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BACKGROUND: Central nervous system (CNS) relapse in systemic non-Hodgkin's lymphoma is associated with a guarded prognosis with a median survival of only 2-6 months. However, information regarding CNS relapse is still limited and there is no consensus regarding which clinical or biologic risk factors should be used to identify patients who need prophylaxis and the optimal prophylactic regimen has not yet been established. The CNS-IPI score represents a robust risk model for CNS relapse in patients with diffuse large B cell lymphoma treated with R-CHOP and may potentially serve as a useful benchmark to evaluate the impact of novel treatment approaches. In particular, patients with chromosomal rearrangements of MYC and BCL2 and/or BCL6 genes, as is encountered in double hit (DHL) or triple hit (THL) lymphoma, have been associated with an increased risk for CNS involvement in retrospective series. CNS prophylaxis is typically administered in patients with DHL/THL treated with DA-R-EPOCH due to this perceived heightened risk, but there are limited data to support this approach. METHODS: We conducted a comprehensive multi-institutional retrospective analysis of outcomes of patients with DHL/THL, who received a minimum of 4 cycles of DA-R-EPOCH therapy with or without CNS prophylaxis, namely intrathecal (IT) or high-dose intravenous (IV) methotrexate or cytarabine. Each academic institution provided clinical data to assess the risk of CNS relapse (CNS-IPI) and FISH testing for MYC/BCL2/BCL6 translocations. Outcomes included overall survival (OS), progression-free survival (PFS), CNS relapse-free survival (CNSFS) and time to CNS recurrence which were calculated from time of diagnosis. Fisher's exact test or Chi-square test and Kaplan-Meier method were used to evaluate associations between outcomes and demographics as well as clinical characteristics including administration of CNS prophylaxis and CNS-IPI risk stratification. RESULTS: We collected data on 109 DHL/THL patients across 6 US academic medical centers. Demographic and clinical variables at diagnosis include - Age >60 57.8%(n=63); Male sex 59.6%(n=65); Stage III/IV 78.9%(n=86); ECOG PS >1 12.8%(n=14); CNS-IPI low risk (score 0-1) 11%(n=12), intermediate risk (score 2-3) 57.8%(n=63), high risk (score 4-5) 31.2%(n=34). A total of 95 (87.2%) patients received CNS prophylaxis [IT 81.1%(n=77); IV ± IT 18.9%(n=18)] with a median of 4 doses. Eight patients developed CNS relapse (7.3%) during a median of 25.9 (range 4.0 to 63.2) months of follow up. The patterns of relapse were predominantly leptomeningeal (n=7/8), as shown in Table 1. Estimated incidence was 4.9% at 12 months and 6.1% at 24 months after diagnosis. 5.6% (1/18) of the patients who received IV ±IT CNS prophylaxis developed CNS relapse, whereas the rates of CNS recurrence for patients who received only IT or no CNS prophylaxis were 6.5% and 7.1% respectively. No statistically significant differences in outcomes were found between baseline patient characteristics with respect to whether or not CNS prophylaxis was received, as well as the route of administration of CNS prophylaxis. The rate of CNS relapse was low for patients with low to intermediate compared to high CNS-IPI scores (4.0% vs. 14.7%, p=0.047). Patients with high CNS-IPI scores had reduced CNSFS (2-yr survival: 85.2% vs 97.3%, p=0.08), as well as reduced OS (2-yr survival: 46.5% vs. 87.5%, p CONCLUSIONS: CNS relapse is associated with significantly reduced OS as compared to systemic non-CNS relapse following R-EPOCH treatment in DHL/THL, justifying the need for a rational CNS prophylaxis strategy in these patients. The rate of CNS relapse was significantly lower in patients in the low-intermediate CNS-IPI risk category but it is unclear whether CNS events are reduced by administration of IT CNS prophylaxis due to the relatively small proportion of DHL/THL patients who did not receive any CNS prophylaxis. Furthermore, only 1 of the 18 DHL/THL patients (including 6 patients with high CNS-IPI scores) who received IV ± IT CNS prophylaxis developed CNS relapse, suggesting that this prophylactic strategy, especially in patients with high risk CNS-IPI scores, may be more effective in preventing this devastating clinical event. Disclosures Haverkos: Viracta THerapeutics: Consultancy. Hughes:Acerta Pharma and HOPA: Research Funding; AstraZeneca: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Grover:Genentech: Research Funding; Tessa: Consultancy. Portell:AbbVie: Research Funding; Amgen: Consultancy; Bayer: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy. Voorhees:AstraZeneca: Research Funding. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy. Kahl:Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding.

Background: Cytomegalovirus (CMV) infection remains an important cause of morbidity and cost following umbilical cord blood transplantation (UCBT). While the introduction of letermovir represents a novel approach to CMV prophylaxis, optimal CMV management strategies remain controversial. An intensive strategy to prevent CMV disease including one week of pre-transplant ganciclovir followed by high-dose acyclovir or high-dose valacyclovir through day 100 reduced post-transplant CMV reactivation (Milano et al, Blood 2011), but this approach is costly and potentially challenging to administer. Insurance approval for outpatient high-dose valacyclovir is variable, and the pill burden of high-dose acyclovir for post-transplant patients may be unmanageable. A recent study demonstrates that the removal of pre-transplant ganciclovir does not decrease CMV reactivation rates (Hill et al, BBMT 2018). At our center we have attempted to implement the high intensity strategy described above, but for patients who are unable to obtain high-dose valacyclovir at hospital discharge, we have transitioned to standard dose 800 mg acyclovir twice daily. Additionally, in November 2016, we discontinued pre-transplant ganciclovir. To examine the efficacy of these approaches, we compared CMV outcomes among these patients. Methods: All consecutive adult CMV seropositive (CMV R+) patients who received their first double UCBT from December 2009 to January 2018 were reviewed. Patients were excluded if they had initial CMV reactivation prior to day 0 or after day 100, graft failure, death or relapse before day 100, or participated in a CMV prophylaxis trial. Starting the day of transplant, CMV R+ patients received either valacyclovir 2 grams orally 3 times daily or acyclovir 500 mg/m2 intravenously every 8 hours until able to tolerate oral medication. At hospital discharge, patients for whom valacyclovir was authorized by insurance received valacyclovir 2 grams orally 3 times daily through day 100. All others received acyclovir 800 mg orally twice a day through day 100. No patients received anti-thymocyte globulin with conditioning. All patients transplanted prior to November 2016 received pre-transplant ganciclovir, after which pre-transplant ganciclovir was discontinued. CMV reactivation was defined as any detectable PCR positive whole blood sample (checked twice weekly through day 100). Thresholds for treatment with ganciclovir or foscarnet evolved over time, but required high initial copies levels, persistent or rising DNAemia, or evidence of end-organ involvement. Acute graft-versus-host-disease (aGVHD) treatment was based on institutional guidelines and uniform for all patients. Results: Demographics of the 101 patients studied are provided in table 1. Forty-one patients received prophylaxis with high-dose valacyclovir until post-transplant discharge only (median 23 days) and 60 received valacyclovir through day 100. Between day 0 and day 100, fewer patients in the high-dose valacyclovir group (n= 20, 36%) had CMV reactivation compared to those in the acyclovir group (n= 23, 57%), p= 0.025 (figure 1). Nine patients (9%) in the acyclovir group and 6 (6%) in valacyclovir group received CMV directed treatment (p= 0.1). Patients who did or did not received pre-transplant ganciclovir had similar rates of CMV reactivation (p= 0.55 in acyclovir arm, p= 0.15 in valacylcovir arm). Overall survival (p= 0.64), neutrophil and platelet engraftment time, and incidence of grade 2-3 (p= 0.7) and grade 3-4 aGVHD (p= 0.3) were comparable between groups. Conclusions: High-dose valacyclovir through day 100 post-transplant as compared to through the day of hospital discharge post-transplant reduced CMV reactivation rates. While threshold for treatment will vary according to institutional protocol, high-dose valacyclovir through day 100 likely reduces treatment episodes. One week of pre-transplant ganciclovir does not reduce CMV reactivation rates. These data provide important baselines for future comparisons of outcomes following letermovir prophylaxis in this population. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Abstract 3404 Poster Board III-292 Long-term survival and disease control following autotransplant have been known to be poor in symptomatic MM patients who were in relapse prior to transplant, had adverse cytogenetic abnormalities (CA) or high LDH (> 190 IU/mL) at diagnosis. In the study, we sought to improve the outcome of these patients by combining bortezomib with standard high-dose melphalan for autotransplant and implementing 3-year post-transplant maintenance with bortezomib, lenalidomide and dexamethasone. Between September 2006 and March 2009, 34 patients (median age 62, range 38 to 77 years) were accrued to the sequential regimens of 1) tandem autotransplant prepared by the MVD of ‘melphalan 200 mg/m2 (D-1) + bortezomib 1.3 mg/m2 × 2 (D-4, D-1) + dexamethasone 20 mg x 4 (D-4 through D-1)’; 2) the VLD of ‘bortezomib 1.3 mg/m2/day x 4 (D1, 4, 8, 11) + lenalidomide 10 mg/day x 14 (D1 through 14) + dexamethasone 20 mg/day x 4 (D1, 4, 8, 11)’ q 3 months for 2 years; 3) the LD of ‘monthly lenalidomide 10 mg/day x 14 + dexamethasone 20 mg q Monday in between of the VLD for the first 2 years, followed by a monthly course for the 3rd year. Of the 34 patients, 11 (32%) had unfavorable CA, 15 (44%) high LDH and 10 (29%) prior relapse. 16 patients (47%) had immunoglobulin (Ig) G, 10 (29%) Ig A, 6 (18%) light chain only and 2 (6%) nonsecretory MM. 14 patients (41%) received tandem transplant and 20 (59%) single transplant due to insurance reasons. 32 patients (94%) were able to maintain the treatment until the last follow-up on August 15, 2009 or until relapse or death. 19 patients achieved either a stringent complete remission (s-CR) (n = 16) or CR (n = 3), with an 1-year cumulative incidence (CI) of 46%. 2 additional patients achieved CR following the 2nd transplant. During the maintenance, 3 additional patients achieved s-CR (N = 1) or CR (n = 2), resulting in 71% of the 18-mo CI of response > CR. By the landmark analysis at the time of transplant, the estimated 3-year Kaplan-Meier survival, CI of relapse and event free survival (EFS) are 96% with 2 deaths (1 of MM, 1 of pulmonary embolism), 15% with 5 relapses and 70% with 6 events, respectively. Presence of CA impacted adversely the EFS: 61% of patients without CA vs. 39% of those with CA (Logrank p = 0.06). However, a history of prior relapse or high LDH was not associated with inferior EFS: 42% with prior relapse vs. 76% without prior relapse (p = 0.27); 45% with high LDH vs. 51% with normal LDH (p = 0.86). Although the current findings are limited by the small number of patients and the short duration of follow-up, the data suggests that additional bortezomib to the standard high-dose melphalan and implementation of long-term maintenance post-transplant with bortezomib and lenalidomide may overcome the adverse factors in high-risk MM patients for relapse. Further study is necessary to confirm the findings. Disclosures: Myint: Seattle Genetics, Inc.: Research Funding.