Prophylaxis is commonly used to prevent central nervous system (CNS) relapse in diffuse large B cell lymphoma, 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 2013-2019. 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=0.4), 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. 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.

There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone (n=35, 21%), DEC alone (n=84, 49%), AZA-VEN (n=24, 14%) and DEC-VEN (n=27, 16%). VEN improved CCR rates to HMAs overall (52% vs. 27%, P<0.05) and to AZA (54% vs. 10%, P<0.05), but not to DEC (43% vs. 32%, P=0.35); it did not improve OS, and only improved EFS for AZA (10.5 vs. 3.8 months, P<0.05). CCR rates were lower with AZA than with DEC (13% vs. 33%, P<0.05), but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN (CCR: 58% vs. 52%, P=0.66), but OS and EFS were longer for AZA-VEN (m-OS: 12.3 vs. 2.2 months, P<0.05; m-EFS: 9.2 vs. 2.1 months, P<0.05). Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC.

Introduction Relapses involving the central nervous system (CNSrel) occur in ~5% of patients (pts) with aggressive non-Hodgkin lymphoma (NHL) in the rituximab era (Ghose et al, Clin LML 2015) with rates exceeding 10% in high risk groups (Villa et al, Ann Onc 2010; Schmitz et al, JCO 2016). CNSrel are generally thought to occur in the first 4-6 months from diagnosis. Prophylaxis (PPx) administration, route, and frequency are not standardized, and the impact of PPx on CNSrel risk is incompletely understood. Methods We performed a multicenter retrospective analysis of pts with aggressive NHL (excluding Burkitt's) without known CNS involvement (inv) who received single-route CNS PPx with during front-line (FL) anthracycline-based therapy (tx) from 2013-2019 across 19 US academic institutions. Recipients of chemotherapy for prior CLL or indolent NHL were ineligible. Method, frequency, and outcomes of CNS PPx administration were evaluated, with significance assessed by various statistical methods via two-tailed P<0.05. Results 1030 patients were identified who met eligibility criteria. Clinical features included median age 61 years (yrs; range 16-86), 40.9% female, ECOG PS 0-1 82.8%, elevated LDH 65.3%, >1 extranodal (EN) site 42.3%, stage 3/4 disease 79.2%. NHL histologies included diffuse large B cell (DLBCL; 75.2%), high grade B cell (16.3%), transformed follicular lymphoma (5.6%) and 3% other; among pts with DLBCL, 46.4% had germinal center (GCB) subtype and 40.5% had non-GCB. 26.2% (n=210) of evaluable pts had double-hit lymphoma (DHL). Among pts with known HIV status, 7.2% (n=65) were HIV-positive. 85.7% had EN inv; common sites included bone (35.4%), liver (13.7%), gastrointestinal (12.7%), lung (11.8%), and marrow (11.5%). FL regimens included RCHOP (45.9%), REPOCH (46.5% total; 79.1% with dose-adjustment), 7.6% other. PPx was given intravenously (IV) in 20% of pts vs 77% intrathecally (IT), over a median 2.9 vs 4.1 doses respectively; see Table 1 for factors associated with PPx route. PPx was generally well-tolerated, with 10.7% PPx-related toxicity reported; see Table 2. CNSrel after FL tx was 5.3% overall without significant difference by PPx route (7% IV vs 5% IT, p=0.178). This lack of difference between PPx routes was observed in all subgroup analyses performed, including by: age, stage, histology, number of EN sites, individual EN site inv, elevated LDH, CNS-IPI, DHL status, HIV status, FL regimen, number of PPx doses. There was no significant difference in anatomic site(s) of CNSrel by PPx route. CNSrel occurred bimodally: 24% by end of FL tx vs 76% delayed (average 2.3 yrs, range 0.4-5.2 yrs). Rates of CNSrel were significantly higher with CNS-IPI high vs moderate risk (8.3 vs 4.1%, p=0.03; Figure 1), elevated LDH (6.9 vs 2.6%, p=0.007) and multiple inv EN sites (7.5% for 2+ vs 4% for 0-1, p=0.01); each additional EN site further increased risk (p=0.03 for trend; Figure 2). Increased CNSrel was noted in pts with testis (13.7 vs 5%, p=0.004) and liver inv (11.1 vs 4.6%, p=0.002) vs those without inv at respective sites. No significant difference was noted at other EN sites, including renal/adrenal (4.8 vs 5.6%, p=0.71), marrow (8.9 vs 5.1%, p=0.09), or lung (8.6 vs 5.1%, p=0.12). All EN site-CNSrel correlations were unchanged when accounting for PPx route. With median follow-up of 2.3 yrs, median PFS and OS for the overall group have not been reached; 2-yr PFS and OS were 70 and 85% respectively. PFS and OS were each predicted by CNS-IPI (p<0.0001) and maintained significance when separated by PPx route. 196 deaths were reported, including 122 disease-related and 34 tx-related (TRM). There was no significant difference in TRM by PPx route (1.9% IV vs 3.6% IT, p=0.24). Death due to progression was more common following IT PPx (13.3% vs 7.9% IV; HR 1.72, p=0.04), driven primarily by DH status (adjusted PPx HR: 1.54, p=0.11). In those with CNSrel, subsequent relapse and/or death was common (n=41, 74.5%) regardless of initial PPx route or salvage tx. Median survival after CNSrel diagnosis was poor (7.1 months, range 1 day-5.3 yrs) and was significantly inferior to those with non-CNSrel (HR 1.488, p=0.03). Conclusion Use of single-route ppx demonstrated similar CNSrel vs established outcomes for this population in the rituximab era, with no difference by PPx route. CNSrel remains a rare but devastating complication, with greater risk even after single-route PPx in those with higher EN burden and inv of key EN sites. Disclosures Kahl: 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; 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. Spinner:Notable Labs: Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Voorhees:AstraZeneca: Research Funding. Grover:Genentech: Research Funding; Tessa: Consultancy. Huntington:Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria; Bayer: Consultancy, Honoraria; DTRM: Research Funding; Astrazeneca: Honoraria; AbbVie: Consultancy. Spurgeon:Beigene: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding; Genmab: Research Funding; AstraZeneca: Research Funding; Acerta: Research Funding. Olszewski:Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding. Landsburg:Seattle Genetics: Speakers Bureau; Morphosys: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Triphase: Research Funding. Kamdar:Roche: Research Funding. Caimi:Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Verastem: Other: Advisory Board; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Celgene: Speakers Bureau. Karmali:Takeda: Research Funding; BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Stephens:Pharmacyclics: Consultancy; Innate: Consultancy; Verastem: Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Research Funding; Arqule: Research Funding; Juno: Research Funding; MingSight: Research Funding; Acerta: Research Funding; Beigene: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Khan:Celgene: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Honoraria. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Portell:Bayer: Consultancy; Xencor: Research Funding; BeiGene: Consultancy, Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding.

