ABSTRACT
Background: COVID-19 has been associated with high mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Aim: To study outcome over time and identify risk factors for mortality in patients reported to the EBMT registry. Methods: 776 allo-HCT patients reported during the first 21 months of the pandemic up until Nov. 2021 were included. Cox regression models were produced to assess risk factors for mortality. Results: The median age was 49.4 years (min-max;1.0 - 80.7). The median time from HCT to COVID-19 diagnosis was 14.1 (0.0-292.7) months during the first period (February 28 - July 31, 2020), 24.4 (0.1-287.6) months during the 2nd (August 1, 2020 - January 31, 2021), and 24.8 (0.1-324.5) months during the 3rd (February 1 - November 30, 2021). 110/776 (14.2%) patients died a median of 21.5 days after diagnosis of SARS-CoV-2 infection. Children had a significantly lower mortality than adults. In multivariate analysis, increasing age (HR 1.27 (95% CI 1.11-1.44;p = .0004), worse performance status (HR 1.48 (1.32-1.65;p <.0001), contracting COVID-19 within the first 30 days after HCT (HR 4.69 (2.44-9.02);p <.0001), ongoing immunosuppression (HR 2.05 (1.20-3.50);p = .009), and recipient CMV seropositivity (HR 2.38 (1.25-4.52);p = .008) had negative impact on overall survival while patients contracting COVID-19 in the 2nd or 3rd period had higher overall survival (p = .0003). Conclusion: Although the outcome of COVID-19 has improved, patients having risk factors still showed high mortality and preventive measures have to be taken.
ABSTRACT
Background and study design: Patients with immunodeficiencies including CLL have an increased risk of severe infections and may not respond well to conventional vaccines. Two early international surveys reported that hospital-admitted Covid-19 patients with CLL had a high fatality rate (Mato et al., 2020;Scarfo et al., 2020). We recently showed that a robust and durable B and/or T cell immunity occurred in most convalescent CLL patients (Blixt et al., 2021). In contrast, the first publication on vaccination against SARS-CoV-2 in CLL reported seroconversion in only 39.5% of patients (Herishanu et al., 2021). We conducted a prospective clinical trial (COVAXID, clinicaltrials.gov: NCT04780659) in patients with various types of immunodeficiency and matched controls (n=539). Five equally sized cohorts were included: primary immunodeficiency, HIV, allogeneic transplantation or CAR-T, solid organ transplantation as well as CLL. The primary endpoint was seroconversion measured 2 weeks after the 2nd dose of the Pfizer-BioNTech vaccine (Comirnaty). Antispike antibodies in saliva (which may better correlate with protection, Khoury et al., 2020) and T cells (IFN-gamma ELISpot) were also measured. We report here the results of the CLL cohort. Results: Ninety CLL patients were included in four predefined subgroups: indolent untreated disease (n=30);prior chemoimmunotherapy including a CD20 mAb 9-30 months ago (n=20);ongoing BTKi therapy (n=30);and stopped/paused ibrutinib (all >3 months ago) (n=10). The median age was 70 years (range 23-87) and 67% were men. Median IgG was 6.7 g/L (range 1.0-20.8) and 50% had a value below the lower normal range. Reactogenicity occurred in 82.9 and 77.1% of the CLL patients and 81.6 and 85.0% of the controls after doses 1 and 2, respectively. The severity of reactogenicity was similar in patients and controls. AEs≥grade 2 was seen in five patients within 2 weeks after dose 2 but none was considered related to the vaccine. No hematological toxicity was observed. Data analysis on seroconversion is ongoing. Preliminary analysis of saliva showed that on D35 (i.e. 14 days after 2nd dose) 62% of CLL patients (95% of healthy controls) had developed IgG to S1S2 spike antigen compared to only 23% on D21 (i.e. 21 days after dose 1). Subgroup analysis (D35) indicates that ibrutinib-treated patients showed the lowest response in saliva whilst indolent and prior chemoimmunotherapy-treated groups were the best responders. A different pattern was observed for IFNgamma positive T cells with the highest responses in the (few) patients who had paused/stopped ibrutinib with other subgroups having lower T cell responses. Conclusions: This prospective clinical trial verified that the BNT162b2 mRNA vaccine was well-tolerated in patients with CLL. Our preliminary results indicate that anti-spike antibodies in saliva and T cell responses were frequently observed after full vaccination but with different response patterns in CLL subgroups. Details of the study including seroconversion and the overall response rate will be presented at the meeting.
