CNS-International Prognostic Index Research Articles

Predicting central nervous system relapse in primary breast diffuse large B-cell lymphoma using the stage-modified IPI score: A retrospective cohort study

ObjectiveThe existing Central Nervous System-International Prognostic Index (CNS-IPI) provides insufficient guidance for predicting central nervous system (CNS) relapse in individuals with primary breast diffuse large B-cell lymphoma (DLBCL). This retrospective cohort study sought to examine the potential of the stage-modified IPI in predicting CNS relapse within this specific patient population. Patients and methodsWe examined the baseline characteristics of 76 consecutive patients diagnosed with primary breast DLBCL, calculating the stage-modified IPI score for each individual. Utilizing a competing risk regression (CRR) model, we conducted both univariate and multivariate analyses to explore the relationship between potential prognostic factors and the occurrence of CNS relapse. ResultsIn our cohort, the rates of CNS disease at 2 and 5 years since the diagnosis of primary breast DLBCL are 3.9% and 7.8%, respectively. Among patients experiencing CNS relapse, 80% presented with a parenchymal brain mass. Individuals with a high stage-modified IPI score (1–3 points) had a significantly higher incidence of CNS relapse (p = 0.031), a shorter time from the initial diagnosis of primary breast DLBCL to the first CNS relapse (p = 0.010), as well as relapse at any site (p = 0.012), compared to those with a low score (0 points). Univariate analysis identified stage (Hazard Ratio (HR): 4.098, p = 0.024), stage-modified IPI score (HR: 11.582, p = 0.012), and radiation therapy (HR: 5.784, p = 0.026) as significant risk factors. In multivariate analysis, in addition to radiation therapy (HR: 7.258, p = 0.012), the stage-modified IPI score (1–3 points versus 0 points) emerged as an independent and reliable predictor for CNS relapse (HR: 12.945, p = 0.016). ConclusionOur study underscores the significance of stage-modified IPI scores in predicting CNS relapse for patients with primary breast DLBCL. Validation of these findings through further research is essential, along with exploring potential prevention and intervention approaches.

Diffuse Large B-Cell Lymphoma CNS Relapse Prophylaxis with Intrathecal or High-Dose Intravenous Methotrexate

Introduction: Central nervous system (CNS) relapse is a relatively infrequent but often fatal complication of the most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL). Median overall survival (OS) after DLBCL relapse in the CNS is about 4 months. Despite identifying patients at high risk of developing CNS relapse using the CNS international prognostic index (CNS-IPI) score, it has been difficult to validate any specific strategy. Various chemotherapies and administration methods have been tested. Thus far, only the addition of rituximab to chemotherapy has yielded significant results. Our objective is to determine if administering prophylactic chemotherapy is efficacious in preventing DLBCL relapse in the CNS. Methodology: We collected retrospective data for patients with newly diagnosed DLBCL treated with rituximab and anthracycline-based chemotherapy from 2010 to 2020 in the Northwell Health system to determine the efficacy of CNS prophylaxis. Patients with CNS disease at diagnosis, primary testicular lymphoma, primary mediastinal large B-cell lymphoma, and HIV-associated lymphoma were excluded from this study. CNS prophylaxis was defined as receiving at least two doses of prophylactic chemotherapy, whether intravenous or intrathecal. Follow up for at least one year after diagnosis was required for inclusion. Overall survival (OS) was defined as the time difference between the date of definitive diagnosis to death or last date of contact. Other potential prognostic factors including double hit status and cell of origin, germinal center B-cell (GCB) vs. non-germinal center B-cell (non-GCB), were also evaluated. Pearson's chi-square analysis was used to compare the rate of DLBCL relapse in the CNS based on whether patients received CNS prophylaxis. Low risk was defined as CNS-IPI score 0 to 3 and high risk as CNS-IPI score 4 to 6. Kaplan-Meier analysis with log-rank (Mantel-Cox) testing was used to determine if any significant OS benefit was observed for the low and high-risk groups based on CNS-IPI score. Results: Of the 437 charts reviewed, 127 were eligible for inclusion. Most patients were male (56.7%). Median age was 69 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 1. Most cases were non-GCB (44.9%, as 25% of cases were missing data) and not double hit (85%). Of the 35 patients at high risk for CNS relapse, 27 (77%) received prophylaxis. Intrathecal methotrexate (IT MTX) was given to 26 patients (96%) and high dose intravenous methotrexate (HD MTX) was given to 1 patient. CNS relapse occurred in 6 patients, of which 5 had a low-risk CNS-IPI score. One of the five patients in the low-risk group and the one patient in the high-risk group that had CNS relapse received prophylaxis. No significant difference in overall relapse rates were observed based on whether prophylaxis was given, X 2 (1, N = 127) = 0.30, p = .59. Kaplan-Meier analysis showed no difference in OS after stratification of patients by CNS-IPI score into the high-risk ( p = .50) and low-risk ( p = .24) groups. HD MTX was not administered frequently enough to determine its efficacy. Neither cell of origin (X 2 (1, N = 95) = 2.95, p = .086) nor double hit status (X 2 (1, N = 127) = 1.512, p = .22) had any significant effect on OS. Conclusions: We did not observe any clear benefit for administering IT MTX to prevent DLBCL relapse in the CNS. Most of the CNS relapse events occurred in the low-risk group, even though 8 patients in the high-risk group did not receive any CNS prophylaxis. This study did not have sufficient power to make a definitive conclusion. As CNS relapse is a rare event, a much larger sample size is required to determine the true efficacy of CNS prophylaxis. Non-GCB cell origin and positive double hit status are not included in the CNS-IPI score but their potential association with risk of DLBCL relapse in the CNS is understudied. Future studies should build upon these findings.

