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Background: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir., Methods: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023., Results: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions., Conclusions: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.

Background: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma., Methods: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18-75 years; with an Eastern Cooperative Oncology Group performance status of 0-2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 10 6 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 10 6 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 10 6 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11., Findings: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53-65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1-13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1-2). No cases of neurotoxic events were observed. Persistent grade 3-4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19., Interpretation: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach., Funding: Instituto de Salud Carlos III (co-funded by the EU), Fundación La Caixa, and Fundació Bosch i Aymerich., Competing Interests: Declaration of interests AO-C declares support for attending meetings from Janssen. VG-C declares receiving honoraria from Janssen, Pfizer, Bristol Myers Squibb (BMS)/Celgene, and GSK; support for attending meetings or travel from Janssen and GSK; and participation on data safety monitoring or advisory board from Janssen. VC declares receiving honoraria from Janssen, BMS, Sanofi, GSK, and Amgen; support for attending meetings or travel from Janssen; and participation on data safety monitoring or advisory board from Janssen, Sanofi, and Amgen. PR-O declares receiving honoraria from consulting activities from BMS, Janssen, Sanofi, Abbvie, Pfizer, Roche, and GSK; honoraria from lectures from BMS, Janssen, Sanofi and GSK; support for attending meetings or travel from Abbvie; and participation on data safety monitoring or advisory board from Janssen. JLR declares receiving consulting fees from Janssen; honoraria from Janssen, Amgen, Sanofi, Kite/Gilead, Novartis, and BMS; support for attending meetings or travel from Kite/Gilead; and participation on data safety monitoring or advisory board from Janssen, BMS, and Novartis. LL-C declares receiving honoraria from Kite/Gilead, Celgene, Janssen, and Novartis; support for attending meetings or travel from Kite/Gilead, Celgene, Janssen, and Novartis; and participation on data safety monitoring or advisory board from Janssen. BM-A declares to be co-inventor in the patent of ARI0002. LR declares honoraria from Janssen, BMS/Celgene, Amgen, Takeda, Sanofi, and GSK; participation on data safety monitoring or advisory board of Janssen, BMS-Celgene, Amgen, Takeda, Sanofi, and GSK. ML-P declares receiving consulting fees from Celgene/BMS; honoraria from Janssen and Kite/Gilead; and participation on data safety monitoring or advisory board from Celgene/BMS and Novartis. LGR-L declares honoraria from Janssen, GSK, Sanofi, and BMS; travel grants from Janssen, Amgen, GSK, Pfizer and Sanofi; and participation on data safety monitoring or advisory board from GSK and Sanofi. AS-S declares receiving travel grants from Jazz Pharmaceuticals, Pfizer, and MSD. JAP-S declares research and travel support Takeda, Abbvie, Gilead, AMGEN, Jazz, Alexion, Pierre Fabre and Beigene; educational activities, speaker, and advisory fees with Gilead, Jazz, Alexion, AMGEN, Novartis, Janssen, BMS, and MSD; and participation on data safety monitoring or advisory board from Gilead, Jazz, Alexion, AMGEN, Novartis, Janssen, BMS and MSD. BP reports research funding from BMS, GSK, Roche, Beigene, and Sanofi; consultancy fees from BMS, GSK, Janssen, Sanofi and Takeda; honoraria from Adaptive, Amgen, Becton Dickinson, BMS/Celgene, GSK, Janssen, Sanofi, and Roche; and support for attending meetings from GSK. FP declares receiving grants from the Spanish Ministry of Health (ISCIII) and the Government of Navarra; honoraria from Janssen, Oryzon, Dialectica, Novartis, Instituto Roche, Servier, ViviaBiotech, and Techspert; support for attending meetings or travel from Gilead, Celgene, and Janssen; and a leadership or fiduciary role in RICORS Terav and IDISNA. MJ declares receiving research or travel support by Fundació Bancaria la Caixa, ISCIII, and CellNex Teleom; honoraria from educational activities, speaker, and advisory roles with Miltenyi and indirectly with sponsors of congresses; and participation on data safety monitoring or advisory boards with MAB Gyala. JMM declares receiving honoriaria from Gilead/Kite, Novartis, BMS/Celgene, and Roche; travel grants, accommodation, and expenses from Jazz Pharma, Gilead-Kite, Janssen, and Sandoz; and consulting or advisory board fees in Jazz Pharma, Novartis, and Sandoz. M-VM declares honoraria derived from lectures and participation in advisory boards from Janssen, BMS/Celgene, Takeda, Amgen, GSK, Pfizer, Regeneron, Roche, and Sanofi. MP declares receiving honoraria from Thermofisher Scientific and LetiPharma. AU-I declares receiving grants from the Spanish Ministry of Health (ISCIII); honoraria for lectures from BMS and Gilead; support for attending meetings from Amgen; 23% of participation in ARI-002 patent ARI-001 patent in preparation; advisory board fees and participation in Miltenyi biomedicine; being coordinator of the Spanish group of CAR T-cell therapy. CFL declares receiving grants through his institution from BMS, Janssen, and Amgen; honoraria from Amgen, Janssen, BMS, GSK, and Sanofi; support for attending meetings or travel from Janssen, BMS, GSK, and Amgen; and participation in data safety monitoring or advisory boards with Janssen, BMS, Amgen, Pfizer, and Sanofi. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The kinetics of SARS-CoV-2 reactive IgG antibodies after full vaccination and booster in allogeneic and autologous stem cell transplantation (allo-HSCT, ASCT) and chimeric antigen receptor T-cell therapy (CAR-T) are of utmost importance for estimating risk of infection. A prospective multicenter registry-based cohort study, conducted from December 2020 to July 2022 was used to analyze antibody waning over time, booster effect and the relationship of antibody response and breakthrough infection in 572 recipients (429 allo-HSCT, 121 ASCT and 22 CAR-T cell therapy). A significant decline in antibody titers was observed at 3 and 6 months after full vaccination in recipients without pre-vaccine SARS-CoV-2 infection, whereas recipients infected prior to vaccination showed higher and stable antibody titers over time. In poor responders, a booster dose was able to increase antibody titers in 83% of allo-HSCT and 58% of ASCT recipients but not in CART-T cell recipients [0%] (p < 0.01). One-year cumulative incidence of breakthrough infection was 15%, similar among cell therapy procedures. Immunosuppressive drugs at the time of vaccination [hazard ratio (HR) 1.81, p = 0.0028] and reduced intensity conditioning (HR 0.49, p = 0.011) were identified as the only conditions associated with different risk of breakthrough infection in allo-HSCT recipients. Antibody titers were associated with breakthrough infection and disease severity. No death was observed among the 72 breakthrough infections. Antibody level decay after the first two vaccine doses was common except in recipients with pre-vaccination SARS-CoV-2 infection. Poorly responding allo-HSCT recipients showed a response advantage with the booster as compared to ASCT and, especially, the null response found in CAR-T cell recipients. Antibody titers were positively correlated with the risk of breakthrough SARS-CoV-2 infection which was mainly driven by the immunosuppression status., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16-20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant., (© 2023. The Author(s).)

