Central Nervous System Relapse In Patients Research Articles

The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas

AbstractLittle is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse–enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.

Prognosis of Patients with Diffuse Large B Cell Lymphoma with Central Nervous System Relapse: USC Experience

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma and a potentially curable disease with systemic immunochemotherapy regimens. Involvement of the central nervous system (CNS) in patients with DLBCL is a relatively rare event which occurs in approximately 2-5% of patients overall, but the CNS relapse rate can be as high as 10-12% in high-risk patients. Unfortunately, CNS relapse confers poor prognosis with some studies estimating median survival of 2.5 months from relapse. Our study evaluates prognostic factors and outcomes in this patient population. Methods: This study is a retrospective review of patients diagnosed with DLBCL who then developed CNS relapse and were treated at Los Angeles General Medical Center (LAGMC) and Norris Comprehensive Cancer Center (NCCC) from 2016-2023. Information regarding patient demographics, prognostic factors to calculate NCCN-IPI scores, pathologic characterization, therapy, clinical course, and survival were collected. CNS relapse was defined as pathologic or imaging diagnosis of CNS involvement after initial treatment was received. Results: A total of 29 patients with CNS relapse of DLBCL were identified with a median age of 60 (range 43-86). The median time from initial diagnosis to CNS relapse was 9 months. The patients were 72.4% male (N=21), 79.3% Hispanic (N=23), and 17.2% (N=5) HIV positive. NCCN-IPI scores were calculated for all patients and divided into NCCN-IPI risk groups. The low-risk group (NCCN-IPI 0-1) made up 10.3% (N=3), low-intermediate risk group (NCCN-IPI 2-3) 48.3% (N=14), high-intermediate risk group (NCCN-IPI 4-5) 34.5% (N=10), and high-risk group (6-8) 6.90% (N=2). Pathologic analysis revealed 41.4% (N=12) of patients had germinal center type lymphoma, 44.8% (N=13) were BCL-2/c-myc double expressors, 13.8% (N=4) were BCL-2/c-myc double hit, and 13.8% (N=4) were BCL-6/c-myc double hit (Table 1). Overall survival (OS) for the entire cohort was 18.5% at five years after CNS relapse of DLBCL with a median survival of 12 months. Patients with a low or low-intermediate NCCN-IPI score (0-3) had an OS of 57.4% at 12 months and 29.1% at five years. Patients with a high-intermediate or high NCCN-IPI score had an OS of 35.7% at 12 months and 0% by 33 months. OS at 12 months for the HIV negative group was 70.4% compared to 40.0% in the HIV positive group, but OS at 5 years was similar in both groups at 19.4% and 20.0%, respectively (Figure 1). Conclusions: CNS relapse in patients with DLBCL is a rare but devastating complication. In our largely male and Hispanic patient population, prognosis at five years was very poor for those with CNS relapse, but higher NCCN-IPI scores demonstrated a trend that conferred a higher likelihood of death at both the one year and five year time points compared to those with lower scores. Survival after CNS relapse in our cohort is longer compared to prior studies, indicating possible improvements in the prognosis of patients with CNS relapse of DLBCL. Given the overall poor prognosis of CNS relapse of DLBCL, improved prognostic stratification is of the utmost importance in this highly curable disease.

How to Treat Isolated Leptomeningeal Relapse of Multiple Myeloma 11 Years after Autologous Stem Cell Transplantation (ASCT)