Differences in Characteristics and Outcomes of Central Nervous System Versus Systemic Relapse after First Line Therapy in DLBCL Patients: A Veterans Health Administration (VHA) Study

Introduction Around 30%-40% of patients with diffuse large B-cell lymphoma (DLBCL) will experience disease progression or relapse after first line (1L) chemoimmunotherapy with most patients relapsing within the first 12 months. Relapse may be systemic, isolated to the central nervous system (CNS), or both with CNS relapse occurring in 2-5% of patients. The purpose of this study is to evaluate the characteristics and outcome differences of Veterans diagnosed with DLBCL within the VHA who experienced systemic relapse, isolated CNS relapse or both. Methods A retrospective chart review of 6,266 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2021 was performed by trained abstractors. Patients diagnosed with DLBCL were included. Patients were excluded if they had a diagnosis other than DLBCL, had incomplete records or were diagnosed and treated outside the VHA, had baseline CNS involvement, did not receive treatment, or died before receiving a scan to assess response to 1L therapy. Outcomes including response to 1L treatment, time to relapse and overall survival (OS) defined as time from diagnosis to death were evaluated. Early relapse was defined as having primary refractory disease (stable or progressive disease (SD or PD) as best response to 1L therapy) or disease progression in ≤12 months in patients achieving a complete response (CR) or partial response (PR). Late relapse was defined as disease progression >12 months. Results A total of 2,658 patients met inclusion criteria for analysis with 97% of the population being male, 65% with stage III-IV disease, and 90% with an ECOG performance status of 0-2. Of the total cohort, 74% of patients received a CHOP-based regimen, 74% had an intermediate- or high-risk CNS International Prognostic Index (CNS-IPI) score, 81% did not receive a baseline diagnostic lumbar puncture (LP) and 86% did not receive any CNS prophylaxis. The median follow-up time for subjects in this study was 54 months. Relapse occurred in 29% of the total cohort with systemic only relapse occurring in 27% of patients, isolated CNS in 1%, and CNS + systemic in 1%. Of the 761 patients who experienced relapse, 77% had an early relapse with a median time to relapse of 4.4 months (IQR 2.8-6.7). For the 23% of patients with late relapse, the median time to relapse was 25 months (IQR 18-41). The characteristics of patients who experienced relapse were similar regardless of type of relapse or time to relapse (table 1). A higher percentage of patients with early relapse had a high-risk CNS-IPI score, bone marrow involvement, and renal or adrenal involvement. Autologous stem cell transplant was performed in 11% of patients, predominately in those with systemic only relapse. The median OS (mOS) was similar between relapse types with systemic, isolated CNS, and CNS + systemic having a mOS of 23.5 months (95% CI: 21-27), 30.6 months (95% CI: 15-71), and 29.6 months (95% CI: 20-45), respectively (p=0.75). Figure 1 describes mOS by relapse type and time to relapse. Overall, patients with early relapse had a poorer prognosis regardless of relapse type with a mOS of 17 months (95% CI: 15-18) compared to a mOS of 68 months (95% CI: 59-88) in patients with late relapse (p<0.001). The 24-month survival rate of those with early versus late relapse was 37% and 78%, respectively. Patients with a late systemic relapse had the longest mOS of 74 months (95% CI: 60-90). Conclusion This is the largest study reporting outcomes of Veterans who experienced relapsed DLBCL within the VHA. Although earlier data suggests specific features may correlate with early versus late relapse, all characteristics were similar in our population across relapse types regardless of time to relapse. The rate of relapse in the total cohort and the rates of CNS relapse were lower than previously reported, adding to recent data suggesting the use of CNS prophylaxis may have limited benefit. Patients with early relapse performed poorly and may benefit from novel therapies including chimeric antigen receptor T-cell therapy, which could not be evaluated with this study. The retrospective nature of this analysis, and a predominately male veteran population may limit external application.

Phase II, Single-Center, Prospective Study of Intrathecal Thiotepa for the Prophylaxis of Secondary Central Nervous System Involvement in Highly Aggressive B-Cell Lymphoma

