Incidence Of Central Nervous System Relapse Research Articles

Validation of German High-Grade Non-Hodgkin's Lymphoma (DSHNHL) Prognostic Model and the Impact of Treatment on Secondary Central Nervous System (CNS) Relapse in Diffuse Large B-Cell Lymphoma (DLBCL) in a Developing Country: Report from the Nationwide Multi-Institutional Registry of Thai Lymphoma Study Group (TLSG)

Introduction: Despite improved treatment outcome of DLBCL in the immunochemotherapy era, secondary CNS relapse remains a serious and fatal complication. Several prognostic models were reported in order to define high-risk patients for CNS relapse and provide proper prophylactic strategies. There is no standard approach for CNS prophylaxis in DLBCL with more data suggesting lack of efficacy of intrathecal chemoprophylaxis. In 2013, the DSHNHL introduced a prognostic model including each international prognostic index (IPI) factor (age, lactate dehydrogenase (LDH), stage, performance status (PS), extranodal involvement (EN) and kidney/adrenal involvement) to stratify patients into 3 groups. Herein, we applied and validated DSHNHL model to DLBCL patients treated at nationwide University hospitals in Thailand including analyzing an impact of rituximab and intrathecal chemoprophylaxis on CNS relapse.Method: From the nationwide multicenter registry of 4,371 newly diagnosed lymphoma patients in Thailand between 2007 and 2014, there were a total of 2,399 DLBCL patients. We looked at the incidence and clinical predictors of CNS relapse, the effect of immunotherapy and intrathecal chemoprophylaxis on CNS relapse in DLBCL who were treated with at least one cycle of CHOP-like or intensive chemotherapy regimens.Result: After excluding patients with CNS/ocular involvement at diagnosis, 2,034 DLBCL patients were included in the analysis. Table 1 summarizes baseline characteristics of DLBCL patients. The median follow up time for living patients was 51 months (interquartile range, 22-75 months). A total of 565 patients (27.8%) progressed or relapsed after first-line induction therapy and 61 patients (3.0%) developed CNS relapse. Median time to CNS relapse was relatively shorter than non-CNS relapse (8.4 vs 10.5 months, P =0.07). A total of 729 (35.8%), 1,024 (50.3%) and 281 (13.8%) patients were classified as low-, intermediate- and high-risk groups based on DSHNHL risk model for CNS relapse. Of high DSHNHL risk group, 45 patients (16%) received intrathecal chemotherapy for CNS prophylaxis along with induction treatments. Using the competing risk regression analysis, 2-year cumulative incidence of CNS relapse was 2.7% (1.5%, 3.1%, and 4.6% for low-, intermediate- and high-risk DSHNHL group respectively). Univariate analysis showed elevated LDH, poor PS, stage III/IV, presence of B symptoms, higher risk IPI and DSHNHL risk group as risk factors of CNS relapse (Table 2). Presence of concurrent EN involvement more than one site and elevated LDH was a significant predictor of CNS relapse (Hazard Ratio [HR] 2.39, P =0.004). Kidney/adrenal gland and gonadal involvement were not associated with higher risk of CNS relapse whereas breast involvement showed a trend toward higher incidence of CNS relapse (HR 2.46, P =0.07). Either immunochemotherapy or intrathecal chemoprophylaxis was not associated with lower risk of CNS relapse; in fact patients who received intrathecal chemotherapy had more CNS relapse though this could be due to selection bias. Median survival of patients with CNS relapse was 13.2 months which was significantly worse than patients without CNS relapse (81.8 months, P<0.001).Conclusion: The 2-year cumulative incidence of CNS relapse in DLBCL in this analysis was 2.7% which was comparable to other series. Using the DSHNHL prognostic model was able to define DLBCL patients into low, intermediate and high risk for CNS relapse. The high-risk group in our series had lower incidence of CNS relapse compared to German and recently reported British Columbia cohorts. Our study confirms poor survival outcome of DLBCL patients with CNS relapse and no protective effect of immunochemotherapy or intrathecal chemoprophylaxis on the incidence of CNS relapse. Novel risk-adapted CNS prophylaxis strategies are warranted to be further investigated in prospective studies. [Display omitted] [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

The Absolute Number of Extranodal Sites Detected By PET-CT Is a Powerful Predictor of Secondary Central Nervous System Involvement in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP

BackgroundCentral nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an infrequent but devastating complication. The German Risk model which includes the 5 IPI risk factors plus involvement of the kidneys has been validated in 2 large independent cohorts (Schmitz, ICML 2013; Savage, ASH 2014; El-Galaly, ICML 2015). In this model, the presence of >1 extranodal site of involvement contributes only 1 point. However, the precise impact of the extent of extranodal disease in PET-CT staged patients is unknown. Patients and MethodsWe identified patients with newly diagnosed DLBCL presenting to hospitals in Denmark, Canada, the United Kingdom and Australia through systematic searches of national/local lymphoma registries. Inclusion criteria were: staging included PET-CT, primary treatment with R-CHOP or similar regimen ± CNS prophylaxis. Patients treated with high-dose regimens (such as R-HyperCVAD) and those with CNS involvement at diagnosis were excluded. Medical records and PET-CT reports were reviewed for clinical information and outcome. Multiple lesions in one organ or set of paired organs/ tissue were counted as a single extranodal site, and the spleen and Waldeyer's ring were not included as extranodal sites. Time to CNS relapse was determined using the method of Kaplan and Meier, with univariate analysis of absolute number of extranodal sites associated with CNS relapse performed using competing risk regression with death before CNS relapse as competing risk. Multivariate analyses (adjusted for elevated LDH, age>60 y and performance status>1) were performed using Cox proportional hazards to identify the specific increase in risk attributable to the absolute number of extranodal sites of involvement. Involvement of the kidney/adrenals and advanced disease stage were not included in the adjustment because of their intrinsic relationship to number of extranodal sites. Results1,536 patients meeting the above criteria were included, with the following characteristics: median age 65 y (range 17-92), 63% stage III/IV, 39% B symptoms, 50% elevated LDH, 15% performance status >1 and 39%, 36%, 15%, 6% and 3% had 0, 1, 2, 3 and 4+ extranodal sites of involvement, respectively. 79% received no specific CNS-directed prophylaxis; 8% received intrathecal chemotherapy alone, 5% received systemic high-dose anti-metabolites and 8% received both intrathecal and systemic. After a median follow-up of 41 (interquartile range 28-61) months, 62 (4%) patients developed CNS relapse at a median of 9 (range 4-78) months from initial diagnosis. The 3-y incidence of CNS relapse, unadjusted and adjusted hazard ratios for CNS relapse according to number of extranodal sites of involvement are presented in Table 1. The competing risk regression analysis for CNS relapse using absolute number of extranodal sites of involvement is displayed in Figure 1; >2 vs 2 or fewer extranodal sites was associated with markedly increased risk of CNS progression (P <0.0001). ConclusionsIn patients with newly diagnosed DLBCL staged with PET-CT and treated with R-CHOP, the presence of 3 or more extranodal sites of involvement is associated with markedly increased CNS relapse risk, even when adjusting for other variables. This finding may reflect the greater sensitivity of PET-CT for detection of extranodal disease compared with CT alone. This population would be suitable for prospective studies evaluating the efficacy of prophylaxis strategies and predictive biomarker studies.Table 1Risk of CNS relapse according to number of extranodal sites at initial diagnosis. *adjusted for LDH, age>60 y and performance status >1Number of extranodal sitesn (%)3-year incidence % (95%CI)Unadjusted hazard ratio HR (95% CI)Adjusted hazard ratio* HR (95% CI)0602 (39)1.7 (0.9-3.5)1.0 (ref)1.0 (ref)1559 (36)4.0 (2.5-6.4)3.0 (1.3-6.7)3.1 (1.3-7.2)2230 (15)4.8 (2.4-9.4)3.4 (1.3-8.5)2.8 (1.0-7.5)392 (6)12.8 (6.6-24.0)8.1 (3.1-20.9)6.3 (2.2-17.6)4+53 (3)32.1 (20.1-48.8)22.0 (9.0-53.6)17.2 (6.5-45.8) [Display omitted] DisclosuresHutchings:Takeda: Research Funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Seymour:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees. Villa:Roche: Research Funding.

Natural History of Central Nervous System Relapse in Diffuse Large B Cell Lymphoma in the Immunochemotherapy Era

IntroductionRelapse in the central nervous system is an uncommon complication of diffuse large B cell lymphoma (DLBCL) associated with a poor prognosis. The addition of rituximab to chemotherapy has improved outcomes in patients with DLBCL but its effect on the outcome of patients with CNS relapse is not well characterized. Here we present the natural history of patients with CNS relapse in a large cohort of patients with DLBCL who were treated in the immunochemotherapy (IC) era.MethodsNewly diagnosed patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) and treated with primary anthracycline based IC were prospectively enrolled on the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. Patients with documented CNS involvement at diagnosis, primary CNS lymphoma, or post-transplant lymphoproliferative disorder at diagnosis were excluded. All CNS relapse and retreatment details were verified by medical record review.Results1017 patients with newly diagnosed DLBCL or PMBCL, no documented CNS disease at diagnosis, and treated with IC were enrolled in the MER between 2002 and 2012. At a median follow-up of 59 months (range 1-148), 36 patients had CNS relapse. The cumulative incidence of CNS relapse was 3.1% (95% CI: 2.2%-4.4%) at 2 years and 3.7% (95% CI: 2.7%-5.0%) at 5 years after diagnosis. CNS involvement was identified after first line IC in 25 patients, and after salvage therapy in 11 patients. 22 patients had an isolated CNS relapse, while 14 had both systemic and CNS disease at relapse. The incidence of isolated CNS relapse at two years from diagnosis was 1.9% (95% CI: 1.2%-3.0%, figure 1). CNS involvement was parenchymal in 22 patients, leptomeningeal in 11, and parenchymal and leptomeningeal in 3 patients.At diagnosis, this subset of 36 patients had a median age of 61 years (range 20-86); 25 (69%) were male. IPI was 0-1 in 6 patients, 2 in 13 patients, 3 in 11 patients and 4-5 in 6 patients. Cell of origin per Hans algorithm was available in 17 patients, 8 were GCB and 9 were non-GCB. Extranodal sites of disease at diagnosis included testicular (2), renal (5), bone (10) and bone marrow (6). 7 patients had no sites of extranodal disease. LDH was elevated in 71%. The German High-Grade Non-Hodgkin Lymphoma Study Group CNS risk score was low risk in 6 patients, intermediate risk in 22 patients, and high risk in 8 patients. 6 patients received CNS prophylaxis with their initial immunochemotherapy, including 3 of the 21 patients who subsequently developed isolated CNS disease.First line therapy after CNS relapse included high dose methotrexate based chemotherapy in 22 patients and other systemic regimens in 6, with intrathecal (IT) chemotherapy in 5. Overall survival in patients after CNS relapse was poor with a median survival of 6.3 months (95% CI: 2.9-15.5) and 12-month survival rate of 29% (95% CI: 17%-49%). Patients who had CNS relapse following initial IC had better subsequent survival (median OS = 7.6 months) compared to patients with first presentation of CNS relapse following salvage therapy (OS = 2.1 months, p=0.005, see figure 2). 10 patients (28%) proceeded to SCT after CNS relapse, of which 6 remain alive at a median follow-up of 39 months. There were no differences in post-CNS relapse survival by age, sex, CNS risk score, cell of origin, extranodal site involvement at diagnosis, or site of CNS relapse (all p>0.10), though power was limited due to small numbers.ConclusionsThe incidence of CNS relapse in DLBCL is approximately 4% in the immunochemotherapy era. The vast majority of CNS relapses occur within 2 years of diagnosis. Isolated relapse in patients without CNS involvement at diagnosis is a relatively rare event with an incidence of approximately 2% at 2 years of diagnosis. Outcomes remain poor, and standard clinical variables do not predict survival after CNS relapse. Novel therapeutic approaches are needed in this population, with consideration to autologous SCT, which produces durable remission in a subset of patients. [Display omitted] [Display omitted] DisclosuresMaurer:Kite Pharma: Research Funding. Farooq:Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Characteristics and Outcomes of Lymphoblastic Lymphoma Patients - the University of Miami Experience