Post transplant relapse of Multiple Myeloma (MM) in the central nervous system (CNS) is rare and it is almost always associated with systematic relapse and in most instances, shortly after initial treatment. We did not encounter reports of relapse isolated to the CNS ten years post-transplant. In October 2009, a 49-year-old male presented with an IgG lambda MM, ISS II. He was treated with Bortezomib/Dexamethasone, autologous PBSCT, followed by two years maintenance with Lenalidomide, attaining stringent CR, confirmed by PET/CT. He discontinued follow up and returned after 11y/8m progression free survival, in June 2021 with paraplegia due to cauda equina syndrome. NMR consistent with leptomeningeal infiltration, single focal intramedullary lesion at L1 level without bone affectation. No MM defining criteria (CRAB). Normal levels of serum Immunoglobulins (IGs), serum and urine immunofixation, and serum free light chains. Flow cytometry negative in bone marrow. Spinal tap was unsuccessful and through an Ommaya reservoir, that was placed after NMR showed evidence of cranial leptomeningeal involvement, CSF showed infiltration by countless malignant plasma cells. Patient received immediate conformational radiotherapy and biweekly IT methotrexate and hydrocortisone. A month later his course was complicated by left leg proximal deep vein thrombosis and pulmonary embolism which was treated with Apixaban. Given the rarity of this type of relapse, we questioned the appropriateness of the treatment and searched the literature with respect to the accessibility of the CNS by the different novel drugs used to treat MM in order to determine the most effective strategy. In addition to corticosteroids, there is clinical evidence that thalidomide crosses the blood-brain barrier (BBB), in murine models pomalidomide also has good penetration into the CNS. Both have a penetration of 30 to 40% into the CSF. Among proteasome inhibitors, only marizomib has been observed to cross the BBB in a murine model, while bortezomib does not. With respect to anti CD38 monoclonal antibodies, mass spectrometry at 12, 15, and 19 days after daratumumab infusion showed antibody levels in CSF 71 times less than in serum on the three sample days. It is not known if weekly doses of daratumumab could attain therapeutic levels in CSF. We found only 14 cases of isolated CNS relapse in patients with MM treated with ASCT with a median interval between transplant and relapse of 3 months (0.5-96m), with only one reported relapse 7.5 years after autologous transplant and the median overall survival was only 3 months. Two cases died in less than a month and only one case survived for a year after the CNS relapse.To date, our patient has received 12 cycles of Pomalidomide/dexamethasone with progressive improvement, now he is able to carry on his life unassisted and there is no evidence of MM relapse anywhere. The rarity of this case scenario highlights the lack of knowledge regarding the best approach to CNS MM relapse. There is no evidence of the effectiveness of methotrexate and Ara C, in MM, and no novel drug can be instilled into the CSF. We conclude that the systemic use of pomalidomide and dexamethasone should be the best approach of MM isolated CNS relapse. Further investigations will clarify if other novel drugs are active in this context.

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 after CAR-T Cell Therapy in B-Cell Malignancies