Background Central nervous system (CNS) recurrence of systemic diffuse large B cell lymphoma (DLBCL) is a well-recognized and almost uniformly fatal complication that tends to occur within 2 years of initiating treatment. The probability of CNS relapse in DLBCL ranges from 4 to 7% overall but is increased to 20% in certain subgroups. Evidence supporting the use of intravenous methotrexate (MTX) or arabinoside (AraC) in high-risk patients is growing, however, the use of other agents remains to be defined. Thiotepa (TT) is a polyfunctional alkylating agent first developed in the 1950s. Both thiotepa and its metabolite tepa demonstrate good CNS bioavailability, making thiotepa a useful adjunctive chemotherapy for primary and secondary CNS lymphoma, particularly in the context of hematopoietic stem cell transplant (HSCT). Herein, we conduct this prospective trial to evaluate the efficacy and safety of prophylactic intrathecal thiotepa for the prevention of secondary CNS involvement in patients with DLBCL. Methods Patients The primary end point is 2-year cumulative incidence of CNS. The secondary end points are 2-year progression free survival (PFS), 2-year overall survival (OS), and safety. The main inclusion criteria include: adults patients ≥18 years old; histopathological confirmed DLBCL without previous antitumor therapy; high-risk CNS involvement (one of the following): primary breast or testicular lymphoma, involvement of any of the following organs: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space or uterus; CNS International Prognostic Index (CNS-IPI)≥4; dual protein expression (DE) or double/triple hit (DH/TH) lymphoma. The main exclusion criteria include: Burkitt lymphoma, primary CNS lymphoma, or large B cell lymphoma transformed from indolent lymphoma; the presence of parenchymal or meningeal lymphoma; history of whole brain radiotherapy or craniospinal cord irradiation; obstructive hydrocephalus patients requiring neurosurgical intervention. Treatment protocol The systemic chemotherapy regimen is determined by investigator. All patients are need to receive IT thiotepa 10 mg and dexamethasone 5 mg on day 1 of each cycle of chemotherapy for at least 4 cycles. All patients are asked to lie flat for 4 to 6 hours after the lumbar puncture. Follow-up Routine biochemical and cytological analysis of cerebrospinal fluid is performed for each cycle. Imaging examination, such as brain magnetic resonance imaging (MRI) and body computed tomography (CT), is repeated every 2 cycles of chemotherapy, then every 3 months during follow-up. Results From February 2022 to June, 2023, 27 patients (female 14, male 13) received IT thiotepa. The clinical characteristics are shown in Table 1. The median age was 66 years old (range: 46-74). As first-line chemotherapy, 15 (55.6%) patients received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP), 5 (18.5%) patients received RCHOP+BTK inhibitor, 3 (11.1%) patients received BTK inhibitor, lenalidomide with rituximab (ZR2) followed by RCHOP, and 4 (14.8%) patients received RCHOP with intravenous MTX. Thirteen (48.1%) patients had IPI score 4-6 and 17 (63%) patients had DE of c-myc and bcl-2. All patients received fluorescence in situ hybridization (FISH) cytogenetic testing for C-MYC, BCL-2, BCL-6 and TP53. Four (14.8%) patients had TP53 deletion, and 11 (40.7%) patients had sole rearrangement of C-MYC or BCL-2 or BCL-6, but no one were diagnosed with DH/TH lymphoma. All patient have received IT thiotepa for at least once, and 12 (44.4%) patients completed 4-6 cycles of IT, 84 cycles totally. IT thiotepa was a safe measure, for no one experienced post-LP headache, local infection, bleeding, or cerebral herniation. But there were 4 patients had five times of inability to identify direction and slow speech response. They could recover normally the next day without any treatment. Although the follow-up period was short, no patient developed CNS involvement. Conclusion Prophylactic intrathecal thiotepa is an effective and side-effects manageable measure for preventing secondary central nervous system involvement in high-risk DLBCL. Longer follow-up and larger-scale prospective trial is needed to testify this measure.

High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma.

CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Model for Predicting Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Discussion of Prophylaxis Measures

Relapse of the central nervous system (CNS) is a rare but fatal complication in diffuse large B-cell lymphoma (DLBCL). The purpose of this study is to learn how to identify high-risk patients and take effective preventive measures. We retrospectively analyzed 1,290 adult patients with DLBCL at Peking University Cancer Hospital and Shanxi Bethune Hospital between 2010 and 2020. There were 55 patients with CNS relapse who had a median follow-up of 5 years. The risk of CNS relapse was 1.58% in the low-risk group, 5.66% in the moderate-risk group, and 11.67% in the high-risk group based on CNS International Prognostic Index (CNS-IPI). We found that CNS-IPI and testicular involvement were risk factors for CNS relapse, with OR 1.913 (95% CI: 1.036∼3.531; P=0.038) vs OR 3.526 (95% CI: 1.335∼9.313; P=0.011), respectively. Intrathecal MTX and/or cytarabine prophylaxis was used in 166 patients (13.94%), intravenous high-dose methotrexate (HD-MTX) prophylaxis in 8 patients (0.67%), and intrathecal plus intravenous prophylaxis in 15 patients (1.26%). There was no significant difference in CNS relapse risk between IT, HD-MTX, and no prophylaxis recipients (12.7% vs 0% vs 23.6%, respectively, P= 0.170). The risk of CNS relapse was similar whether or not patients accepted prophylaxis (5-year risk 4.1% vs 2.2%, P=0.140). CNS relapse is associated with high risk CNS-IPI and testicular involvement. Therefore, it is necessary to pursue novel prophylactic strategies for CNS relapse.

A survey evaluating hematology physicians’ perspectives on central nervous system prophylaxis.

