Timing of high dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1,384 patients

Prophylactic 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 1,384 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=0.98, 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=1,253). In patients with high CNS international prognostic index (n=600), 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 reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in 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 versus 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.

Favorable Outcomes with Thiotepa/Busulfan-Based Conditioning and Autotransplant for Patients with Aggressive B-Cell Lymphoma and Secondary CNS Involvement

Introduction : Central nervous system (CNS) relapse is a devastating complication affecting ~5% of patients with diffuse large B-cell lymphoma (DLBCL). The optimal management is unknown and survival rates are ~20% in contemporary series. Thiotepa/busulfan-based high-dose chemotherapy (HDT) and autotransplant (ASCT) has demonstrated efficacy in primary CNS lymphoma, but there have been fewer studies of this conditioning regimen in secondary CNS lymphoma (SCNSL). Methods : This multicenter retrospective study included all consecutive patients ≥18 years old with aggressive B-cell lymphoma and secondary CNS involvement treated with thiotepa/busulfan-based HDT/ASCT at the University of Calgary and University of Alberta since 2005. Kaplan-Meier curves were used to estimate progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) from the time of ASCT. Data collection is underway for all consecutively diagnosed SCNSL patients at our institutions to evaluate frequency and predictors of HDT/ASCT use. Results : This study included 57 patients with DLBCL (n=45), double-hit lymphoma (n=6), high-grade B-cell lymphoma NOS (n=2), intravascular large B-cell lymphoma (n=2), or T-cell/histiocyte-rich large B-cell lymphoma (n=2). Two (4%) had previously treated indolent B-cell lymphoma and 1 (2%) had multiply relapsed DLBCL. Median International Prognostic Index was 4 (range 0-5) at DLBCL diagnosis and median time to CNS relapse was 4 months (range 0-139). Median age was 58 years (range 20-73) and median ECOG was 3 (range 0-4) at diagnosis of SCNSL. CNS involvement was present at initial diagnosis in 20 (35%) patients or developed during frontline treatment in 10 (18%) or after completion of treatment in 27 (47%). For those without SCNSL at diagnosis, isolated CNS relapse occurred in 31 (84%) patients while 6 (16%) had concurrent CNS and systemic relapse. Most patients (n=54, 94%) received high-dose methotrexate (HD-MTX)-based multiagent induction chemotherapy (median HD-MTX doses 4, range 1-5) followed by peripheral blood stem cell mobilization with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) in 41 (72%). HDT conditioning regimens were thiotepa, busulfan, melphalan, rituximab (TBMR, n=52, 91%) or thiotepa, busulfan, cyclophosphamide (TBC, n=5, 9%). Median time from SCNSL diagnosis to ASCT was 116 days (range 7-201). Median time to neutrophil engraftment was 10 days (range 7-15) and to platelet engraftment 16 days (range 9-93). Overall response rates (ORR) for systemic/CNS disease were 93%/89% pre-ASCT and 95%/100% post-ASCT. Combined ORR pre-ASCT was 88%, with complete response in 21% and partial response in 67%. Two (4%) patients who developed CNS relapse immediately prior to ASCT achieved long-term remission after TBMR conditioning without any other systemic chemotherapy. With a median follow-up time of 4.0 years (range 0.1-15.9), PFS was 75% (95% CI 61-85%), OS was 76% (95% CI 62-86%), and DSS was 79% (95% CI 64-88%) at 4 years after ASCT. Lymphoma recurred in 9 (16%) patients at median 88 days (range 54-346) after ASCT with CNS relapse (n=4), systemic relapse (n=3), or both (n=2). There were 2 (4%) deaths due to peri-transplant toxicity and 1 (2%) death at 1.5 years due to therapy-related acute myeloid leukemia; no other unexpected toxicities of HDT/ASCT were observed. Among the 45 (79%) patients achieving long-term disease-specific survival, none were treated with CNS radiation therapy and only 1 (2%) had persistent neurocognitive impairment. There were no significant differences in DSS with respect to timing of CNS relapse, concurrent presence of systemic disease, or TBMR versus TBC conditioning (78% vs 80%, p=0.87). Conclusion : In one of the largest studies of this conditioning regimen in SCNSL to date, we found that high-dose thiotepa/busulfan-based conditioning with ASCT is associated with favorable outcomes for patients with aggressive B-cell lymphoma and secondary CNS involvement, with 4-year OS ~75% in this study. Although SCNSL has been historically associated with a poor prognosis, an increasing proportion of patients may achieve long-term survival after intensive therapy with HD-MTX-based induction and thiotepa/busulfan-based HDT and ASCT. Figure 1 Figure 1. Disclosures Chua: Eisai: Honoraria; Pfizer: Honoraria; Merck: Honoraria; Gilead: Honoraria. Stewart: Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Teva: Honoraria.

A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in Low Risk (LR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs): A Report from Children's Oncology Group Study AALL1331

Standard treatment of children and AYAs with LR first relapse of B-ALL [LR defined as bone marrow with or without extramedullary (BM±EM) relapse ≥36 months or isolated EM (IEM) relapse ≥18 months from initial diagnosis, and low (<0.1%) BM minimal residual disease (MRD) at the end of reinduction chemotherapy] consists of approximately 2 years of standard chemotherapy without hematopoietic stem cell transplant. The objective of this study was to compare survival [primary: disease-free (DFS); secondary: overall (OS)] of LR first relapse B-ALL patients aged 1-30 years randomized following reinduction chemotherapy (Block 1 of UKALLR3/mitoxantrone arm) to receive either two intensive chemotherapy blocks (Blocks 2 and 3 of UKALLR3) followed by continuation and maintenance chemotherapy of UKALLR3 (chemotherapy control) vs. the same except with integration of three 4-week cycles of blinatumomab, one replacing Block 3 chemotherapy and two added during continuation and maintenance (blinatumomab experimental). All patients with central nervous system (CNS) leukemia at relapse (isolated or combined with BM relapse) received additional intensified CNS-directed chemotherapy (intrathecal and systemic) and 1800 cGy of cranial radiation during maintenance. Patients with testicular leukemia at relapse that persisted after Block 1 reinduction received 2400 cGy testicular radiation during Block 2. A total of 255 LR patients were randomized: Blinatumomab: 127; Chemotherapy: 128. Selected baseline characteristics are shown in Table 1. With median follow up of 2.9 years (data cut-off 12/31/20), the intent-to-treat (ITT) 4-year DFS (%±standard error) was 61.2±5.5% for blinatumomab vs. 48.2±6.0% for chemotherapy (p=0.15, 1-sided stratified log-rank test per pre-specified statistical plan). The 4-year OS was 91.6±3.0% for blinatumomab vs. 83.3±4.5% for chemotherapy (p=0.096). Striking differences in DFS and blinatumomab efficacy were noted according to site of first relapse (Figure 1). For BM±EM relapses, 4-year DFS was 74.0±6.4% for blinatumomab vs. 51.8±7.9% for chemotherapy (p=0.016), and 4-year OS was 96.6±2.5% for blinatumomab vs. 84.4±5.6% for chemotherapy (p=0.013). Significant predictors of DFS in Cox multivariable regression for BM±EM relapses included treatment arm, age at relapse, and time from diagnosis to first relapse (Table 2). For IEM relapses, 4-year DFS was 34.2±8.6% for blinatumomab vs. 39.3±8.5% for chemotherapy (p=0.73), and 4-year OS was 81.7±7.0% for blinatumomab vs. 80.8±7.2% for chemotherapy (p=0.61). The only predictor of DFS in IEM patients was site of first relapse [hazard ratio for testes vs. CNS 0.19 (0.04-0.87), p=0.015]. The difference in DFS between BM±EM and IEM patients was driven by excess of second relapse in isolated CNS relapse patients (Table 3). Of 64 CNS relapses, 39 (61%) had a second relapse, of which 28 (72%) were also isolated CNS, with no difference by treatment arm. Of the 191 remaining patients, 35 (18%) had a second relapse [13 (14%) blinatumomab (6 BM±EM, 7 IEM), 22 (23%) chemotherapy (15 BM±EM, 7 IEM)]. Blinatumomab cycle 1 was better tolerated than Block 3 chemotherapy, with lower rates of CTCAEv4 grade ≥3 febrile neutropenia (3% vs. 47%, p<0.001), infections (5% vs. 51%, p<0.001), anemia (12% vs. 57%, p<0.001) and mucositis (1% vs. 7%, p=0.018). The rate of selected blinatumomab-related adverse events (AEs) in blinatumomab cycles 1/2/3 (all grades) were: Cytokine release syndrome (CRS) 12%/7%/7%, seizure 3%/1%/3%; other neurotoxicity (e.g., cognitive disturbance, tremor, ataxia, dysarthria) 19%/9%/5%. All blinatumomab-related AEs were fully reversible. In conclusion, for children and AYA patients with LR first relapse of B-ALL, while there was no significant difference in outcome for the entire population, the blinatumomab arm was superior to the standard chemotherapy arm for patients with BM±EM relapse, establishing this regimen as a new standard therapy for these patients. The blinatumomab arm was not superior in IEM relapse. Isolated CNS relapse patients had a strikingly high relapse rate on both arms; better treatments are urgently needed for this subset. Figure 1 Figure 1. Disclosures Brown: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; KIte: Membership on an entity's Board of Directors or advisory committees. Borowitz: Amgen, Blueprint Medicines: Honoraria. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Gore: Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Mirati: Current equity holder in publicly-traded company; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; OnKure: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Sanofi Paris: Current equity holder in publicly-traded company. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Hunger: Amgen: Current equity holder in publicly-traded company. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Blinatumomab, used as post-reinduction consolidation without regard to MRD

High Frequency of CNS Involvement in Transformed Waldenström Macroglobulinemia

INTRODUCTION Central 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. METHODS This 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). RESULTS Baseline 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). CONCLUSION CNS 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. Figure 1 Figure 1. Disclosures Vos: 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.

R-CHOP Chemotherapy Including Biosimilar Rituximab (Redditux ®) for De-Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single Center Experience

Background The biosimilar rituximab (Redditux) was approved in Turkey for all indications of the reference molecule (MabThera) in March 2018. Large clinical trials and real-life experiences are lacking in hematological malignancies. Aims We aimed to evaluate the efficacy and safety of Redditux in de-novo diffuse large B-cell lymphoma (DLBCL). Methods Our institution decided to provide Redditux for hematological indications since February 2019. We retrospectively analyzed medical records of 51 consecutive de-novo DLBCL patients (pts) diagnosed between February 2019 and September 2019 in the hematology department of Istanbul University Istanbul Medical Faculty. We compared the response rates with historical controls treated with MabThera-CHOP at Cerrahpaşa Medical Faculty. Our study was approved by I.U. Istanbul Medical Faculty Ethical Committee (2019/1454). Results A total of 51 pts without CNS involvement received Redditux-CHOP. Median follow-up was 24 months (range: 8-31). A median of 6 cycles of biosimilar (range: 4-8) was administered. Four pts with high CNS-IPI score received four intrathecal methotrexate injections and 13 pts had additional radiotherapy for their initial bulky disease. The patient characteristics and response rates of the Redditux and historical MabThera cohorts are summarized in Table 1. Apart from 6 cases who were refractory to Redditux-CHOP, 8 pts had progressive disease (6 with CR, 1 with PR and 1with SD) in the follow-up. The median time to relapse was 11.5 months for 6 cases who had CR following first-line treatment. Five of 8 cases with PD experienced CNS relapse. Their CNS-IPI score (Schmitz et al. J Clin Oncol 2016) were low in 2 pts, intermediate in 2 pts and high in 1 patient. Of 11 pts with bone involvement at the time of diagnosis, three cases had CNS relapse (p=0.028). Two pts with CNS relapse were treated with intrathecal chemotherapy only due to their poor performance status. Eight pts received salvage combination chemotherapy [R-ICE (n=3); R-benda (n=3); R-DHAP (n=1); MATRix (n=1)] and two of them responded. One of these 2 cases underwent auto-SCT and the other proceeded to allo-SCT; however, he died during conditioning treatment. Ten pts died in the follow-up. Causes of death were progressive disease (n=7, two cases with CNS involvement), infection during allo-conditioning (n=1), post-COVID herpes zoster infection (n=1) and unknown (n=1). The 24 month PFS and OS rates were 75.8% (95% CI: 0.61-0.85) and 80.3% (95% CI: 0.67-0.89) for Redditux cohort, respectively. In the historical MabThera group, the 24 month PFS and OS rates were 85.2 (95% CI: 0.79-0.90) and 81.4% (95% CI: 0.75-0.86), respectively. For pts with high R-IPI score in the Redditux cohort (3-5); the 24-month PFS and OS rates were 54.2% (95% CI: 0.29-0.74) and 55.6% (95% CI: 0.31-0.75), respectively. In the historical Mabthera group, the 24-month PFS and OS rates were 68.7% (95% CI: 0.53-0.80) and 59.4% (95% CI: 0.47-0.70), respectively. Although the PFS rates seems to be worse in high R-IPI cases receiving Redditux, the difference was not significant (p=0.18; Figure 1). AEs were reported in 51% (n=26) of patients. Most common AE was grade 2 infusion reactions (shivering, nausea, fever) requiring medical intervention in 20% of pts, accompanied with rash in half of them. Grade 3&4 AEs were leucopenia (n=2; 4%), neutropenia (n=20; 39%) febrile in 2 cases, anemia (n=6; 12%), thrombocytopenia (n=3; 6%). Grade 2 pneumonia (n=2) and urinary tract infections (n=2) were other infectious complications. Conclusion Although the PFS rate at 24 months in high-IPI group treated with Redditux seems to be lower compared to MabThera treated historical control group, survival rates were not significantly different. Our results should be cautiously evaluated due to small sample size. Compared to the original trial of MabThera added to CHOP based regimen, (Coiffier et al N Eng J Med. 2002), our CR rates in stage 2-4 pts seem to be slightly lower (70.7% vs 76%), although the OS rates are quite similar (86.3% vs 82%). Grade 3&4 neutropenia requiring empirical administration of G-CSF was 39% in our cohort. Infusion reactions were observed in 20% of pts, which was reported to be around 30% with original molecule (Patel et al. Clin Lymphoma Myeloma Leuk 2019). The CNS relapse rate was relatively high (9.8%) in our cohort. Prospective randomized clinical trials are needed to determine the efficacy and safety profile of Redditux. Figure 1 Figure 1. Disclosures Ferhanoglu: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Retrospective Review of the Safety and Efficacy of High-Dose Methotrexate for Prevention of CNS Relapse in Diffuse Large B-Cell Lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)

Retrospective review of the safety and efficacy of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019) Background: Central nervous system (CNS) relapse occurs in 10-12% of high-risk diffuse large B-cell lymphoma (DLBCL) patients. Prophylactic intravenous high-dose methotrexate (HD-MTX) is recommended by international guidelines to reduce this risk despite limited evidence to support such practice. Recent retrospective studies have cast doubt on the clinical benefit of such treatment. There is limited data on safety and efficacy of such treatment in a community oncology setting. Methods: We conducted a retrospective analysis of adults ≥ 18 years diagnosed with DLBCL treated with systemic therapy and HD-MTX as CNS prophylaxis at Kaiser Permanente Northern California from 1/2015 - 6/2019. We abstracted patient demographics, clinical information, treatment, toxicity, and health care utilization from the electronic health record. Descriptive statistics were used to evaluate patients' outcomes. Results: Of 33 patients (median age: 61; range: 23 - 81; age ≥ 60: 57.5%), most had stage IV disease (78.7%) and an ECOG performance status of 0 or 1 (66.5%). Patients with CNS-IPI score of 2-3 (intermediate-risk) was 30.3%, while higher CNS-IPI scores of 4-6 (high-risk) was 51.5%. Other patient characteristics include double hit lymphoma (12.1%), kidney/adrenal gland involvement (33%), and/or epidural involvement (24.2%). Most common therapies were R-CHOP (51.5%) and R-EPOCH (27.2%). The median number of HD-MTX doses was 3 (range 1-4). The median cumulative dose was 7 gm/m2 (range 3-10.5). With regards to the treatment schedule, 63.6% received HD-MTX intercalated with systemic chemotherapy and 36.4% received HD-MTX after completion of preplanned treatment. Overall, renal toxicity was the most common adverse side effect. The rates of grade 1, 2 and 3 renal toxicity were 12.1%, 9% and 6%, respectively. Other notable side effects experienced were neutropenic fever requiring hospitalization (27.2%) and grade 3 transaminitis (6%). No patients experienced grade 3 mucositis. The median duration of hospital stay was 12 days (range 4-37) and 12.1% required suspension of future HD-MTX. With a median follow up of 31.3 months (range: 0.79 - 58.4) 69.6% are alive and 15.1% had CNS relapse despite prophylactic HD-MTX. Conclusions: In this community oncology setting, patients with DLBCL who were deemed high risk for CNS relapse and received HD-MTX for prophylaxis experienced similar CNS relapse rate compared to those who did not in previous studies. Our findings are in line with recent retrospective reviews, which further support the lack of benefit of such prophylactic treatment. This study underscores the need for further research to prevent CNS disease and improved patient selection criteria for prophylactic treatment among high risk DLBCL patients. Disclosures No relevant conflicts of interest to declare.

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

Introduction Around 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. Methods Trained 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. Results A 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). Conclusions When 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. Figure 1 Figure 1. Disclosures Nooruddin: AstraZeneca: Research Funding.