Aims & Objectives: Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the landscape of cancer therapy, obtaining significant efficacy especially in relapsed and refractory (R/R) B cell malignancies. In clinical patients, CAR-T cells are able to migrate into various organs and exert cytotoxicity on tumor cells, including the central nervous system (CNS), which serves as an immunological privileged site protected from peripheral blood. However, whether there is a possibility of the CNS relapse in patients with B-cell lymphoma who achieved complete remission (CR) after CAR-T cell therapy has not been reported yet. We aim to describe the features of the CNS relapse after CAR-T cell therapy in B-cell lymphoma, and try to identify correlated factors and propose potential management strategy in the upcoming research. Patients/Materials & Methods: We preliminarily reviewed 12 patients (5 presented) who received CAR-T cell therapy for the treatment B-cell lymphoma in our center and Shenzhen University General Hospital. We compared the baseline of patient characteristics before CAR-T cell therapy, described the clinical response and efficacy during the treatment, and reported the occurrence of CNS relapse after achieving CR. Results: All 5 patients were heavily pre-treated with multiple lines of chemotherapy prior to CAR-T cell therapy, with 2 of them received additional autologous hematopoietic stem cell transplantation (HSCT) (Table 1). All patients suffered from previous relapse in multiple peripheral lymph nodes, with 2 of them involved in other organs like liver and breast, and 1 of them involved in the CNS. Three patients received CD19-22 bispecific CAR-T product, 1 patient received CD19-20 bispecific CAR-T product, and 1 patient received CD19 CAR-T product (Table 2). All patients responded well with tolerable toxicities by monitoring body temperature, inflammation markers, cytokines, and hemogram, and all achieved CR by PET/CT after CAR-T treatment (Figure 1). All patients eventually developed isolated CNS relapse with different locations, respectfully, which was confirmed by imaging along with pathological diagnosis or targeted drug treatment (Figure 2). Discussion & Conclusion: We first reported the CNS relapse after CAR-T cell therapy in patients with B-cell lymphoma, suggesting that routine monitory is required for patients who achieved remission after CAR-T treatment to manage the CNS involvement in time. If possible, additional application of PD-1 monoclonal antibody, BTK inhibitors or other immunomodulatory drugs that can function in the CNS might prevent the CNS relapse without affecting CAR-T cell function. Conflict of Interest Statement: No conflict of interest to disclose. Figure 1. Clinical responses and hematological toxicities during CAR-T treatment among 3 patients with CNS relapse after therapy. (A) Body temperature. (B) Levels of inflammation markers including C reactive protein (CRP), ferritin, and D-dimer. (C) Levels of cytokines, including interleukin (IL)-2, IL-6, IL-10, and interferon-γ (INF-γ). (D) Hemogram (ie. Neutrophils, lymphocytes, platelet, and hemoglobin). Figure 2. Central nervous system relapse among 3 patients after CAR-T cell therapy. (A) Patient 1 with one single focus in left lateral ventricle confirmed by CT plus puncture with pathology (not shown). (B) Patient 3 with one focus in left frontotemporal lobe confirmed by MRI plus puncture with pathology (not shown). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

648TiP Reduction of methotrexate (MTX) levels after glucarpidase in patients with diffuse large b cell lymphoma (DLBCL) at risk of central nervous system (CNS) involvement who receive cycles of HDMTX: An open-label, interventional, non-randomized, phase II, pilot, multicenter study

CNS relapse in patients with Diffuse Large B Cell Lymphoma (DLBCL) is usually an early complication and with poor prognosis. R-CHOP, the standard treatment for DLBCL plays a minimal role preventing leptomeningeal and/or brain parenchyma relapse. Risk factors have been previously identified for this complication and high dose intravenous methotrexate (HDMTX) has been suggested as an effective strategy to prevent CNS lymphoma relapse (GELTAMO guidelines Haematologica 2017 and British guidelines BJAEM 2020).

Controversies and current practices in CNS relapse of diffuse large B-cell lymphoma

Central nervous system (CNS) relapse is an uncommon complication of diffuse large B-cell lymphoma (DLBCL), occurring in approximately 3–5% of patients and at a median timepoint of 6–9 months from diagnosis. Approximately half of these cases present as isolated CNS relapse caused by occult seeding of the CNS early in the disease course, while the remaining cases occur in the context of concurrent systemic relapse. The median survival after CNS relapse is only 4–6 months, highlighting the unmet need to identify effective prophylaxis and management strategies. This article provides an overview of current controversies and optimal strategies for prognosticating, preventing, and treating CNS relapse in patients with DLBCL.

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.

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Lack of Effectiveness of Intravenous High-Dose Methotrexate for Prevention of CNS Relapse in Patients with High-Risk DLBCL: A Retrospective Analysis from Alberta, Canada