Central nervous system (CNS) prophylactic options for diffuse large B-cell lymphoma (DLBCL) are administered differently in most centers. Unfortunately, there is still not a consensus on which patients, which regimen, for how many cycles, and when prophylaxis should be administered. Thus, this remains an unmet clinical need. We administered a survey study under the Lymphoma Scientific Subcommittee of the Turkish Society of Haematology. The questions were directed to hematologists through the monkey survey system. The CNS International Prognostic Index score is a factor that clinicians frequently use when deciding on prophylaxis and is considered reliable. Although the perspective on anatomical risk factors is similar to that reported in the literature, breast involvement is still considered a critical risk factor in Turkey. Participants considered double or triple hit and double/triple expressor lymphoma as significant risk factors. Various methods have been used to demonstrate CNS relapses. Intrathecal prophylaxis is the preferred method. There are diverse methodological and technical ideas. The controversial results reported in the literature on the effectiveness of CNS prophylaxis may explain this finding. Although CNS prophylactic methods for patients with DLBCL are still controversial, the effect of secondary CNS involvement on survival is inevitable. Standard practices followed by national guidelines may be effective in reducing the variety of application methods and creating homogeneous results for efficacy and survival follow-up studies.

Application of the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice: a retrospective analysis apart from the clinical trial at two centers in Brazil

IntroductionThe diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) and, despite all the progress in this field, central nervous system infiltration (CNSi) still occurs at an incidence of 2–10%. The objective of the present study was to evaluate the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice regarding the reproducibility in a heterogeneous cohort apart from a clinical trial. MethodsPrimary DLBCL patients were eligible for this study, between January 2007 and January 2017. All patients were treated with rituximab-based chemotherapy, mostly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The CNSi was diagnosed by liquor (positive cytology and/or immunophenotype), computerized tomography, magnetic resonance image and/or fluorodeoxy-glucose-positron emission tomography, requested only in symptomatic patients when the CNSi was clinically suspected. The CNS-IPI was assessed by graphical comparison and calibration. ResultsAfter applying the inclusion/exclusion criteria, 322 patients were available for the analysis. The median follow-up was 60 months and the median age was 58 years. Seven patients experienced CNSi, characterizing an incidence of 2.17% (7/322). Comparing groups of patients with and without CNSi, we observed that the lactate dehydrogenase (LDH), number of extranodal sites, IPI, kidney/adrenal and absence of complete response were statistically different. The CNS-IPI model stratified patients in a three-risk group model as low-, intermediate- and high-risk. In our cohort, using the same stratification, we obtained an equivalent the 2-year rate of CNS relapse of 0.0%, 0.8% and 13.8%, respectively. ConclusionOur study reinforces the reproducibility of the CNS-IPI, specifically apart from clinical trials, and suggests the CNS-IPI score as a tool to guide therapy.

Risk assessment and prophylactic treatment strategies for central nervous system relapse of diffuse large B-cell lymphoma

Rituximab treatment significantly improved the outcomes of diffuse large B-cell lymphoma (DLBCL). A central nervous system (CNS) relapse remains a serious and fatal event for patients with DLBCL; therefore, the clinical question of the optimal treatment regimen for reducing the risk of CNS relapse remains unknown. The CNS-International Prognostic Index was identified as a predictive model for CNS relapse. No factors can completely predict CNS relapse although several reports regarding high-risk factors for CNS relapse have been reported. In practice, intrathecal methotrexate (MTX) and high-dose MTX therapy have been used for CNS prophylaxis. Unfortunately, evidence of the optimal therapy for CNS prophylaxis in patients with DLBCL remains lacking. This study aimed to review CNS relapse assessment and discuss study results with clinical impacts on CNS prophylaxis treatment strategies in DLBCL.

CNS prophylaxis in aggressive B-cell lymphoma

The prevention of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) continues to be one of the most contentious areas of lymphoma management. Outcomes for patients with secondary CNS lymphoma (SCNSL) have historically been very poor. However, in recent years improved responses have been reported with intensive immunochemotherapy approaches, and there is a growing interest in potential novel/cellular therapies. Traditional methods for selecting patients for CNS prophylaxis, including the CNS International Prognostic Index, are hampered by a lack of specificity, and there is accumulating evidence to question the efficacy of widely employed prophylactic interventions, including intrathecal and high-dose methotrexate (HD-MTX). Given the potential toxicity of HD-MTX in particular and the ongoing need to prioritize systemic disease control in high-risk patients, there is an urgent need to develop more robust methods for identifying patients at highest risk of CNS relapse, as well as investigating prophylactic interventions with greater efficacy. Here we review new evidence in this field from the last 5 years, focusing on the potential use of molecular diagnostics to improve the identification of high-risk patients, recent large data sets questioning the efficacy of HD-MTX, and the current approach to management of patients with SCNSL. We provide a suggested algorithm for approaching this very challenging clinical scenario.

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

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

Risk of Central Nervous System Involvement in High-Grade B-Cell Lymphoma with MYC and BCL2 Rearrangements: Analysis of a Population-Based Cohort with Routine Fluorescence in Situ Hybridization Testing in British Columbia