Background: The clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has not yet been established., Patients and Methods: A prospective multicenter registry-based cohort study conducted from December 2020 to December 2021 by the Spanish transplant and cell therapy group was used to analyze the relationship of antibody response at 3-6 weeks after full vaccination (2 doses) with breakthrough SARS-CoV-2 infection in 1394 patients with hematological disorders., Results: At a median follow-up of 165 days after complete immunization, 37 out of 1394 (2.6%) developed breakthrough SARS-CoV-2 infection at median of 77 days (range 7-195) after full vaccination. The incidence rate was 6.39 per 100 persons-year. Most patients were asymptomatic (19/37, 51.4%), whereas only 19% developed pneumonia. The mortality rate was 8%. Lack of detectable antibodies at 3-6 weeks after full vaccination was the only variable associated with breakthrough infection in multivariate logistic regression analysis (Odds Ratio 2.35, 95% confidence interval 1.2-4.6, p = 0.012). Median antibody titers were lower in cases than in non-cases [1.83 binding antibody units (BAU)/mL (range 0-4854.93) vs 730.81 BAU/mL (range 0-56,800), respectively (p = 0.007)]. We identified 250 BAU/mL as a cutoff above which incidence and severity of the infection were significantly lower., Conclusions: Our study highlights the benefit of developing an antibody response in these highly immunosuppressed patients. Level of antibody titers at 3 to 6 weeks after 2-dose vaccination links with protection against both breakthrough infection and severe disease for non-Omicron SARS-CoV-2 variants., (© 2022. The Author(s).)

This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo-HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3-6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA-based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS-CoV-2-reactive antibodies were observed in 242 (78%) of allo-HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo-HSCT recipients identified lymphopenia < 1 × 10 9 /ml (odds ratio [OR] 0.33, 95% confidence interval [95% CI] 0.16-0.69, p = .003), active graft versus host disease (GvHD; OR 0.51, 95% CI 0.27-0.98, p = .04) and vaccination within the first year of transplant (OR 0.3, 95% CI 0.15-0.9, p = .04) associated with lower antibody detection whereas. In ASCT, non-Hodgkin's lymphoma (NHL; OR 0.09, 95% CI 0.02-0.44, p = .003) and active corticosteroid therapy (OR 0.2, 95% CI 0.02-0.87, p = .03) were associated with lower detection rate. We report an encouraging rate of SARS-CoV-2-reactive antibodies detection in these severe immunocompromised patients. Lymphopenia, GvHD, the timing of vaccine, and NHL and corticosteroids therapy should be considered in allo-HSCT and ASCT, respectively, to identify candidates for SARS-CoV-2 antibodies monitoring., (© 2021 Wiley Periodicals LLC.)