Introduction: Central nervous system (CNS) relapse occurs in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and carries a poor prognosis. The CNS-IPI score identifies patients at high-risk (10-12%) of CNS relapse based on the presence of 4-6 risk factors: age &amp;gt;60 years, ECOG performance status &amp;gt;1, elevated LDH, stage III to IV, &amp;gt;1 extranodal site, and renal or adrenal involvement. International guidelines recommend prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high-risk of CNS relapse. However, there is limited evidence supporting this practice, and prophylactic HD-MTX requires hospital admission and increases the risk of treatment-related toxicity. Therefore, we conducted a real-world study to determine the effectiveness of HD-MTX for prevention of CNS relapse in high-risk DLBCL. Methods: We performed retrospective chart reviews of patients aged 18-70 years with DLBCL treated with curative intent at two academic medical centers in Alberta, Canada between 2012-2019. Since 2015, the Alberta Provincial Lymphoma Clinical Practice Guideline (APLCPG) has recommended CNS prophylaxis with HD-MTX 3.5g/m2 IV after cycles 2, 4, and 6 of R-CHOP for patients with the following high-risk criteria: CNS-IPI 4-6, double hit lymphoma, or testicular involvement. Between 2012-2015, HD-MTX was recommended for patients with elevated LDH, ECOG &amp;gt;1, and &amp;gt;1 extranodal site. In addition, eligible patients at risk of poor outcomes (e.g. double hit lymphoma or IPI score 4-5) could be offered higher intensity chemoimmunotherapy (e.g. da-EPOCH-R or R-CODOXM/R-IVAC) or R-CHOP followed by consolidative autotransplant. The log-rank test was applied to determine risk of CNS relapse and the Cox proportional-hazards model was used to determine factors associated with CNS relapse, progression-free survival (PFS), and overall survival (OS). Analyses were performed using SPSS version 25 and GraphPad Prism 8 statistical software. Results: We included 906 patients with a median follow-up time of 35.3 months (range 0.29-105.7). Risk of CNS relapse was 1.9% (95% C.I. 0.0-30.7%) for patients with CNS-IPI 0-1, 4.9% (95% C.I. 0.5-18.0%) for CNS-IPI 2-3, and 12.2% (95% C.I. 4.0-25.2%) for CNS-IPI 4-6 (p&amp;lt;0.0001). Risk factors for CNS relapse included APLCPG high-risk criteria (HR 4.69, 95% C.I. 2.51-8.76), CNS-IPI score 4-6 (HR 4.26, 95% C.I. 2.22-8.16), and testicular involvement (HR 3.45, 95% C.I. 0.43-27.34). Among the 326 patients meeting APLCPG high-risk criteria, median CNS-IPI was 4 (range 0-6), 67 (20.6%) had double hit lymphoma, and 17 (5.2%) had testicular involvement. Risk of CNS relapse was significantly increased for patients meeting APLCPG high-risk criteria (11.8% vs 3.0%, p&amp;lt;0.0001). Prophylactic HD-MTX was administered to 115 (35.3%) high-risk patients; median number of doses given was 2 (range 1-3). The risk of CNS relapse was 11.2% (95% C.I. 2.1-28.9%) for patients who received HD-MTX versus 12.2% (95% C.I. 2.8-28.8%) for those who did not (p=0.82). Patients who underwent higher intensity chemoimmunotherapy (n=35) or consolidative autotransplant (n=68) tended to have a lower risk of CNS relapse than patients treated with conventional R-CHOP (6.0% vs. 14.6%, p=0.09). In multivariate analyses, HD-MTX and higher intensity chemoimmunotherapy demonstrated no significant association with CNS relapse, PFS, or OS; however, consolidative autotransplant was associated with a tendency toward lower risk of CNS relapse (HR 0.30, 95% C.I. 0.09-1.01) and a significantly improved PFS (HR 0.41, 95% C.I. 0.24-0.71) and OS (HR 0.56, 95% C.I. 0.32-0.98). Conclusion: The APLCPG high-risk criteria of CNS-IPI 4-6, double hit lymphoma, or testicular involvement identify patients with DLBCL at significantly increased risk of CNS relapse. The risk of CNS relapse was similar for all high-risk patients (11.8%) and those who received prophylactic HD-MTX (11.2%) in our study relative to previously published data for patients who did not receive CNS prophylaxis (10-12%). Based on this analysis, we could not demonstrate a benefit to the current practice of prophylactic HD-MTX. However, the lower rate of CNS relapse and improved PFS and OS in patients who received consolidative autotransplant in our study suggests that optimizing frontline therapy to achieve better systemic disease control may be a more effective strategy to reduce the risk of CNS relapse than prophylactic HD-MTX alone. Disclosures Stewart: Teva: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Management and Outcomes of Testicular Lymphoma in the Rituximab Era at an Australian Tertiary Centre