Introduction: Secondary central nervous system (CNS) involvement in aggressive B-cell lymphoma (SCNSL) is associated with dismal outcomes, highlighting the need to identify at-risk patients (pts). High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) is a cytogenetically-defined entity associated with poor outcomes, partly attributed to a high rate of SCNSL. However, historic estimates of SCNSL vary widely across studies, confounded by selective fluorescence in situ hybridization (FISH) testing. The CNS International Prognostic Index (CNS-IPI) is a robust model used to estimate the risk of CNS relapse in de novo diffuse large B-cell lymphoma (DLBCL). However, it has not yet been applied to HGBCL-DH-BCL2. Here we performed a population-based analysis to determine the rates of SCNSL in HGBCL-DH-BCL2 identified by non-selective FISH testing in British Columbia (BC) stratified by the CNS-IPI. Methods: All HGBCL-DH-BCL2 pts diagnosed in BC since the introduction of routine FISH testing in all de novo aggressive B-cell lymphoma biopsies and provincial guidelines implementing treatment with dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and rituximab (DA-EPOCH-R) with intrathecal methotrexate (IT-MTX) CNS prophylaxis for appropriately fit HGBCL-DH-BCL2 pts aged ≤75 years (y) (DA-EPOCH-R era: 2015-2020) were included. The cohort was supplemented with HGBCL-DH-BCL2 pts from a historic province-wide cohort of aggressive B-cell lymphoma with FISH performed on all evaluable diagnostic biopsies in a research setting (R-CHOP era: 2005-2010). Time to CNS relapse was measured from the date of diagnosis accounting for the competing risk of death from other causes. Biopsies underwent institutional pathology review for consensus assignment to DLBCL or high-grade (HG) morphology. Results: 191 pts with HGBCL-DH-BCL2 were identified (DA-EPOCH-R era n =125, R-CHOP era n = 66). Median (interquartile range) follow up of alive pts was 3.3y (2.3-4.7y) in the DA-EPOCH-R era and 11.9y (11.4-13.2y) in the R-CHOP era. Baseline characteristics are shown in Table 1. Five (3%) pts had CNS involvement at diagnosis (4 DLBCL and 1 HG morphology). Excluding pts with CNS involvement at diagnosis, the 2y cumulative risk of CNS relapse in all HGBCL-DH-BCL2 pts treated with curative intent was 6% (Figure 1), and estimates were 5.5% and 11% in DLBCL and HG morphologies, respectively (p= 0.2). Leptomeningeal involvement was found in 8/10 (80%) of CNS relapses. High CNS-IPI (> 4) was observed in 44% of pts and was associated with a significantly higher rate of CNS relapse (12% high vs < 5% low/intermediate (int) CNS-IPI, p = 0.04). CNS-IPI was also predictive in those with DLBCL morphology (p=0.02). Limited by a small number of events, of the 3/27 pts with HG morphology that developed CNS relapse, 2 had high CNS-IPI and 1 had int CNS-IPI. CNS prophylaxis did not impact CNS relapse risk in either the entire group or when restricting the analysis to pts with high CNS-IPI. CNS relapse was similar in those treated with R-CHOP or DA-EPOCH-R (p = 0.6). To minimize potential bias introduced by treatment selection, we performed an era-on-era comparison in pts aged ≤75y at diagnosis to determine whether the introduction of DA-EPOCH-R with integrated IT-MTX, was associated with a decrease in CNS relapse risk. 79% of pts received R-CHOP in the R-CHOP era whereas 66% of pts received DA-EPOCH-R in the DA-EPOCH-R era. There were no significant differences in CNS-IPI distribution or morphology proportions between the two eras. Competing risk regression analysis found no significant difference in CNS relapse risk between the two eras after adjusting for morphology (hazard ratio and 95% confidence interval of DA-EPOCH-R vs R-CHOP era: 0.47 (0.12-1.84), p = 0.3). Conclusions: In the largest series to date examining SCNSL in HGBCL-DH-BCL2 identified through routine FISH testing, SCNSL rates are considerably lower than previously reported. For those with CNS relapse, leptomeningeal involvement was frequent. The CNS-IPI remains predictive of SCNSL in this entity, suggesting that the overall risk is driven by additional clinical risk factors. Further, as the CNS relapse risk is <5% in pts with low/int CNS-IPI, CNS-directed procedures and prophylaxis may not be required in this subset. Larger series are required to examine the impact of treatment regimen on CNS relapse risk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Central Nervous System (CNS) Involvement, Prophylaxis, and Recurrence Risk in a Multi-Institutional Series