BACKGROUND: Lymphoblastic lymphoma (LBL) is an uncommon adult malignancy accounting for <2% of non-Hodgkin´s lymphomas. This high-grade lymphoma is most commonly of T-cell immunophenotype and it is thought to be the nodal/extra nodal presentation of acute lymphoblastic leukemia (ALL). Arbitrarily, 25% bone marrow involvement has been considered cut-off in differentiating between LBL and ALL. The optimal standard treatment for adult with LBL is not yet defined due to rarity of the disease and absence of large randomized prospective studies. Therefore, current recommendation are based on ALL and pediatric population experience. Hyper-CVAD is one of the most commonly utilized regimens for this disease in US. The purpose of this study was to review our experience in LBL patients, most of whom received therapy with Hyper-CVAD regimen followed by POMP maintenance.METHODS: Retrospective review of patients with LBL treated at University of Miami (UM) Health System from January 1995 to June 2015. HIV positive patients were excluded.RESULTS: 32 patients were identified in review of clinical and pathological lymphoma databases. Patients with >25% bone marrow involvement or leukemic presentation in the peripheral blood were excluded. Median age at diagnosis was 34 years (range 17 to 76 years), 23 (72%) patients were male, 14 (44%) were Hispanics, and 30 (94%) had an ECOG performance status of 0-2, and 2 had ECOG of 3-4. 30 (94%) LBL tumors were of T cell origin. Bulky disease was present in 13(41%), mediastinal involvement in 23(72%), pleural/pericardial effusion in 19(59%), SVC syndrome in 6(19%), CNS disease at presentation in 4(12%), and bone marrow involvement (6 to 25%) in 10(31%) patients. 20(62%) patients presented with stage III/IV, 21(66%) with elevated LDH, 13(41%) with B symptoms and 15(47%) patients had high IPI. Median follow-up of all patients was 54 months (range 3.5 to 195months). 30 patients received induction therapy while 2(6%) patients were referred to hospice without receiving any treatment because of their general condition. These 2 patients were excluded from further analyses. 26(87%) of treated patients received Hyper-CVAD (7 received <4 cycles because of side effects and 19 >4 cycles) while others received different ALL-type regimens. 2(6%) patients underwent upfront consolidation with allo-BMT after induction chemotherapy. CR rate was 67% and PR 21%. 13 patients are alive with a median follow up of 63 months (95% CI 75-147). Of the 2 patients treated with allo-BMT one is alive in CR and the other presented CNS relapse after transplant and died of septic shock. Median overall survival (OS) of treated patients was 26 months (95% CI 34-79) and median progression free (PFS) was 21 months (95% CI 29-73). 3-year and 5-year OS rates were both 44% (95% CI 26-61%). 3-year and 5-year PFS rates were 45% (95% CI 26-61%) and 40% (95% CI 22-58%), respectively. Two patients (6%) developed CNS relapse. OS was statistically significantly longer in patients receiving more than 4 cycles of hyper-CVAD (p=0.05). No statistically significantly difference in OS and PFS was associated with following variables: ethnicity, BM involvement, IPI score, stage, presence of bulky disease, ECOG performance status and treatment with mediastinal RT. Patients treated with Hyper-CVAD demonstrated following responses: 17 (65%) achieved CR (95% CI 36-106) and 6(23%) PR (95% CI 0.54-46). Of those who achieved CR 11 are still alive in continuous CR and 6 patients died. Median OS was 26 months (CI: 29-76 months) and median PFS was 21 months (CI: 24-66 months) for Hyper-CVAD treated patients. In these patients 3-year OS and PFS were 44% (95% CI 24-62%) and 44% (95% CI 24-62%), respectively.CONCLUSIONS: Our study describes characteristics and outcomes of patients (mainly indigent) living in Miami area and treated at UM with no referral bias. Many of these patients did not have medical insurance, preventing upfront consolidation with BMT. The observed remission, OS and PFS rates were inferior to rates reported in the literature. However, similar to previous reports, the incidence of CNS relapses was low, suggesting that appropriate intrathecal CNS prophylaxis together with systemic chemotherapy agents penetrating CNS are adequate for CNS prophylaxis. However, our results in this unbiased cohort suggest that either current chemotherapy treatments need be consolidated upfront with BMT or more efficient regimens are needed. DisclosuresNo relevant conflicts of interest to declare.