INTRODUCTION Testicular lymphoma accounts for &amp;lt;5% of all testicular neoplasms and 1-2% of non-Hodgkin's lymphoma (NHL). Historically, outcomes for testicular lymphoma have generally been inferior to systemic diffuse large B cell lymphoma (DLBCL) with a higher incidence of central nervous system (CNS) relapse. Although intrathecal methotrexate is currently considered standard of care for testicular lymphoma, there has been significant debate about its efficacy in preventing CNS relapse. Due to the rarity of testicular lymphoma, prospective data in this field is lacking. Our study aims to examine treatment practices and outcomes for all newly diagnosed patients with testicular lymphoma in a large tertiary centre in Australia since the introduction of rituximab. METHODS We conducted a retrospective review of all patients diagnosed with primary testicular lymphoma (PTL) between 2003 and 2019 at the Princess Alexandra Hospital, Brisbane, Queensland, Australia (Human Research Ethics Approval: LNR/2019/QMS/56644). RESULTS During this period, 18 patients were diagnosed with PTL; all patients had DLBCL histology. The median follow-up period for living patients was 6.5 years (range 1.3-13.4 years). The median age was 61.3 years (interquartile range: 58.3 - 71.1 years). All patients were HIV negative. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) score of zero (n = 13; 72.2%) with no B symptoms (n = 14; 77.7%) and a normal LDH (n = 11; 61.1%). 50% of patients had Stage IV disease (Table 1). 17 patients (94.4%) underwent an orchidectomy (unilateral: 16, bilateral: 1) at diagnosis. Following on, as first-line systemic therapy, 14 patients (77.7%) received R-CHOP chemotherapy. Other regimens used were CHOP (n=1), modified HyperCVAD (n=1), R-HyperCVAD (n=1) and R-CVP (n=1). 17 patients (94.4%) received CNS prophylaxis with intrathecal chemotherapy; one patient declined intrathecal therapy and was given high dose intravenous methotrexate instead. 15 (83.3%) patients received loco-regional radiation therapy. Outcomes to first-line treatment were: 13 patients (72.2%) achieved complete remission (CR); one patient (5.5%) achieved partial remission (PR) (Deauville score 4 on interim PET assessment, prompting escalation to salvage therapy); three patients (16.6%) had progressive disease (and were subsequently managed with salvage chemotherapy) and one patient elected for palliation after a single cycle of R-CVP. Among the four patients who received salvage therapy, two patients (50%) achieved CR and two patients had progressive disease and were palliated. Among the 15 patients who achieved CR (n=13 R-CHOP; n=2 salvage chemotherapy), two patients relapsed, and both had CNS involvement (n=1 CNS only relapse; n=1 CNS and systemic relapse). Despite intrathecal prophylaxis, the CNS relapse rate was 12% (n=2/17). Of note, the patient who did not receive intrathecal chemotherapy remained in CR at the date of last follow-up. In total, there were seven deaths. The causes of death were: lymphoma (n=4), treatment-related mortality (n=2) and other (n=1; due to aspiration pneumonia after stroke). The 2-year and 5-year progression free survival (PFS) rates were 77.8% and 52.4%, respectively (Figure 1A). The 2-year and 5-year overall survival (OS) rates were 83.3% and 56.8%, respectively (Figure 1B). CONCLUSION With the practice of R-CHOP, intrathecal prophylaxis for CNS disease and loco-regional radiation therapy, our outcomes are comparable to the literature (5y OS ~50%). Despite intrathecal prophylaxis, our CNS relapse rate was 12%. Better strategies are required to improve the control of systemic disease and reduce the incidence of CNS relapse in patients with testicular lymphoma. Disclosures Mollee: Janssen:Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS/Celgene:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Takeda:Membership on an entity's Board of Directors or advisory committees;Pfizer:Membership on an entity's Board of Directors or advisory committees;Caelum:Membership on an entity's Board of Directors or advisory committees.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

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.