Background: HGBL, NOS encompasses aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology which are otherwise unclassifiable. We have previously described characteristics and outcomes of HGBL, NOS treated in 20 academic centers across the United States (Zayac et al, ASH 2021). Here, we report the CNS-related outcomes from this multi-institutional dataset. Methods: We collected retrospective data on adult patients (pts) with HGBL, NOS diagnosed by academic hematopathologists in 2017-2021, excluding cases with unknown MYC rearrangement (MYC-R) status, double/triple-hit lymphomas, any diffuse large B-cell lymphoma (DLBCL, NOS) or other specified entities. Ten participating institutions conducted formal local pathology review; immunohistochemistry and cytogenetics were performed locally. Outcomes included progression-free (PFS) and overall survival (OS), and cumulative incidence function (CIF) of CNS recurrence (CNSrec accounting for competing risk of systemic relapse), estimated with 95% confidence intervals (CI). Results: Among 160 pts (median age 64 years, 68% male, 82% germinal center B-cell [GCB] tumors), the CNS International Prognostic Index (IPI) was low in 21%, intermediate (int) in 44%, high in 30%, and missing in 5%. Baseline CNS involvement (CNSinv) was present in 11 pts (7%), including leptomeningeal in 6, parenchymal in 4, and both in 1 case. Only 2 factors were significantly associated with CNSinv: testis or female pelvis involvement (odds ratio [OR]=6.40; 95%CI: 1.09-37.7) and MYC-R (OR=3.51; 95%CI: 1.01-12.2). Pts with CNSinv were treated with R-CODOX-M/IVAC (27%), R-EPOCH (18%), R-hyperCVAD (18%), or R-CHOP + high-dose methotrexate (HDMTX, 18%). CNSinv was associated with numerically lower complete response rate (55% with vs 70% without, P=.32), PFS (3-year PFS: 53% and 55%, respectively; log-rank P=.45), and OS (2-year OS, 51% and 69%, respectively, P=.54). Data on CNS-directed prophylaxis (ppx) were available for 139 pts without baseline CNSinv. CNS ppx was administered to 48%, including intrathecal (IT)-only in 29% (median 4 doses, range 1-10), intravenous HDMTX in 7% (median 2 doses, range 1-5), and both IT and HDMTX in 12%. Among 59 recurrences after initial therapy, 16 involved the CNS: 7 leptomeningeal-only, 4 parenchymal-only, 4 involving both compartments, and 1 unspecified. Median time to CNSrec was 4.4 months (95% CI: 2.6-9.0), not significantly different from systemic recurrences (median 5.3 months, P=0.58). Median OS after CNSrec was 5.3 months (95% CI: 2.9-13.6), also not significantly different from systemic recurrences (median 7.7 months, P=.18). For all 160 pts, the CIF of CNSrec at 3 years was 11.7% (95% CI: 6.9-17.9), but pts with baseline CNSinv were at highest risk (CIF=57.6% vs. 8.0% for others; P<0.001 on Gray's test) and were excluded from further analysis of risk factors. Among other CNSrec events, 4/10 (40%) were in non-GCB HGBL, 5 of 6 tested (83%) had dual MYC/BCL2 expression (DEL), and 4 of 4 tested carried a TP53 alteration. CNSrec was associated with high-int/high IPI (CIF=13.4% vs. 1.7% for low/int; P=.020) but not CNS-IPI (7.5% high vs. 6.8% low/int; P=.85). Other significant risk factors for CNSrec included: involvement of bone marrow (CIF=20.5% vs. 4.5% for none, P=.002) or blood (47.2% vs. 5.3% for none, P<.001), non-GCB (20.5% vs. 5.9% for GCB, P=.021, Fig. A), DEL (10.8% vs. 1.5% for others, P=.019), and CD5+ HGBL (27.5% vs. 6.0% for CD5-, P=.013). The risk of subsequent CNSrec did not differ according to first-line therapy, including comparing R-CHOP (CIF=10.2%) vs. more intensive regimens (7.0%, P=0.77), or R-CHOP vs. R-EPOCH specifically (CIF=6.7%, P=.74). We also observed no difference in CNSrec after receipt of any form of CNS ppx (P=.59; Fig. B), or specifically HDMTX (P=.18) or IT methotrexate MTX (P=.94). Conclusions: In HGBL, NOS baseline CNSinv is uncommon, but highly prognostic for future CNSrec. Both CNS and systemic recurrences portend poor prognosis. CNS-IPI may not predict higher risk of CNSrec in HGBL, NOS. Although our study is limited by the sample size in this rare and heterogeneous disease, the CNSrec was higher in pts with blood/marrow involvement or the non-GCB or MYC/BCL2 DEL HGBL. Because the >10% risk of CNSrec is not mitigated by standard CNSppx modalities, HGBL, NOS should be included in trials of novel CNSppx approaches along with high-risk DLBCL or double-hit lymphoma. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ2 test to compare the two subgroups, the Kaplan-Meier survival method with log-rank test to calculate and compare the survival rates, and regression analysis to determine the risk factors for CNS relapse and death. The study included 358 patients (n=32 with HDMTX CNS prophylaxis and n=326 without CNS prophylaxis). Patients in the CNS prophylaxis group had a significantly higher CNS relapse rate than those in the non-CNS prophylaxis group (12.5% vs. 1.8%; P=0.008). Patients who received CNS prophylaxis were younger and had an advanced stage of disease, with extranodal involvement and a high serum lactate dehydrogenase level at presentation. CNS prophylaxis was significantly associated with CNS relapse, while relapsed disease was associated with the risk of death (all P<0.05). In conclusion, the present study found that patients with intermediate and high CNS-IPI who received HDMTX CNS prophylaxis did not have fewer CNS relapses; however, those without CNS relapse had higher survival rates. In addition to CNS prophylaxis, Stage of DLBCL and IPI were significantly associated with CNS relapse. Future randomized control trials are needed to evaluate the efficacy of HDMTX CNS prophylaxis in patients with DLBCL.