Treatment of young children with CNS-positive acute lymphoblastic leukemia without cranial radiotherapy.

Due to the long-term sequelae of cranial radiotherapy (CRT), contemporary treatment protocols for children with acute lymphoblastic leukemia (ALL) aim to limit the use of prophylactic CRT. For patients with central nervous system (CNS) involvement with ALL at diagnosis, the use of CRT remains common. Children <5 years of age are a particularly challenging subgroup in whom the consequences of CRT can be devastating. This study retrospectively describes the overall (OS) and event-free survival (EFS) of young children (1-5 years) who were treated for CNS-positive ALL at the Hospital for Sick Children between 2000 and 2013. Of a total of 19 patients, two were treated with upfront CRT, both as part of the conditioning regimen prior to HSCT. All patients received intensification of CNS-directed chemotherapy by triple intra-thecal chemotherapy (84.2%), use of dexamethasone in induction (57.9%) and maintenance (66.7%), and high-dose methotrexate (77.8%). The OS was 84.2 ± 8.4% and EFS was 79.0 ± 9.4% with a median follow-up time of 4.3 years (range, 2.6-8.2). The cumulative incidence of CNS relapse was 5.2 ± 5.1%. We conclude that omission of CRT from the treatment of young children with ALL involving the CNS is associated with acceptable survival and avoids potentially devastating late effects in this group.

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.

Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis--A Systematic Review of Prospective Studies.

Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis.

Risk of CNS Relapse with Diffuse Large B-Cell Lymphoma (DLBCL) in the Rituximab Era: Results from the UK NCRI R-CHOP 14 v 21 Trial

Risk of CNS Relapse with Diffuse Large B-Cell Lymphoma (DLBCL) in the Rituximab Era: Results from the UK NCRI R-CHOP 14 v 21 Trial

Lack of Influence of Rituximab and CNS Directed Prophylactic Therapy on CNS Relapse in High-Risk Diffuse Large B Cell Lymphoma

Abstract Background/method: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although uncommon, can be devastating. Conflicting reports have been published regarding the reduction in incidence of CNS relapse in post-rituximabera.We retrospectively identified all the patients with DLBCL who has received rituximab-based chemotherapy at initial presentation in our institute between 2004 and 2014. Patients were divided into two groups, ‘high risk’ group and ‘standard risk’ group, based on following definition. High risk group will have at least one of the following risk factors 1) LDH ≥ 650 U/L 2) Age adjusted International Prognostic Index (IPI) of ≥ 4 3) Involvement of &gt; 1 extra nodal site 4) Involvement of testis 5) Breast 6) Bones 7) Kidneys 8) Adrenal glands 9) Retroperitoneal lymph nodes 10) Para-meninges or 11) Bone marrow. Patients without any of these risk factors were deemed standard risk. Descriptive statistics were used to analyze the incidence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results:One hundred and forty two consecutive patients with DLBCL were included in our study. One hundred and twenty two patients received rituximab-based therapy at the initial diagnosis. Forty-nine patients (40%) met the criteria for ‘high risk’ based on the above definition. Seventy-three patients (60%) qualified for standard risk group. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapses. Thirty-one of 49 ‘high risk’ patients received CNS prophylaxis, mainly intrathecal methotrexate. Total 5 patients (4.09%) developed CNS relapse. CNS relapse in high-risk group was 10.2% (5/49). Median age at diagnosis in patients with CNS relapse was 53 years. Median time to relapse was 8.76 months. Median survival after the CNS relapse was 9.16 months. Four out of 5 patients received CNS prophylaxis with intrathecal methotrexate or systemic methotrexate or systemic cytarabine or a combination of them. Average number of doses of prophylaxis received by each patient was 3.2 (range 1-7). Only one patient who developed CNS relapse did not receive any CNS directed therapy as prophylaxis. Conclusion:No significant reduction in the incidence of CNS relapse was noted with upfront use of rituximab. Our study confirms that majority of the DLBCL patients do not need CNS directed therapy. For high risk DLBCL patients, we not only need to develop better predictive markers for CNS relapse but also need better CNS directed therapies to prevent this fatal complication of highly curable disease. Disclosures No relevant conflicts of interest to declare.

Incidence of Central Nervous System (CNS) Relapse in De Novo Adult Acute Lymphoblastic Leukemia (ALL)