The Magnitude of Lactate Dehydrogenase Elevation As a Predictive Factor for Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma

Introduction: The incidence of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is approximately 5%. Although the introduction of rituximab for the treatment of DLBCL has reduced the risk of CNS relapse, the median overall survival of these patients remains only few months, emphasizing the need to accurately identify at-risk patients, screen for CNS disease, and develop effective therapeutic/prophylactic strategies. Aim: To identify risk factors for CNS relapse in patients with DLBCL. Methods: Retrospective analysis of patients with DLBCL diagnosed from January 2012 to December 2017 at a Cancer Institute. Patients with exclusive extranodal (EN) disease were excluded. Factors associated with CNS relapse were evaluated using Chi-square, Fisher's Exact Test, Mann-Withney U or T-Test, according to variable types and distributions. Survival was evaluated by Kaplan-Meier method and groups were compared by Log-rank test. Independent predictive factors were identified using Logistic Regression. A p value &lt; 0.05 was considered statistically significant. Results: Four hundred and seventy-nine patients were identified, 122 were excluded due to exclusive EN disease, and 357 patients were included in the study. With a median follow-up of 33 months, there were 10 (3%) CNS relapses. According to International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI), 5 (50%) of these patients were classified as high risk, 4 (40%) intermediate risk and 1 (10%) low risk. Patients who development CNS involvement were significantly younger (57 vs. 65 years, p=0.036), presented higher levels of lactate dehydrogenase (LDH) (median 738 vs. 282 U/L, p&lt;0.001) and lower levels of hemoglobin (median 10,3 vs. 12,1 g/dL, p=0.010) at diagnosis. No differences were found regarding to performance status, stage or number of EN areas. Two patients (18%) in the CNS relapse group had done CNS prophylaxis versus twenty two (6,3%) patients in the group without CNS relapse. In multivariate analysis, LDH &gt;600 was the only independent predictive factor (HR 15.3, CI 95% 3.5 - 65.8, p&lt;0.001). Overall survival in CNS relapse group was 22 months, versus not reached (p&lt;0.001). Conclusion: Although CNS-IPI is a robust model to estimate the risk of CNS relapse, it does not capture the full spectrum of those at high risk. Other clinical risk factors and biomarkers beyond this model might play an important role in this setting, such as the magnitude of LDH elevation Disclosures No relevant conflicts of interest to declare.

Abstract PD3-12: Central nervous system as first site of relapse in patients with HER2 positive early breast cancer treated in the BCIRG-006 trial

