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Patients receiving chimeric antigen receptor T cells (CAR-T cells) therapy may be particularly susceptible to coronavirus disease 2019 (COVID-19) because of several factors including the immunosuppression associated to the underlying disease and delayed cytopenias. Regrettably, data on outcomes of CAR-T recipients with COVID-19 are extremely scarce. The aim of this study was to investigate the characteristics and outcomes of COVID-19 in patients treated with CAR-T therapy. The European Hematology Association - Scientific Working Group Infection in Hematology endorsed a survey to collect and analyze data from patients developing COVID-19 after CAR-T therapy. Overall, 459 patients treated with CAR-T cells were reported from 18 European centers. The prevalence of COVID-19 cases was 4.8%. Median time from CAR-T therapy and COVID-19 diagnosis was 169 days. Severe infection occurred in 66.7% of patients and 43.3% of the subjects required admission to ICU. The COVID-19 mortality was 33%. In multivariable analysis, the disease status at the time of COVID-19 trended marginally towards adverse outcome (P=0.075). In conclusion, we documented a high fatality rate for CAR-T patients with COVID-19, supporting the need to design successful interventions to mitigate the risk of infection in this vulnerable group of patients.

Patients with previous CD19 directed chimeric antigen receptor T cell therapy (CAR T)-cell therapy have a prolonged vulnerability to viral infections. Coronavirus diseases 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real world data of the impact of vaccination and treatment on patients with COVID-19 after CD19 directed CAR T-cell therapy are lacking. Therefore, this multicenter retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared to patients infected with previous variants (7% versus 58% (P=0.012)). Twenty-six patients were vaccinated at time of COVID-19 diagnosis. Two vaccinations showed marked but unsignificant reduction risk of COVID-19 caused mortality (33.3% versus 14.2% (P=0.379)).Also the course of disease appears milder with less frequent ICU admissions (39% versus 14% (P=0.054)) and shorter duration of hospitalization (7 versus 27.5 days (P=0.022)). Of the available treatment options, only monoclonal antibodies seemed to be effectively reducing mortality from 32% to zero (P=0.036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death.

Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody dependent cellular cytotoxicity (ADCC) that targets a unique epitope on CD20. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, registration-directed Phase 2 study designed to evaluate the safety and efficacy of the umbralisib + ublituximab (umbra+ubli, U2) combination in patients with previously treated NHL . Umbra has been recently approved for the treatment (tx) of previously treated marginal zone lymphoma (MZL) based on reported data (Fowler JCO 2021), and the U2 combination has been shown to be active with a manageable safety profile in patients with relapsed/refractory (R/R) NHL (Lunning Blood 2019). In contrast with other PI3Kis, there has been a low incidence of immune-mediated toxicities with umbra, possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε. Herein, we present results from the MZL cohort treated with U2. Methods: Eligible patients had histologically confirmed MZL (splenic, nodal, extranodal) and were R/R to ≥1 prior lines of tx which must have included an anti-CD20. Patients were treated with U2: umbra was given orally at 800 mg once daily until progression or unacceptable tolerability and ubli was administered intravenously on Days 1, 8, and 15 of Cycle 1, on Day 1 of Cycles 2-6, and on Day 1 every 3 cycles until Cycle 24 in 28-day tx cycles. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee according to the revised IWG criteria (Cheson 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Results: 72 MZL patients were enrolled and received U2. The median age was 70 years (range 40-89), 53% were female, 74% had stage III or IV disease, and 25% were refractory to their immediate prior therapy. Patients had received a median of 2 prior regimens (range 1-9). As of the cutoff date, 41 patients remain on tx. The ORR was 68%, with 19% achieving complete response (CR). At a median follow-up of 16 months, median DoR was not reached (12 - not estimable). 90% of patients had a reduction in disease burden from baseline while on U2. Figure 1a depicts efficacy data for U2, and Figure 1b shows the best % change in target lesions from baseline for MZL patients treated with at least 1 dose of U2. The most common adverse events (AEs) were diarrhea (all grades: 49%, grade ≥3: 13%), nausea (all grades: 30%, grade ≥3: 0%), and fatigue (all grades: 36%, grade ≥3: 6%). Other AEs of interest included non-infectious colitis (all grades: 2.8 %, grade ≥3: 2.8%) and rash (all grades: 11%, grade ≥3: 0%). Four patients (5.6%) discontinued due to an AE. Conclusions: U2 was highly active in patients with R/R MZL, with improved efficacy when compared to a prior cohort of MZL patients treated in this study with umbra mono (Fowler JCO 2021). The safety profile of the U2 combination was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. Figure 1 Figure 1. Disclosures Chavez: Bristol Myers Squibb: Speakers Bureau; AstraZeneca: Research Funding; BeiGene: Speakers Bureau; Epizyme: Speakers Bureau; MorphoSys: Speakers Bureau; Karyopharm Therapeutics: Consultancy; Merck: Research Funding; Adaptive: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Kite/Gilead: Consultancy. Goldschmidt: AbbVie: Consultancy, Research Funding. Samaniego: Imbrium: Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding. Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Servier: Speakers Bureau. Fonseca: Sanofi: Honoraria; Karyopharm: Honoraria; Epizyme: Honoraria; Dava Oncology: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Abbvie: Honoraria. Drgona: Abbvie: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sandoz: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Teva: Honoraria; Viatris: Honoraria. Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Specialised Therapeutics: Consultancy; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Regeneron: Speakers Bureau; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Levi: AbbVie: Consultancy, Research Funding. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Zinzani: ROCHE: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; SANDOZ: Other: Advisory board; BMS: Other: Advisory board, Speakers Bureau; Incyte: Other, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; ADC Therap.: Other.