In the era of improved outcomes with systemic chemotherapy for de novo adult ALL, prevention of CNS relapse becomes even more paramount. Isolated CNS relapse may herald eventual marrow relapse in the absence of definitive CNS-directed and systemic chemotherapy strategies. CNS prophylaxis can be successfully achieved with intrathecal chemotherapy treatments (IT) in conjunction with systemic chemotherapy inclusive of high-dose methotrexate (MTX) and/or high-dose cytarabine (ara-C) without use of radiation therapy (XRT). The hyper-CVAD regimen (cycles of fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with cycles of high dose MTX (1 g/m2) and cytarabine (3 gm/m2; 1 gm/m2 for age > 60 yrs) incorporates IT MTX alternating with IT ara-C during the intensive phase of induction-consolidation. The number of IT treatments was determined by CNS risk (4 IT for low risk = LDH < 1400 U/L and low proliferative index; 16 IT for high risk = LDH > 1400 U/L or high proliferative index; 8 IT for indeterminate risk = one of parameters unknown). An analysis performed in 2000 (Kantarjian et al, J Clin Oncol 18: 547, 2000) identified CNS relapse rates of 6%, 2%, and 0% for the low, high, and indeterminate CNS risk groups, respectively. The number of IT administered was modified from 4 to 6, from 16 to 8, and maintained at 8 for these CNS risk groups, respectively, until 2010, at which point all pts received 8 IT. An analysis was conducted to examine the incidence of CNS relapse for 565 pts with de novo ALL treated with hyper-CVAD-based regimens (n=453, inclusive of nelarabine, monoclonal antibodies such as rituximab, ofatumumab or inotuzumab, and/or tyrosine kinase inhibitors such as imatinib, dasatinib or ponatinib) from 2001 to 2014 or with the augmented BFM regimen (one IT ara-C, 15 IT MTX, Capizzi methotrexate) (n=112) from 2006 to 2014. T-lymphoblastic lymphoma (designated for 8 IT) and Burkitt leukemia/lymphoma (designated for 16 IT) cases were excluded from the analysis. The incidence of CNS relapse (n=42) was 7% overall; 59% were isolated CNS relapses (n=25, 5%) without concurrent marrow relapse. Median time to isolated CNS relapse was 19 mos versus 10 mos for concurrent relapse. The incidence of CNS relapse for cases with CNS disease at initial presentation (n=70) was 19%. Factors predictive of higher incidence of CNS relapse included younger age (12% for 30 yrs or younger, 3.5% for 60 yrs or older, p=.01), elevated LDH > 1400 U/L (13% vs 4%, p<.001), and Philadelphia chromosome positivity (12% vs 6%, p=.05). The overall CNS relapse rates were 4% for the hyper-CVAD and monoclonal antibody regimens; 11% for the augmented BFM regimen, and 14%-15% for the hyper-CVAD and imatinib/dasatinib regimens. The CNS relapse rate declined from 10% for pts treated prior to 2010 to 8% thereafter (8 IT for all risk groups). Overall, the 3-yr survival rates for CNS relapse was 47% vs 63% without CNS relapse (p=0.006). Modifications to the hyper-CVAD and tyrosine kinase inhibitor regimens for Philadelphia positive ALL have been implemented to increase the number of IT from 8 to 12. Similar modifications will be implemented for the augmented BFM regimen with consideration for incorporation of high dose MTX. Additional analyses will further refine the CNS risk model in order to guide CNS prophylaxis. Alternative agents such as IT rituximab may improve outcomes for CD20 positive cases with CNS disease at presentation; a clinical trial in the setting of active CNS disease is underway. DisclosuresNo relevant conflicts of interest to declare.

Ki-67 Is a Strong Predictor for Central Nervous System Relapse in Patients with Mantle Cell Lymphoma (MCL)

AbstractBackground: CNS relapse is uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor that identification of high risk population is therefore critical in whom prophylactic chemotherapy may play a role.Patients and Methods: A total of 405 patients (median age, 66 years; range 22-85) with MCL newly diagnosed between 1994 and 2012 at 48 institutions in Japan were analyzed.Pathological specimens were centrally reviewed in all patients. We evaluated risk factors for CNS relapse in patients with MCL using competing risk regression analysis. Patients were excluded if they had evidences of CNS involvement at initial diagnosis. Overall, 81% of the patients received rituximab containing regimen with 222 patients received CHOP, 133 patients received high-dose cytarabine containing regimen and 50 patients received other regimen such as fludarabine. At a median follow up duration of 40.4 months, 25 patients (6.2%) experienced CNS relapse. Five patients presented with brain parenchymal mass, 13 patients presented with leptomeningeal disease, and 7 patients presented with both. The median time from initial diagnosis to CNS relapse was 18.5 months. Two-year cumulative incidence of CNS relapse was 4.7% (95%CI: 2.8-7.3). No difference was seen in the incidence of CNS relapse between the treatment with or without rituximab. Univariate analysis revealed blastoid or pleomoriphic variant, Ki-67 ≥ 30, serum total protein < 6.0g/dl, leukemic presentation and high risk group in simplified-MIPI at diagnosis as significant risk factors for CNS relapse. Within these five factors, Ki-67 was the strongest predictive factor for CNS relapse with hazard ration of 8.7 (95%CI: 3.4-22.2). 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 patients with Ki-67 < 30 was 1.5% (95%CI: 0.2-2.9) (Figure). Ki-67 ≥ 30 was a significant risk factor for CNS relapse both in patients who received CHOP and hyper-CVAD/MA. Survival after CNS relapse was dismal with median survival time of 5.7 months.Summary: We identified four risk factors for CNS relapse in patients with MCL. Within these factors, Ki-67 ≥ 30 is the strongest predictive factor with 2-year cumulative incidence of 25.4%. Evaluation for CNS involvement at the diagnosis and assessment for value of prophylactic IT chemotherapy is mandatory in patients with Ki-67 ≥ 30. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Secondary CNS Relapse in DLBCL in the Rituximab Era - an Analysis of Prospective Studies

INTRODUCTIONCNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy.METHODExtensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords “CNS”, “diffuse large B-cell lymphoma”, “relapse”, “prophylaxis”, “rituximab”, “CHOP” were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P<0.05) between groups and couplets were determined by one-way ANOVA and by two-tailed unpaired t-test respectively. Significance of the Kaplan-Meier survival curves was determined using Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests.RESULTSThe study population characteristics are shown in Table. The mean incidence of CNS relapse with rituximab-chemotherapy (R-CHOP/R-CHOEP) was found to be 5.52% (3.21%-7.73%), while that with CHOP-based chemotherapy alone was 4.43% (3.53% -5.33%). No significant difference was observed by two-tailed unpaired t test (P = 0.94). The median time from diagnosis to CNS relapse was 6.5-7 months. The mean incidence of leptomeningeal, parenchymal and both relapses in the rituximab-chemotherapy group were 38.62(±1.93)%, 57.32(±3.06)%, 5.36(±1.79)% compared to 16.17(±0.44)%, 66.17(±0.44)%, 22.06(±0.41)% with chemotherapy alone. One-way ANOVA also showed that use of rituximab resulted in statistically significant (P<0.0001) differences between the patterns of CNS relapse. About 74.1% of CNS relapses among patients receiving rituximab-chemotherapy were isolated CNS relapse, compared to 69.2% for those receiving CHOP chemotherapy. The mean incidence of CNS relapse with the use of any prophylactic CNS directed therapy was observed to be a significantly (P = 0.044) lower [2.97% (2.32%-3.62%)] compared to that without [6.12% (5.91%-6.335]. Median survival following CNS relapse of 365 days following rituximab based chemotherapy and 75 days after CHOP were significantly different (HR for CHOP use 4.867±0.77 at P<0.05).CONCLUSIONRituximab hasn’t significantly decreased overall incidence, but causes less parenchymal CNS relapse. CNS prophylaxis has a definite role in high risk population. There is significantly better survival after CNS relapse in the rituximab era.Abstract 1644. TABLESTUDYAge (yr)Sex (M:F)No.Stage 3/4IPI int-high/ high (>=3 IPI or >=2 aa IPI)Extranodal (>=2)high LDHFollow up (m)Criteria for CNS prophylaxisPatients receiving CNS prophylaxis (IT=intrathecal,S=systemic)ChemoTilly 200361-69ACVBP vs CHOP : M 182 vs 177 F 141 vs 135635 (501 DLBCL)267 vs 253210 vs 207 (aa IPI)155 VS 156231 VS 24168None for CHOP VS ACVBP (IV methotrexate, etop + IT mtx)323 (ACVBP)323 ACVBP vs 312 CHOPFeugier 200469M 92 (CHOP-R) vs 107 (CHOP)202 vs 197161 vs 157121 vs 12061 vs 51131 vs 13224NAno prophylaxis202 R-CHOP Vs 197 CHOPBernstein 200997/ 225 for CHOP were >60 yrsNR899 aggressive lymphoma191/ 225 CHOP95/ 225 CHOP81/225 CHOP146/ 225 CHOP20 yearsnone for CHOP121 IT MTX or radiation (24 Gy)225 CHOP vs ProMACE-CytaBOM vs mBACOD vs MACOP-BBoehme 200968648 vs 5691217 (944 DLBCL)68750721260224bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands.475/1217 (IT-MTX)608 RCHOP Vs 609 CHOPKim 201259.5NR564276192193NR10.5≥1 risk factor59 ITRCHOPKumar 201256 (prophylaxis) VS 58 (no prophylaxis)male: 74 vs 476 female: 43 vs 39698985 vs 45455 vs 24066 vs 22057 vs 37230High risk site involvement : orbit, testis, peripheral blood, vertebra, bone marrow, nasal/paranasal sinuses117/989 IT- 84/117 (AraC/MTX) S–33/117 (MTX)R-CHOPHolte 20135497 vs 59156 (145 DLBCL)1501564115136everyone156/156 (S- Ara-c+ MTX) 1 dose of IT-MTXRCHOEP [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of TCF3 Rearrangement on CNS Relapse in Egyptian Pediatric Acute Lymphoblastic Leukemia

Background: TCF3 rearrangement mostly t(1;19) (q23;p13)/ TCF3-PBX1 gene is associated with favorable outcome in acute lymphoblastic leukemia (ALL) upon treatment with intensification protocols; however, it is associated with higher incidence of central nervous system (CNS) relapse which may affect outcome of patients. Objectives: We aimed to assess TCF3 rearrangement in newly diagnosed pediatric ALL patients in relation to clinical and laboratory parameters, CNS relapse, and clinical outcome. Patients and Methods: Eighty newly diagnosed pediatric ALL patients following at Pediatric Hematology Oncology Clinic, Ain Shams University Hospitals were included in this study. Their ages ranged from 0.75 to 16 years. Seventy six (95%) patients had B-lineage ALL and four (5%) had T-lineage ALL. Data recorded included; age, sex, extramedullary manifestations, CNS, and testes infiltrations, risk stratification, response to treatment, and CBC and BM findings. TCF3 rearrangement was assessed by FISH technique using dual color break-apart probe. Results: TCF3 rearrangement [t(1;19) (q23;p13)] was detected in 16 (20%) out of the 80 studied patients, and it was significantly associated with splenomegaly, lymphadenopathy, CNS infiltration at presentation, high total leucocytic count, low platelet count, high-risk group, and isolated CNS relapse. These results identify a group of high-risk ALL patients with high incidence of CNS relapse and poor response to standard therapeutic regimen. Conclusion: Analysis of TCF3 rearrangement [t(1;19) (q23;p13)] at diagnosis may provide a valuable target for modified and intensified CNS-directed chemotherapeutic protocol aiming to improve the patients’ outcome.