Abstract Introduction: Central Nervous System (CNS) metastases as first site of relapse is seen in 2-3% of patients with HER2+ early breast cancer (EBC) during or after treatment with adjuvant trastuzumab. Data about long-term follow-up outcomes in this population is scarce. Methodology: BCIRG-006 was designed to assess the efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of HER2+ EBC. 3,222 patients were randomized to standard AC-T or two trastuzumab-based regimens (AC-TH or TCH). Ten year follow-up outcomes were previously presented; we have used this data to assess the frequency and course of CNS relapses as first site of distant recurrence. DFS and OS in these patients were estimated and compared using the Kaplan-Meier method and Log-Rank test respectively. Univariate and multivariate analyses for DFS were conducted considering patient's age, nodal status, tumor size and estrogen receptor (ER) status in the primary tumor. Results: Of the 3,222 patients randomized, 575 (17.8%) experienced a distant relapse and in 17.5% of these (n=101) CNS was the first site of recurrence. With a median follow-up of 10.3 years, the frequency of CNS relapses did not differ when comparing the trastuzumab containing arms with the control arm (OR 0.86, 95% CI: 0.56-1.33; p= 0.519). No difference was observed either between AC-TH and TCH (OR 1.14, 95% CI: 0.67-1.94; p= 0.704). There were no differences in DFS (HR 1.21, 95% CI: 0.74-1.99; p= 0.621) nor in OS (HR 0.74, 95% CI: 0.43-1.27; p= 0.377) between AC-T, AC-TH and TCH arms. Positive axillary nodes (≥4 nodes) and ER negative status at baseline remained independent risk factors for CNS relapse after univariate and multivariate analysis (HR 0.60, 95% CI: 0.8-0.95; p= 0.007 for nodal status and HR 0.56, 95% CI: 0.37-0.85; p= 0.029 for ER status). Conclusion: Among the pivotal adjuvant trastuzumab trials, BCIRG-006 is the one with the longest median FUP in which data about CNS relapses has been presented. CNS relapse in patients in this trial was an infrequent event. Its frequency and outcomes were similar across the three treatment arms. Patients with ER negative and/or ≥ 4 positive nodes are at higher risk of CNS relapse irrespective of trastuzumab therapy and may be the patient population where research efforts should be focused. BC outcomes in patients with CNS metastases per treatment arm in the BCIRG-006 trial AC-T N=1073 n(%)AC-TH N=1074 n(%)TCH N=1075 n(%)p valueFrequency of CNS relapse37 (3.44%)30 (2.79%)34 (3.16%)0.519 ^Median DFS (months; 95% CI)23.8 (13.3-30.4)19.9 (16.6-25.1)19.9 (15.0-27.2)0.621 ⫲Median OS (months; 95% CI)42.5 (28.3-62.7)53.2 (31.2-103.6)30.3 (23.4-39.0)0.377 ⫲ ^ comparing control vs. trastuzumab-containing arm using Fisher's Exact test. ⫲ comparing control vs. trastuzumab-containing arms using Log Rank test. Citation Format: Chan A, Spera G, Machado A, Fung H, Bee V, Fresco R, Slamon DJ. Central nervous system as first site of relapse in patients with HER2 positive early breast cancer treated in the BCIRG-006 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-12.

Arsenic trioxide and all-trans retinoic acid (ATRA) treatment for acute promyelocytic leukemia in all risk groups: study protocol for a randomized controlled trial

BackgroundThe treatment of acute promyelocytic leukemia (APL) has been revolutionized in the past two decades by the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). It suggests that non-high-risk APL patients can be cured without chemotherapy. However, ATRA plus chemotherapy is still the standard therapy for the high-risk patients. Central nervous system (CNS) relapse remains a significant cause of treatment failure in high-risk patients. However, increasing the ATO concentration in cerebrospinal fluid (CSF) may reduce CNS relapse in high-risk patients. Mannitol can allow ATO to penetrate the blood-brain barrier (BBB) and reach therapeutically effective levels in the CSF. It is used for the treatment of CNS relapse in patients APL. We compare ATRA-ATO with ATRA-ATO plus chemotherapy in both high-risk and non-high-risk patients with APL.MethodsThis study was designed as a multicenter randomized controlled trial. Patients with APL were randomly assigned into two groups: the ATRA-ATO group (experimental group) and the ATRA-ATO plus chemotherapy group (control group). The experimental group receives therapy with ATRA-ATO for induction, consolidation and maintenance therapy. In the high-risk patients, mannitol will be used with ATO in the consolidation and maintenance therapy. Hydroxyurea will be used in patients who developed leukocytosis in the induction therapy. The control group receives therapy with ATRA-ATO plus chemotherapy for induction and consolidation therapy.DiscussionIn this study, a randomized clinical trial design is described. It aims to compare the efficacy of ATRA-ATO versus ATRA-ATO plus chemotherapy in all-risk patients with APL.Trial registrationChinese Clinical Trials Registry, ID: ChiCTR-IPR-15006821. Registered on 27 July 2015.