ABSTRACT
Introduction COVID-19 is usually a mild disease in immunocompetent children, with ~1% requiring intensive care unit (ICU) admission and <0.1% mortality. Data on its course in children following hematopoietic cell transplantation (HCT) is limited. Methods Data on children following HCT who developed COVID-19 (diagnosed by positive SARS-CoV-2 PCR on respiratory tract samples) during 3.2020-4.2021 were prospectively collected by EBMT and GETH, including demography, HCT data, COVID-related manifestations, ICU admission and mortality. Factors associated with worse outcomes (ICU admission or mortality) were characterized. Results Sixty-two children (34 boys;median age 9;min-max;0.7-17 years) were reported from 27 centers, 16 countries;57 (92%) following allogeneic and 5 (8%) following autologous HCT. Underlying diseases were acute leukemia (23;37%), inherited disorders (9;15%), hemoglobinopathies (7;11%), solid tumor (6;10%), bone marrow failure (5;8%), other malignant (8;13%) and non-malignant (4;6%) diseases. Five (8%) children had high blood pressure;6 (10%) had underlying lung pathology. The median time from the most recent HCT to COVID was 5 months (min-max;0-169). The stem cell source was bone marrow (33);peripheral (22) or cord blood (1). Among the patients with information available, 34 (62%) underwent in-vivo T cell depletion, 20 (33%) received corticosteroids, and 36 (60%) other immunosuppressant drugs(s) within two months prior to and after the COVID-19 episode. The presence of acute grade 2-4 or chronic graft versus host disease (GVHD) was reported in 12/54 (23%) and 8/51 (16%) children, respectively. Clinical presentation (n=57) included fever (28;49%), cough (18;32%), diarrhea (8;14%), upper respiratory tract disease (as rhinorrhea, sinusitis, otitis, or pharyngitis;12;21%);six (10%) required oxygen to maintain oxygen saturation above 92%;20 children (35%) were asymptomatic. The median time from symptoms onset to COVID diagnosis was 1 day (-43-40). Sixty-three percent of patients were hospitalized;43% due to COVID. The proportion of children with neutropenia or lymphocytopenia (<500 cells/mm 3) was 75% and 73%, respectively. Sixteen children (26%) had evidence of viral (n=10), bacterial (n=6) or fungal (n=2) coinfections. The median time from COVID diagnosis to the last follow-up in alive patients was 69 days (min-max;2 - 294). Six (10%) children who developed COVID at a median 6.5 (min-max;2- 16) months following allo-HCT (median age 6 years;5 boys) required ICU care within a median 6 (min-max;-5-15) days after diagnosis. All of them were neutropenic, received steroids, and other immunosuppressive drugs at COVID diagnosis;5 had undergone in-vivo T cell depletion;5 were lymphocytopenic, 5 had GVHD (2 acute and 3 chronic);3 received non-invasive and 2 invasive ventilation. Three children had viral or bacterial coinfections. Three children died. Six (10%) children (5 boys, median age 10.5 years;min-max;4-13) who developed COVID at median 2 (min-max;0-147) months following allo-HCT died within median 35 days (min-max;5-54) after diagnosis. One had high blood pressure, and none suffered from underlying lung pathology. At the time of COVID, 3 were neutropenic, 2 lymphocytopenic;4 had GVHD (2 acute, 2 chronic);3 received steroids and 4 immunosuppressive drugs. Two had viral or bacterial coinfections. Five had positive SARS-CoV-2 PCR at the time of death. In 3, COVID was the primary cause of death. We compared nine children with the worse outcomes to 53 children with benign course. Among patients alive at 100-day post HCT, the probability of worse outcomes was higher in patients with vs. without chronic GVHD (Figure). No other significant differences were observed in demographic, underlying disease, and HCT-related characteristics. Compared to adults following HCT (Ljungman, Leukemia 2021), children had: - Shorter median time from HCT to COVID diagnosis, 5 vs 18 months;- Higher proportion of asymptomatic infections, 35% vs 9%;- Lower proportion of those who required oxygen, 10% vs 35%;- Lower all-cause mortality, 10% vs 29%. Conclusions Children following HCT with COVID-19 have a higher risk of ICU admission and mortality compared to immune competent children. The presence of chronic GVHD at COVID diagnosis was associated with worse outcomes. COVID course following HCT is milder in children compared to adults. [Formula presented] Disclosures: Averbuch: Takeda: Consultancy;Pfizer: Consultancy;GSK: Speakers Bureau. De La Camara: Roche: Consultancy;IQONE: Consultancy. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria. Mikulska: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Gilead: Speakers Bureau;MSD: Speakers Bureau;Janssen: Speakers Bureau;Biotest: Speakers Bureau. Kulagin: Roche: Speakers Bureau;Sanofi: Speakers Bureau;Generium: Speakers Bureau;Biocad: Research Funding;Apellis: Research Funding;Alexion: Research Funding;X4 Pharmaceuticals: Research Funding;Novartis: Speakers Bureau;Johnson & Johnson: Speakers Bureau;Pfizer: Speakers Bureau. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees;Gilead: Speakers Bureau. Lawson: Alexion: Honoraria. Kroeger: Neovii: Honoraria, Research Funding;Sanofi: Honoraria;Jazz: Honoraria, Research Funding;Celgene: Honoraria, Research Funding;Riemser: Honoraria, Research Funding;Gilead/Kite: Honoraria;AOP Pharma: Honoraria;Novartis: Honoraria. Styczynski: MSD, Pfizer, Giled, TEVA, Jazz, Novartis: Honoraria, Speakers Bureau. Ljungman: Takeda: Consultancy, Other: Endpoint committee, speaker;Enanta: Other: DSMB;Janssen: Other: Investigator;OctaPharma: Other: DSMB;Merck: Other: Investigator, speaker;AiCuris: Consultancy.
ABSTRACT
Background The ongoing Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having an enormous impact on society worldwide and is especially posing a threat to health in vulnerable patients, such as patients with immune deficiencies. It is expected that patients who received Chimeric Antigen Receptor T-cell (CAR T-cell) therapy for hematologic malignancies are at risk for poor outcomes after COVID-19 due to their severely immunocompromised state caused by prior cumulative immunochemotherapy, on-target/off-tumor B-cell depletion, hypogammaglobulinemia and ongoing cytopenias. Current data are limited to small case series and case reports. This study describes the clinical characteristics and outcomes of CAR T-cell therapy recipients after developing COVID-19 in the largest cohort to date. Methods In response to the COVID-19 pandemic, the European Society for Blood and Marrow Transplantation (EBMT) developed a special COVID-19 report form to capture data from all patients with COVID-19 after treatment with CAR T-cell therapy for hematologic malignancies. Only PCR positive SARS-CoV-2 diagnosed patients before June 1 st, 2021 were included. The aim of this study was to describe the clinical course after COVID-19 diagnosis and evaluate overall survival. Overall survival probabilities were calculated using the Kaplan Meier method. Factors associated with mortality after COVID-19 diagnosis were examined using a Cox proportional hazard model. Results A total of 57 patients from 11 countries were reported to the EBMT. One patient with incomplete data at diagnosis and without any follow up information had to be excluded from the analysis. The median age of these 56 patients was 57.7 years (min-max 5.2 - 72.8) including 55 adults and one child. Of these patients, 32 were male. CAR T-cell therapy was given to 46 patients with B-cell-non-Hodgkin lymphoma, 7 patients with B-cell acute lymphoblastic leukemia, and 3 patients with multiple myeloma. The median time from CAR T-cell infusion to COVID-19 diagnosis was 7.4 months (min-max 0.03 - 25.3). At the time of COVID-19 diagnosis, 62.5% of patients were in complete remission, 12.5% of patients had a partial response and 25% of patients had relapsed/refractory disease. Forty-five patients (80%) were admitted to hospital (median 26,5 days, min-max 3-171) due to COVID-19. Of the admitted patients, 24 (53%) needed oxygen support. Twenty-two (49%) patients were admitted to the intensive care unit (median 14 days, min - max 2-65) and 16 (73%) of these patients