Purpose BRCA gene mutations (BRCAm) have an impact on patients’ characteristics and clinical outcomes of ovarian cancer (OC). The frequency and patterns of BRCAm vary among countries and ethnicities. There are limited data from Saudi Arabia (SA); thus, this study aims to determine the frequency, pattern, and impact on patient characteristics and outcomes of BRCAm OC compared to wild-type BRCA (BRCAw) in Saudi women. Methods This retrospective study evaluated women diagnosed with non-mucinous OC, fallopian tube, or peritoneal carcinoma who had BRCA status tested in an accredited lab between January 2016 and December 2017. The associations between various parameters and BRCAm were estimated using logistic regression. Statistical analysis performed with SPSS (Version 27). Result Sixty-one women with a median age of 52 at diagnosis were analyzed. Germline BRCA mutations were found in 41% of cases (25/61). The most common deleterious germline BRCA1 mutation was c.1140dupG (39%). Most women (72%) had no family history of cancers and 82% had advanced stage. Regardless of BRCA mutations, an optimal overall response rate (ORR) to first-line treatment has been achieved although most cases relapsed (84%) and the majority were platinum-sensitive relapse (85%). Higher ORR to subsequent lines and better survival were obtained in women with BRCA-mutation. Conclusion The prevalence of BRCAm of OC was higher in Saudi women compared to regional and most of the international figures. The better clinical outcomes of BRCAm women agreed with the reported evidence. Further studies on BRCA mutations of OC and genetic counseling are highly recommended. Trial registration Trial approved by the Institutional Review Board of King Faisal Specialist Hospital and Research Center (RAC # 2171137) and conducted at King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11,211, Saudi Arabia.