The risk of central nervous system relapses in patients with peripheral T-cell lymphoma.

We performed a retrospective analysis to identify risk factors and survival outcome for central nervous system (CNS) relapse of peripheral T-cell lymphoma (PTCL) by histologic type. Records of 600 PTCL patients diagnosed between 1999 and 2014 were analyzed including PTCL not otherwise specified (PTCL-NOS, 174 patients), angoimmunoblastic T-cell lymphoma (AITL, 144), ALK+anaplastic large cell lymphoma (ALCL, 74), ALK-ALCL (103), extranodal NK-cell lymphoma (ENKL, 54), or others (51). With a median follow up of 57 months, 13 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 ENKL) experienced CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.5% (95%CI: 0.7–2.8%) and 2.1% (95%CI: 1.1–3.5%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.4% in ALK+ALCL, 2.1% in ALK-ALCL and 3.7% in ENKL. Extranodal involvement >1 site was the only significant factor associated with higher chance of CNS relapse (HR: 4.9, 95%CI: 1.6–15.0, p = 0.005). Patients with ALK+ALCL who had extranodal involvement >1 (N = 19) had very high risk of CNS relapse with one year cumulative incidence of 17% (95%CI: 4%-37%), all occurring within six months after diagnosis. All patients with CNS relapse eventually died (median, 1.5 months; range, 0.1–10.1 months). CNS relapse in patients with PTCL is rare event but the risk varies by subtype. ALK+ALCL patients with extranodal involvement >1 site have a very high risk of early CNS relapse, and thus evaluation of CNS involvement at the time of diagnosis and possible CNS-directed prophylaxis may be considered.

Augmenting Total Body Irradiation with a Cranial Boost before Stem Cell Transplantation Protects Against Post-Transplant Central Nervous System Relapse in Acute Lymphoblastic Leukemia

The purpose of this study was to determine the effect of a pretransplant cranial boost (CB) on post-transplant central nervous system (CNS) relapse and survival in acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using a total body irradiation (TBI)-containing preparation regimen. Two hundred thirteen ALL patients were treated consecutively at our institution with allogeneic HSCT. Conditioning included TBI (1320 cGy in 8 fractions given twice daily) and cyclophosphamide (120 mg/kg) with or without fludarabine (75 mg/m2). Patients were divided into 4 groups based on history of CNS disease and whether a CB was given. Of the 160 patients with no history of CNS disease, none received a CB (CNS−/CB−). Of the 53 patients with prior CNS disease, 41 had not received prior cranial irradiation. Thirty of these 41 received a CB of 900 to 1000 cGy in 5 daily fractions (CNS+/CB+), whereas the other 11 did not receive a CB because of physician preference (CNS+/CB−). The remaining 12 patients with prior CNS involvement had previously received cranial irradiation and thus were not candidates for a CB (CNS + PriorRT). Two-year CNS relapse risk, overall survival (OS), and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Seven patients experienced post-transplant CNS relapse: 4 in the CNS−/CB− group, 2 in the CNS+/CB− group, and 1 in the CNS + PriorRT group. None of the 30 patients who received a CB relapsed in the CNS. Two-year CNS relapse risk was 0% in the CNS+/CB+ group compared with 21% (95% CI, 0% to 45%) in the CNS+/CB− group (P = .03). Two-year OS and DFS did not differ between the groups. In conclusion, among ALL patients with prior CNS leukemia, there was a trend toward a reduced risk of post-transplant CNS relapse in patients who received a CB. However, the addition of a CB did not appear to have an impact on OS or DFS.

Central nervous system disease in pediatric acute myeloid leukemia.

Central nervous system disease in pediatric acute myeloid leukemia.