ABCL-455 Multicenter Retrospective Analysis of Single-Route Prophylaxis in Aggressive B-Cell Lymphomas

Relapses involving the central nervous system (CNS) are uncommon among patients with diffuse large B-cell lymphoma (DLBCL) but carry very poor prognosis. Prophylaxis is heterogeneously prescribed around the time of frontline therapy, with no clear standard of care in terms of recipient selection or route of administration. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline chemoimmunotherapy between 2013-2019. Primary endpoint was CNS relapse rate. Secondary endpoints included PFS, OS, and treatment-related toxicities following frontline and salvage therapies. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.40), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. Median OS following CNS relapse was 6.2 months (IQR 2.9-24.6) and was significantly shorter among patients achieving less than CR to first salvage therapy (HR 3.39, 95% CI 1.76-6.54, p=0.0003). Additional analyses of outcomes following CNS relapse will be presented. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated; treatments following CNS relapse were heterogeneous, with poor outcomes for the vast majority of patients. Reconsideration of SCNSL prophylaxis and treatment strategies is of critical need.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients

AbstractProphylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Поражение центральной нервной системы при диффузной В-клеточной крупноклеточной лимфоме

Introduction. Current approaches used to predict the recurrence of diffuse large B-cell lymphoma (DLBCL) with involvement of the central nervous system (CNS) need to be improved. Data from national studies on the incidence and clinical and laboratory characteristics of primary CNS DLBCL and secondary CNS involvement in systemic DLBCL are fragmentary and do not allow us to assess the overall picture. Aim. An assessment on the territory of the Siberian metropolis of data on the incidence and clinical and laboratory characteristics of DLBCL patients with primary CNS lymphoma (PCNSL) and secondary CNS involvement, as well as validation of the CNS-International Prognostic Index (CNS-IPI) on this sample. Materials and methods. The study group consisted of 47 patients with PCNSL and 35 with secondary CNS involvement in systemic DLBCL, the comparison group consisted of 202 patients with DLBCL without CNS involvement. Results. All patients with secondary CNS involvement in DLBCL belonged to the medium and high risk groups (p = 0.007) according to the CNS-IPI, which confirms its prognostic value. The risk factors for secondary CNS involvement in DLBCL were ECOG performance status ≥ 2, HIV infection, age over 60 years, a history of chronic kidney disease, ≥ 2 extranodal sites, and high expression of Ki-67 (&gt;75% positive tumor cells), non-GCB subtype of lymphoma, and presence of anemia. When assessing the characteristics of the clinical course of the disease, a number of peculiarities of the primary and secondary CNS involvement in DLBCL were identified. In particular, in terms of overall survival, the PCNSL group had a more favorable prognosis (p = 0.051). Conclusion. The results of the study confirm the importance of the CNS-IPI as a tool of a hematologist to determine the group of patients needing prevention of recurrence of DLBCL in the CNS. New data on a higher incidence of chronic kidney disease, arterial hypertension and thyroid disorders in the group of patients with PCNSL require further study.

Characteristics of Patients with Central Nervous System Relapse in Veterans with Diffuse Large B-Cell Lymphoma within the Veterans Health Administration

IntroductionAround 2-5% of patients with diffuse large B-cell lymphoma (DLBCL) will experience central nervous system (CNS) relapse resulting in a poor prognosis. The Central Nervous System International Prognostic Index (CNS-IPI) is a validated risk model used to help identify DLBCL patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy who are at risk for CNS relapse. CNS prophylaxis is recommended for those with high-risk CNS-IPI scores; however, the role of CNS prophylaxis has been called into question given recent large datasets showing no impact on CNS relapse. The purpose of this study is to evaluate the characteristics of Veterans who experienced CNS relapse within the Veterans Healthcare Administration (VHA) and to validate the CNS-IPI risk stratification within this population.MethodsTrained abstractors performed a retrospective chart review of 3287 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2017. Figure 1 describes the selection of the study cohort. We evaluated baseline patient and disease characteristics including CNS-IPI score, performance of diagnostic lumbar puncture (LP) and first-line chemotherapy regimen. Pathology reports to identify cell of origin (COO), and additional risk factors for CNS relapse present at the time of original diagnosis including HIV associated lymphoma, testicular lymphoma, and high-grade B-cell lymphomas (HGBLs) defined as double or triple-hit DLBCL were evaluated. We also assessed response to first-line treatment, type of CNS prophylaxis used, including number of doses, and time to CNS relapse.ResultsA total of 1621 patients met criteria for analysis. Patients were predominately male, white, had a median age of 67, and presented with advanced disease (Table 1). At the time of diagnosis, 81% of the cohort had an ECOG performance status of 0-2, 73% received a CHOP based regimen, and 52% were designated as having a high-risk CNS-IPI score. Patients were about twice as likely to have a germinal center B-cell (GCB) COO rather than activated B-cell (ABC), but the COO was unavailable for almost 30% of the cohort. About 6% of the patients were known to have HGBLs, but the “hit status” of around 65% of the patients was unknown. Diagnostic LP was performed in 10%, 14%, and 19% of patients in the low-, intermediate-, and high-risk CNS-IPI groups respectively.The median follow-up time for the subjects in the study was 44 months. The low-risk group (12% of all patients analyzed), the intermediate-risk group (36%) and the high-risk group (52%) showed rates of CNS relapse of 1% (with a 95% CI: 0% to 2.4%), 2.4% (CI: 1.2% to 3.7%), and 2.4% (CI: 1.3% to 3.4%) respectively with no statistically significant difference across the risk groups (p=0.30). In patients with CNS relapse, only 35% of patients had a diagnostic LP. More than 90% of patients deemed high-risk for CNS relapse did not receive CNS prophylaxis. Among the 36 patients with CNS relapse, only 3 were given CNS prophylaxis at baseline (Table 2). Of the patients with CNS relapse, 75% of patients achieved a complete response with initial treatment. When categorized by the CNS-IPI score, there is no significant difference between intermediate- and high-risk based on type of CNS relapse, type of CNS prophylaxis used, response to first-line therapy, median time to relapse, median survival time, or median time from relapse to death. Those with CNS relapse had a shorter survival time compared to those with systemic relapse or no relapse (Figure 2).ConclusionsWhen compared to the previously validated CNS-IPI study, there were fewer instances of CNS relapse in our patient population in the intermediate- and high-risk groups, however, about a quarter of the patients in these groups did not receive CHOP based therapy. Although there is published data demonstrating COO and HGBLs as contributing factors to CNS relapse, our data did not show any statistically significant difference in relapse rates. Potential limitations include that the study is a retrospective chart review of a predominately male veteran population. Our data suggests the CNS-IPI may not identify patients at risk for CNS relapse with adequate accuracy. [Display omitted] DisclosuresNooruddin: AstraZeneca: Research Funding.

High Frequency of CNS Involvement in Transformed Waldenström Macroglobulinemia

INTRODUCTIONCentral nervous system (CNS) relapse is a challenging situation in diffuse large B-cell lymphoma (DLBCL). High CNS-International Prognostic Index (IPI), activated B-cell (ABC) subtype and MYD88 L265P mutation, features often found in transformed Waldenström macroglobulinemia (WM), are associated with a higher risk for developing CNS relapse. This study was aimed to describe CNS involvement in a large cohort of transformed WM.METHODSThis international multicenter retrospective study included patients with a diagnosis of WM and a concurrent or sequential histological diagnosis of DLBCL. CNS disease was diagnosed by detection of DLBCL cells in the cerebrospinal fluid and/or by brain biopsy. Patients with CNS involvement by lymphoplasmacytic cells (Bing-Neel syndrome) were excluded. Of 254 identified patients with a diagnosis of histological transformation (HT) between 1988 and 2020, 19 were excluded due to lack of data on extranodal involvement. The first part of the analysis focused on baseline CNS involvement. Clinicobiological characteristics were compared between groups using Chi-square or Fisher's exact tests or Mann Whitney tests as appropriate. We analyzed CNS recurrence in the second part of the study. Forty-eight additional patients were excluded due to baseline CNS involvement (n = 25), absence of treatment at HT (n = 14) and lack of details on follow-up (n = 9). Cumulative incidence of CNS relapse was analyzed using competing-risk models that accounted for other events like systemic relapse or death from any cause, reporting sub-hazard ratio (SHR).RESULTSBaseline CNS involvement was present in 25 patients (11%) with transformed WM, including 10 (4%) with parenchymal disease, 10 with leptomeningeal, 4 (2%) with both, and 1 with unspecified CNS involvement. Characteristics associated with baseline CNS involvement were performance status 2-4 (P=0.03) and ≥2 extranodal sites (P=0.02). Median survival after HT was 1 year [0.7-2.5], comparable to the one of patients without CNS disease (1.8 year [1.2-2.6], P=0.74). We observed no difference in survival based on isolated CNS involvement (n = 10) compared to CNS and systemic involvement (n = 15) (P=0.94).Twenty-three CNS relapses occurred (12%). The 2-year and 3-year rates of CNS relapse were 9% (95% CI, 6-14) and 11% (95% CI, 7-16) (Figure 1). The median time to relapse in the CNS was 11 months (95% CI, 7-25). Thirteen CNS recurrences (57%) occurred during the first year of follow-up. Seventy percent were isolated CNS relapses. The location was leptomeningeal in 43% of cases, parenchymal in 35%, both in 17%, and unspecified in 4%. According to CNS-IPI risk groups (data available for 20 patients), 9 patients (45%) belonged to the high-risk group, 10 (50%) to the intermediate-risk group and 1 (5%) to the low-risk group. Prior to CNS relapse, 87% of patients had received rituximab, and 39% had received CNS prophylaxis (30% intrathecal chemotherapy, 4% high-dose methotrexate (HD-MTX), and 4% both). After CNS recurrence, 96% of patients received salvage treatment: combination of HD-MTX and HD-cytarabine (48%), HD-MTX alone (30%), or HD-cytarabine alone (9%). Four patients underwent consolidative autologous stem cell transplantation. The median survival after CNS relapse was 5.6 months. Factors associated with 3-year cumulative incidence of CNS recurrence in univariate analysis were involvement of kidney/adrenal glands (HR, 4.4; P=0.01) and MYD88 L265P mutation (P=0.01) (Figure 2A and B). Of note, among 74 patients (over 187, 40%) with data available for MYD88 mutation status, 11 CNS relapses occurred in patients with MYD88 L265P mutation (n = 54, 20%) whereas no relapse were observed in MYD88 WT cohort (n = 20). A trend toward higher risk of CNS relapse for ≥2 extranodal sites (HR, 2.3, 95% CI 0.98-5.3; P=0.06) was observed. Cumulative incidence according to CNS-IPI risk groups (0% in the low-risk, 9% in the intermediate-risk and 14% in the high-risk group) was not statistically significant (P=0.47).CONCLUSIONCNS involvement occurs frequently in transformed WM. Rate of CNS relapse seems similar to DLBCL patients belonged to the CNS-IPI high-risk group. Special attention should be paid to patients with kidney/adrenal involvement and MYD88 L265P mutation. [Display omitted] DisclosuresVos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. Treon: X4: Research Funding; Janssen: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria. Kapoor: Cellectar: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions

AbstractProphylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.