Isolated central nervous system relapse of acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and may exhibit central nervous system (CNS) involvement. Advances in chemotherapy and effective CNS prophylaxis have significantly decreased the incidence of CNS relapse of ALL to 5-10%. Here, we report the case of a patient with isolated CNS relapse of standard risk group pre-B-cell type ALL in an 11-year-old girl, relapsed 3 years after successful completion of chemotherapy. An 11-year-old girl visited our hospital complaining of headache, dizziness, vomiting, and visual field defects. Neurological examination revealed left-side homonymous hemianopsia. Brain magnetic resonance imaging showed a large irregular dural-based sulcal hematoma in the right parietal and occipital lobes. Surgery to remove the hematoma revealed the existence of hematopoietic malignancy after pathologic evaluation. Bone marrow biopsy was subsequently performed but showed no evidence of malignancy.

Extranodal Diffuse Large B Cell Lymphoma In The Rituximab Era and The Risk of Central Nervous System (CNS) Relapse. A Single Center Experience From 2008-2012

BackgroundDiffuse large b-cell lymphoma (DLBCL) with CNS relapse or progression has a poor prognosis. Prior studies noted certain factors which increased the risk of CNS relapse: bone marrow involvement, type as well as number (1+) of extra-nodal sites, age over 60, and increasing International Prognostic Index (IPI) score. However, these were prior to the advent of rituximab (R), which has been suggested to lower CNS relapse when used in combination with CHOP therapy. To our knowledge, no one has looked at the incidence of CNS relapse with regards to extranodal disease in the rituximab era. MethodsRetrospective chart review of patients with DLBCL treated with multiagent induction therapy including rituximab from July‘08 to Jan'12 at Moffitt Cancer Center. Age, stage, IPI score, extra-nodal site, number of nodal sites, and use of intrathecal prophylaxis (IT), were evaluated for their impact on the risk of developing CNS relapse. For those who had complete response to initial therapy, time to progression(TTP) for CNS relapse was measured from completion date of first set of chemo cycles to date of CNS relapse (those who did not CNS relapse were censored at last follow up). TTP was censored at 6 years. Progression free survival(PFS) was measured from date of diagnosis to date of CNS or systemic relapse or death (those who were alive without relapse were censored at last follow up). Overall survival (OS) was measure from date of diagnosis to date of death. Stratified Kaplan Meier curves(with log rank p-values) and Cox PH models(with Wald p-values) were used to explore potential risk factors associated with relapse. ResultsSixty-four patients with DLBCL who received induction therapy were evaluated: median age (range) = 65 (24-93) years; male =56%; IPI scores at diagnosis: 1 (43.8%), 2(21.9%), 3(15.6%); median length of follow up from time of diagnosis = 32 months. All the patients received a regimen containing rituximab, and 92% of patients received R-Chop as treatment. IT prophylaxis with methotrexate was used in 28% of the patients. Incidence of CNS relapse in our study population= 17.3% (n=9) The risk of CNS relapse varied depending on the extranodal site. Those with bone marrow and/or musculoskeletal involvement had an increased risk, with 78% of the CNS relapses occurring in patients with one or both of these sites of involvement. The hazard ratio (HR) for CNS relapse for patients with bone marrow and musculoskeletal involvement was 2.53 and 2.74, respectively (p=0.20 and p=0.13). Other extranodal sites of disease such as visceral organs, genital urinary tract, nasopharynx, or skin did not seem to significantly contribute to the risk of CNS relapse. Patients with bone marrow involvement also had an inferior overall survival (HR=3.05, Wald p=0.02) (see figure 1). Though not statistically significant (log rank p=0.126), those receiving IT methotrexate prophylaxis appear to have longer PFS than those who did not, with 83% alive without relapse at 6 years compared to 43% (see figure 2). [Display omitted] [Display omitted] ConclusionsDespite the addition of rituximab to multiagent chemotherapy, those with bone marrow and musculoskeletal involvement still had a significantly higher risk of CNS relapse. There is a trend which suggests intrathecal prophylaxis with methotrexate can improve progression free survival and is still possibly beneficial in high risk DLBCL patients even in the rituximab era. Larger prospective studies are needed to determine the true benefit of prophylactic IT therapy in this population. Disclosures:No relevant conflicts of interest to declare.

Central Nervous System Relapse In Adults With Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

▪ IntroductionCentral nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. MethodsIn this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. ResultsWe included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy.The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. ConclusionCNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Incorporating High-Dose IV Methotrexate Into Initial Therapy Results In Lower Rates Of Central Nervous System (CNS) Relapse In Patients With High-Risk Diffuse Large B-Cell Lymphoma (DLBCL)

▪ Aim/BackgroundCNS relapse in DLBCL is a devastating complication and the optimum strategy for prevention remains unclear. MethodsWe performed a multi-centre, retrospective analysis of CNS relapse rates in patients (pts) identified at risk of CNS relapse according to the type of CNS-directed prophylaxis administered. Pts receiving initial therapy for DLBCL between 1996 and 2011 (to allow ≥2 years of follow up) were included; DLBCL after histologic transformation of low-grade lymphoma and HIV-associated DLBCL were included, however pts with Burkitt or Burkitt-like lymphoma or CNS involvement at diagnosis were excluded. Selection for CNS prophylaxis strategy was by the primary managing hematologist if they fulfilled ≥2 of the following criteria: 1) multiple extranodal sites 2) raised serum LDH 3) B-symptoms, OR involvement of specific high-risk anatomical sites. We compared 3 prophylaxis strategies: prior to 2003 intrathecal (IT) methotrexate (MTX) in conjunction with CHOP chemotherapy “group 1” was the main strategy; from 2003 onwards, R-CHOP (mostly) with IT MTX was followed by two cycles of high dose intravenous (IV) MTX (1-3g/m2) “group 2”; patients<65 years of age with age adjusted IPI of ≥2 were treated with dose intensive therapy containing high-dose anti-metabolites (Hyper-CVAD or CODOXM-IVAC, with rituximab after it became available) which included both IT and IV MTX “group 3”. ResultsOverall, 208 pts were identified, with 32, 134 and 42 in groups 1, 2 and 3 respectively. Markedly fewer pts in group 1 received rituximab and pts selected for intensive approaches (group 3) were younger, had higher risk disease features (higher serum LDH ratio, more extranodal sites and more B-symptoms) and received fewer doses of IT chemotherapy. The distribution of extranodal sites for each of the three groups was similar, except for epidural/paraspinal disease which was more frequent in group 1 (18%, 5%, 0% in groups 1-3 respectively, P=0.004). With a median follow up of 3.7 years (range 0.4 – 18.6) years, 19 CNS relapses occurred (7, 11 and 1 in groups 1-3 respectively). The 3-year actuarial incidence of CNS relapse was 17.6% (3.5 – 32.7%), 7.3% (3.7 – 11.9%) and 2.4% (0 – 7.1%) in groups 1, 2 and 3 respectively (P=0.026). The 3-year event free survival (EFS) was 70% (53 - 86%), 83% (76 – 90%) and 70% (56 – 84%) in Groups 1 – 3, respectively (P=0.15, data not shown). Use of rituximab, presence of paraspinal disease and decade of treatment were not associated with CNS relapse by univariate analysis. However amongst pts receiving IT MTX, there was a trend toward reduction in CNS relapse for pts receiving 4-6 doses of IT MTX compared to 1-3 (P=0.052) and patients receiving their first dose of IT MTX within seven days of diagnosis (P=0.08). ConclusionThe use of IV MTX and dose-intense chemotherapy was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. [Display omitted] Disclosures:No relevant conflicts of interest to declare.group 1CHOP + intrathecal MTXgroup 2R-CHOP-like chemo +high dose intravenous MTXgroup 3HyperCVAD or CODOXM/IVAC +/- rituximabpatients3213442Time period1992-20032003 - 20111991-2011median age, years (range)55 (29-79)62 (19-84) yrs45 (16-74) yrsmale (%)22 (68%)87 (65%)24 (57%)stage III/IV (%)21/31 (68%)103/132 (82%)38 (93%)B symptoms10 (32%)47 (36%)27 (64%)median serum LDH ratio (range)1.1 (0.3-5.9)1.3 (0.3 – 11.4)1.7 (0.8 – 25.7)ECOG PS ≥117 (55%)67 (55%)19 (46%)IPI 3-515 (44%)78 (63%)26 (65%)extranodal sites ≥215 (48%)45 (51%)30 (86%)chemotherapyCHOP 30RCHOP 2CHOP 2R-CHOP 122R-MACOPB 8Hyper CVAD 22R-Hyper CVAD 16R-CODOXMIVAC 2CODOXMIVAC 1rituximab2 (6%)122 (98%)18 (43%)IT methotrexate (any)4-6 doses1-3 dosesno IT32 (100%)26 (81%)6 (19%)0 (0%)84/104 (81%)75 (72%)9 (9%)20 (19%)28/33 (85%)21 (64%)7 (21%)5 (15%)

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.

Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group

The Children's Oncology Group's A5971 trial examined central nervous system (CNS) prophylaxis and early intensification in paediatric patients diagnosed with CNS-negative Stage III and IV lymphoblastic lymphoma. Using a 2 × 2 factorial design, the study randomized patients to Children's Cancer Group (CCG) modified Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukaemia (ALL) regimen with intensified intrathecal (IT) methotrexate (MTX) (Arm A1) or an adapted non-Hodgkin lymphoma/BFM-95 therapy with high dose MTX in interim maintenance but no IT-MTX in maintenance (Arm B1). Each cohort was randomized ± intensification (cyclophosphamide/anthracycline) (Arms A2/B2). For the 254 randomized patients, there was no difference in 5-year event-free survival (EFS) for the four arms: Arm A1, 80% [95% confidence interval (CI) 67-89%] and Arm A2, 81% (95% CI 69-89%); Arm B1, 80% (95% CI 68-88%) and Arm B2, 84% (95% CI 72-91%). The cumulative incidence of CNS relapse was 1·2%. Age <10 years and institutional imaging response at 2 weeks was associated with improved outcomes (P < 0·001 and P = 0·014 for overall survival). CNS positive patients (n = 12) did poorly [5-year EFS of 63% (95% CI 29-85%)]. For CNS-negative patients, there was no difference in outcome based on CNS prophylaxis (IT-MTX versus HD-MTX) or with intensification.

XVI. CNS prophylaxis in aggressive lymphomas: for whom and how

Dissemination in the central nervous system (CNS) in patients with aggressive lymphoma is a relatively rare but a frequently deadly complication that occurs between 5 (diffuse large B-cell lymphoma, DLBCL) and 30% (Burk itt lymphoma, BL and B-cell lymphoblastic lymphoma, B-LL) [1] in different subtypes of non-Hodgkin lymphoma (NHL). However, although a CNS prophylaxis is normally included into treatment regimens for BL and B-LL, in other NHL a prophylactic treatment is not systematically warranted because it may increase the toxicity of systemic chemotherapy.