received invasive ventilation. At the time of analysis, 25 of the 56 patients had died (44.6%), most (23/25) due to COVID-19, resulting in a COVID-19 attributable mortality rate of 41%. The Kaplan-Meier estimate of overall survival is shown in Figure 1. The median follow-up from COVID-19 diagnosis was 20.9 weeks. In 1 of the 32 alive patients there was no resolution of COVID-19 at the time of analysis. In multivariate analysis, older age (hazard ratio (HR) 1.50, 95% CI 1.11-2.03, p=0.009) and comorbidities (HR 2.56, 95% CI 1.05-6.23, p=0.001) had a negative impact on overall survival. Better performance status at time of admission (HR 0.72, 95% CI 0.59-0.88, p=0.038) had a positive impact on overall survival. Sex, time from CAR T-cell therapy to COVID-19 diagnosis, disease remission status and the occurrence of neurotoxicity or cytokine release syndrome after CAR T-cell infusion did not have a significant effect on overall survival in the multivariate analysis. Conclusion Patients with COVID-19 after B-cell-targeted CAR T-cell therapy have a very poor outcome. As it remains uncertain whether currently applied vaccination strategies against SARS-CoV-2 are effective after CAR T-cell therapy, vaccination of health-care personnel and family members in combination with protective measures against viral exposure are likely to play the most important role in protecting this vulnerable group of patients. Better treatment strategies are urgently needed. [Formula present d] Disclosures: Ljungman: OctaPharma: Other: DSMB;Enanta: Other: DSMB;Janssen: Other: Investigator;Takeda: Consultancy, Other: Endpoint committee, speaker;AiCuris: Consultancy;Merck: Other: Investigator, speaker. De La Camara: IQONE: Consultancy;Roche: Consultancy. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Barba: Novartis: Honoraria;Gilead: Honoraria;BMS: Honoraria;Amgen: Honoraria;Pfizer: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Sesques: Novartis: Honoraria;Chugai: Honoraria;Kite, a Gilead Company: Honoraria. Bachy: Kite, a Gilead Company: Honoraria;Novartis: Honoraria;Daiishi: Research Funding;Roche: Consultancy;Takeda: Consultancy;Incyte: Consultancy. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Janssen: Consultancy, Honoraria. Thieblemont: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Mutsaers: BMS: Consultancy;AstraZeneca: Research Funding. Nicholson: Kite, a Gilead Company: Other: Conference fees, Speakers Bureau;Novartis: Consultancy, Other: Conference fees;BMS/Celgene: Consultancy;Pfizer: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy;Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Ribera: NOVARTIS: Consultancy, Speakers Bureau;TAKEDA: Consultancy, Research Funding, Speakers Bureau;ARIAD: Consultancy, Research Funding, Speakers Bureau;SHIRE: Consultancy, Speakers Bureau;AMGEN: Consultancy, Research Funding, Speakers Bureau;Pfizer: Consultancy, Research Funding, Speakers Bureau. Sanderson: Kite, a Gilead Company: Honoraria;Novartis: Honoraria. Bloor: Kite, a Gilead Company: Honoraria;Novartis: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Ayuk: Novartis: Honoraria;Janssen: Honoraria;Takeda: Honoraria;Mallinckrodt/Therakos: Honoraria, Research Funding;Gilead: Honoraria;Miltenyi Biomedicine: Honoraria;Celgene/BMS: Honoraria. Kröger: Novartis: Research Funding;Riemser: Honoraria, Research Funding;Sanofi: Honoraria;Neovii: Honoraria, Research Funding;Jazz: Honoraria, Research Funding;Gilead/Kite: Honoraria;Celgene: Honoraria, Research Funding;AOP Pharma: Honoraria. Kersten: Celgene: Research Funding;Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support;Roche: Consultancy, Honoraria, Other: Travel support, Research Funding;BMS/Celgene: Consultancy, Honoraria;Takeda: Research Funding;Novartis: Consultancy, Honoraria, Other: Travel support;Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Mielke: DNA Prime SA: Speakers Bureau;Im unicum: Other: Data safety monitoring board;Novartis: Speakers Bureau;Miltenyi: Other: Data safety monitoring board;Gilead/KITE: Other: Travel support, Expert panel;Celgene/BMS: Speakers Bureau.