patients analyzed in this study, a total of 27 patients (6.5%) eventually developed CNS relapse. The 5-year probability of CNS relapse was 8.4%. The median time from diagnosis of DLBCL to CNS relapse was 15months, and the median survival after CNS relapse was 7months. In univariate analysis, the risk factors significantly associated with CNS relapse were Ann Arbor stage 3 or 4, albumin level <3.2mg/L, number of extranodal sites >1, and involvement of retroperitoneal lymph node. We developed a new prognostic model consisting of these four factors. The 5-year probability of CNS relapse was significantly higher in patients with at least three of these four factors than in those with two or fewer factors (26.4 vs. 3.0%, P < 0.001). Using this model, we evaluated the incidence and the risk factors of CNS relapse in DLBCL patients. The new risk model consisting of the four factors demonstrated good risk stratification for CNS relapse, and could help to identify high-risk patients for whom CNS prophylaxis is warranted.

Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma.

Although HER2-positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2-positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2-targeted therapies that penetrate the blood-brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative-intent surgery during a time period (1980-1997) when no patient received HER2-targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow-up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2-positive (vs -negative) primary tumors showed a higher 5-year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases.

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL)

Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach. A total of 608 patients (median age, 67 years; range 22-92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis. None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2-141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9-19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5-39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4-4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.

Very high levels of lactate dehydrogenase at diagnosis predict central nervous system relapse in acute promyelocytic leukaemia

Very high levels of lactate dehydrogenase at diagnosis predict central nervous system relapse in acute promyelocytic leukaemia

Absolute peripheral monocyte count at diagnosis predicts central nervous system relapse in diffuse large B-cell lymphoma.

Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed the data from a total of 550 patients with diffuse large B-cell lymphoma and evaluated the relationship between central nervous system relapse and absolute monocyte counts at diagnosis. Twenty-six patients developed central nervous system relapse. The central nervous system relapse-free survival rate was significantly lower in patients with the absolute monocyte counts ≥ 0.51 × 10(9)/L (87.8% versus 96.4%; P<0.001). This association was independently significant after adjusting for other significant factors, including systemic relapse as a time-dependent covariate by multivariate analysis (hazard ratio 2.46; 95% confidence intervals 1.05-5.75; P=0.039). These results suggest that the absolute monocyte count at diagnosis is an independent significant risk factor for central nervous system relapse in patients with diffuse large B-cell lymphoma.

Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis

The impact of rituximab (R) on the incidence of central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is unclear. We performed a meta-analysis to explore the risk factors and assess the association between R-chemotherapy (R-chemo) and CNS relapse. We searched MEDLINE, PubMed, EMBASE and OVID for eligible studies. Published group statistics were extracted from each study for analysis; individual patient data from each study were not accessed. Fixed- or random-effects models were used to estimate the odds ratio (OR) with a 95% confidence interval (CI). Eight studies were identified. The OR for R-chemo compared with identical chemotherapy was 0.70 (95% CI 0.54–0.91). Stage III/IV (OR 2.25, 95% CI 1.64–3.08), International Prognostic Index (IPI) > 1 (OR 2.62, 95% CI 1.59–4.33), performance status (PS) > 1 (OR 1.67, 95% CI 1.23–2.27), elevated lactate dehydrogenase (LDH) (OR 2.23, 95% CI 1.54–3.22), bone marrow involvement (OR 2.85, 95% CI 1.99–4.07), more than one extranodal involvement (OR 2.61, 95% CI 1.93–3.54), presence of B symptoms (OR 1.87, 95% CI 1.37–2.56) and testicular involvement (OR 3.83, 95% CI 1.84–7.97) were associated with increased risks of CNS relapse. This meta-analysis demonstrated a lower incidence of CNS relapse of DLBCL in the rituximab era. The risk of CNS relapse can be assessed by stage, IPI, PS, LDH, presence of B symptoms, number of extranodal sites, bone marrow and testicular involvement.

Isolated central nervous system relapse in patient with blast-crisis chronic myeloid leukemia in durable complete cytogenetic remission on dasatinib treatment: pharmacokinetics and ABL mutation analysis in cerebrospinal fluid

Central nervous system involvement is a relatively common complication in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) and chronic myeloid leukemia in blast crisi...

Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: analyses with competing risk regression model

Central nervous system (CNS) relapse is a challenging complication in patients with diffuse large B-cell lymphoma (DLBCL). Thus, identification of the high-risk population, in whom prophylactic treatment may play a significant role, is critical. We calculated the incidence of CNS relapse and evaluated the risk factors for CNS relapse using competing risk regression analysis. A total of 386 patients who received CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) with (n = 203) or without (n = 183) rituximab were analyzed. The 5-year cumulative incidence of CNS relapse was 6.7%. Multivariate analysis identified three independent risk factors: bulky disease (subhazard ratio [SHR] 3.34, 95% confidence interval [1.45–7.66], p = 0.004), absolute lymphocyte count <1.0 × 109/L (SHR 2.38 [1.05–5.39], p = 0.037) and extranodal involvement (SHR 2.90 [1.01–8.33], p = 0.047). Patients with three risk factors represented 6% of patients, in whom the 5-year cumulative incidence was 26%. Larger scale studies are needed to validate our results. A better management strategy in patients with high-risk disease is critically needed.

Diffuse large B-cell lymphoma with involvement of the kidney: outcome and risk of central nervous system relapse

Renal involvement is uncommon in diffuse large B-cell lymphoma. Recent data suggest that it is an independent risk factor for central nervous system relapse. We reviewed the clinical features, risk of central nervous system involvement, and survival of patients with diffuse large B-cell lymphoma with involvement of the kidney at diagnosis. All patients with diffuse large B-cell lymphoma and renal involvement diagnosed from January 1, 1982 to December 31, 2008 at the British Columbia Cancer Agency were retrospectively identified in the Lymphoid Cancer Database. Patients were included if they were 16 years old or over, had advanced stage disease [stage III/IV, or stage I/II with B symptoms or bulky mass (>10 cm)] and were treated with curative intent. Central nervous system involvement was diagnosed by cerebrospinal fluid cytology, radiology or clinically. We identified 55/2656 (2%) patients with diffuse large B-cell lymphoma and renal involvement at diagnosis. The male to female ratio was 2:1. The patients' median age was 58 years. Bilateral renal involvement was present in 24 (44%) and stage IV disease in 50 (91%). The International Prognostic Index score was 3, 4 or 5 in 52 (95%), the glomerular filtration rate was less than 30 mL/min/m² in 9 (16%) and elevated lactate dehydrogenase was recorded in 46 (84%). Twenty-five (46%) patients received CHOP plus rituximab and 30 (54%) received CHOP-like regimens without rituximab. In total, 20 (36%) patients had central nervous system involvement: four at the time of diagnosis and 16 at relapse. The median time to central nervous system relapse was 5.6 months (range, 1.2 months-4.6 years), and was not affected by the addition of rituximab (P=0.547). The 5-year overall and progression-free survival rates for the whole cohort were 29% and 25%, respectively. In patients who received rituximab, there were trends towards improved 5-year overall survival (43% versus 18%, P=0.071) and progression-free survival (40% versus 13%, P=0.057). There is an exceptionally high incidence of central nervous system relapse in patients with diffuse large B-cell lymphoma and kidney involvement at diagnosis. The addition of rituximab may improve overall survival in this poor-risk population, likely through improved control of systemic disease.

Best of the Month: A Round Up of Articles Published in Recent Months

With the abundant number of articles published in lung cancer, it has become very difficult to stay updated. After a search through variety of medical journal for articles published between March and June 2010, we selected the studies considered to have the greatest relevance for oncologists involved in the treatment of lung cancer. The nine selected studies covered a broad range of topics including possible hormonal role in the development of lung adenocarcinoma, lung cancer in never smokers, stereotactic radiotherapy for early-stage lung cancer, prognostic role of pleural lavage cytology, neoadjuvant chemotherapy for operable lung cancer, maintenance erlotinib, use of erlotinib after gefitinib, comparison of the two epidermal growth factor receptor tyrosine kinase inhibitors, and risk of central nervous system relapse in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors.