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<0.001) and PFS (47.1% vs 82.6%, p=0.001). As shown in Figure 1, when comparing OS from the advent of disease relapse, OS after CNS relapse was significantly worse than OS after systemic non-CNS relapse. 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: High-grade B-cell lymphomas (HGBLs) with rearrangement of MYC and BCL2 and/or BCL6, known as "double-hit" or "triple-hit" B-cell lymphomas (DHL/THL), are an aggressive sub-type of non-Hodgkin mature B-cell lymphoma with chromosomal rearrangements involving MYC with BCL2 and/or BCL6 genes. DHL/THLs typically have poor outcomes and early relapses with first-line R-CHOP, and intensive induction chemoimmunotherapy regimens are associated with improved outcomes. Infusional dose-adjusted (DA)-R-EPOCH is commonly used, yet there is a lack of clear evidence that dose-adjustment enhances survival, and variations in compliance with dose-adjustment exist. DA-R-EPOCH has been incorporated as the backbone of prospective clinical trials testing the addition of novel agents for frontline management of DHL/THL, and these combinations may lead to a greater degree of myelosuppression that may disrupt dose-adjustments and hinder dose-escalations relative to using DA-R-EPOCH alone. Therefore, we sought to determine if patients with DHL/THL treated with induction DA-R-EPOCH have differences in clinical outcomes (OS, PFS, treatment-related adverse events and others) based upon compliance with dose-adjustment and cumulative doses of R-EPOCH administered. METHODS: Adult (age ≥18 years) patients with DHL/THL treated with induction DA-R-EPOCH chemoimmunotherapy from 2014 to 2019 at six collaborating medical centers were included in this study. To be included, patients must be without CNS-involvement at diagnosis, have received ≥4 cycles of DA-R-EPOCH, have adequate clinicopathologic data regarding chemoimmunotherapy dosing, survival, treatment response/remission status, cell counts, CNS and antimicrobial prophylaxis, admissions for cytopenias or IV antibiotics, and demographic data including age, international prognostic index (IPI), CNS-IPI, ECOG performance status, and cumulative illness rating score (CIRS, if available). An initial cycle of R-CHOP was permitted. De-identified data from participating sites were combined, and chemotherapy doses were aggregated and divided into quartiles based on cumulative doses of doxorubicin, etoposide, and cyclophosphamide received. Correlation between CIRS and dose was assessed by Spearman's correlation. OS and PFS were estimated using the Kaplan-Meier method and compared using log-rank test. RESULTS: 109 total patients were included in this study. The median age was 63 years (range 29-83), and approximately 60% of patients were male, 58% were age 60 or older, 60% had an IPI score of ≥3, and 66% were Ann Arbor Stage IV at induction. For all patients, 2-year and 5-year OS rates were 75% (95% CI: 67-84%) and 70% (59-82%), with 27 total deaths in the study period. 2-year and 5-year PFS rates were 65% (56-75%) and 60% (49-72%), respectively. 94 of 109 patients received CNS prophylaxis (86%). 26 patients had received an initial cycle of R-CHOP (24%). PFS and OS were significantly worse for patients with higher risk IPI score (P = 0.03, 0.04, respectively), but there was no difference in PFS or OS based on CIRS score (P = 0.70, 0.60, respectively). 75 patients (68.8%) were dose-escalated while 34 patients (31.2%) were not; there was no difference in PFS (Fig 1) or OS (Fig 2) between these groups. When stratified by cumulative dose-level in quartiles, those who received the lowest cumulative doses (1st quartile) had a significantly reduced OS (1st, 2nd, 3rd and 4th quartile 2-year OS of 55%, 75%, 85%, and 84%, P = 0.046). Cause of death was largely from disease progression (74%), with only one treatment-related death in each dosing quartile. Dose intensity was not correlated with baseline CIRS score (R = -0.06, P = 0.56), but did correlate negatively with IPI (R = 0.22, P = 0.04). CONCLUSIONS: OS and PFS did not differ for DHL/THL patients treated with R-EPOCH with dose-escalation in at least one cycle as compared to those with no dose-escalation. Although cumulative doses beyond the 1st quartile were associated with improved OS, there was no significant difference between 2nd, 3rd and 4th quartiles. Dose-escalation was negatively associated with IPI scores but not CIRS scores. Further investigation into factors affecting adherence to dose-adjustment is warranted. The effect of adding novel agents to the DA-R-EPOCH backbone on dose-adjustment and cumulative doses of chemotherapeutic agents received should be evaluated in prospective clinical trials. 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:Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy. Voorhees:AstraZeneca: Research Funding. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; 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. Kahl:Genentech: Consultancy; Pharmacyclics LLC: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Roche Laboratories Inc: Consultancy; Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

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