SARS-CoV-2-reactive antibody waning, booster effect and breakthrough SARS-CoV-2 infection in hematopoietic stem cell transplant and cell therapy recipients at one year after vaccination.

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.

One-year breakthrough SARS-CoV-2 infection and correlates of protection in fully vaccinated hematological patients.

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.

SARS-CoV-2 vaccine response and rate of breakthrough infection in patients with hematological disorders.

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.

Applicability of probabilistic graphical models for early detection of SARS-CoV-2 reactive antibodies after SARS-CoV-2 vaccination in hematological patients.

Prior studies of antibody response after full SARS-CoV-2 vaccination in hematological patients have confirmed lower antibody levels compared to the general population. Serological response in hematological patients varies widely according to the disease type and its status, and the treatment given and its timing with respect to vaccination. Through probabilistic machine learning graphical models, we estimated the conditional probabilities of having detectable anti-SARS-CoV-2 antibodies at 3-6 weeks after SARS-CoV-2 vaccination in a large cohort of patients with several hematological diseases (n= 1166). Most patients received mRNA-based vaccines (97%), mainly Moderna® mRNA-1273 (74%) followed by Pfizer-BioNTech® BNT162b2 (23%). The overall antibody detection rate at 3 to 6 weeks after full vaccination for the entire cohort was 79%. Variables such as type of disease, timing of anti-CD20 monoclonal antibody therapy, age, corticosteroids therapy, vaccine type, disease status, or prior infection with SARS-CoV-2 are among the most relevant conditions influencing SARS-CoV-2-IgG-reactive antibody detection. A lower probability of having detectable antibodies was observed in patients with B-cell non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibodies within 6 months before vaccination (29.32%), whereas the highest probability was observed in younger patients with chronic myeloproliferative neoplasms (99.53%). The Moderna® mRNA-1273 compound provided higher probabilities of antibody detection in all scenarios. This study depicts conditional probabilities of having detectable antibodies in the whole cohort and in specific scenarios such as B cell NHL, CLL, MM, and cMPN that may impact humoral responses. These results could be useful to focus on additional preventive and/or monitoring interventions in these highly immunosuppressed hematological patients.

SARS-CoV-2-reactive antibody detection after SARS-CoV-2 vaccination in hematopoietic stem cell transplant recipients: Prospective survey from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group.

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 × 109 /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.

Prospective Pilot Study of Telehealth As Domiciliary Follow-up after Hematopoietic Cell Transplantation during the COVID19 Pandemic

IntroductionAn increased risk of mortality has been documented in transplanted patients affected by Coronavirus Disease 2019 (COVID19) with an estimated mortality rate between 20-40%. Multiple efforts are ongoing to control COVID19 pandemic, and clinical practice is being adapted at the same time as the pandemic progresses around the world. To reduce unnecessary in-person appointments has become crucial to minimize hospital exposition. Digital technologies allow us to perform real-time monitoring of patients' clinical status. A real-time patient monitoring system through the use of a smartphone application and wearable devices was implemented at our Center during the COVID19 pandemic.MethodsSince March 2020, a real time patient monitoring system was implemented at our HCT program. All consecutive adults patients transplanted between April 2020 and July 2020 were considered for the study. Vital signs and relevant clinical information were reported during 14 consecutive days after being discharged, through the online platform provided by Trilema Fundation (saludencasa.trilema.org, Fundación Trilema, Valencia, Spain). Vital signs (cardiac frequency, blood pressure, oxygen saturation) were measured with validated oxymeters (Onyx II®, Nonin Inc, Plymouth MN USA) and blood pressure monitors (iHealth Track®, Mountain View, CA USA). Temperature was measured through domiciliary thermometers. Patients were educated to measure their respiratory frequency. A checklist of clinical symptoms was filled daily. An analogue visual scale (0-10) to detect potential cases of anxiety or depressive disorders was reported daily. Scores of >6 were evaluated by a psycho-oncologist through videoconference. All the data were reported to the online platform using a smartphone app compatible with iPhone and Android systems. A direct chat between patients and physician was available through the app. Clinical information was daily supervised by an experienced HCT hematologist. Clinical interventions were arranged if significant clinical abnormalities were documented. A hematologist with experience in HCT patients revised all the patients' data daily. Programmed alarms were set in case of any of the following situations: fever >38 oC;oxygen saturation <92%;tachicardia >125/bpm, hypotension (sytolic<90 mmHg, diastolic >60 mmHg;altered mental status;persistent emesis or diarrhea). Patient´s satisfaction questionnaires were evaluated individually after finalizing the 14-days clinical monitoring.ResultsDuring the study period, 21 adults underwent HCT and 16 were s were eligible to be recruited into the study (80% feasibility) with team effort and without additional costs. Reasons for not being enrolled were: language incompatibility (1 patient), no consent (1 patient), not compatible smartphone (3 patients). Of the 16 enrolled patients, median age was 50 (range 22-70 years), 37% were female and 94% had lymphoid diseases. Thirty-eight percent of HCTs were autologous and 62% allogeneic.Of the 16 enrolled patients, 25% were not able to adequately use the app due to inability in using smartphone applications. Of the remaining 12 patients, adherence in reporting study data (number of days reported of the planned 14 days study period) was as follows (average):temperature 89%, oxygen saturation 90%, respiratory frequency 70%, cardiac frequency 85%, blood pressure 89%, symptoms reporting 65%, emotional distress 71%.Automatic alarms were activated only 3 times: twice for the presence of clinical symptoms and once, for emotional distress. A videoconference with the psycho-oncologist was requested by one patient only. The chat service to communicate with hospital personnel was used in 4 patients. Data collected with the digital system helped the clinician to early recognize arterial hypertension (1 patient) and acute cutaneous GVHD grade 1 (1 patient).Only two patients of the whole cohort were readmitted within 14 days from discharge due to grade 4 odynophagia due to HSV1/2 reactivation.Patients´ experiences with telehealth systems ar reported in table 1.ConclusionTelehealth monitoring can potentially improve patient's follow-up in terms of both physical and psychological outcomes. Technological problems still represent a barrier to a wider application of telehealth monitoring systems in the medical setting.

Use of Telehealth for Domiciliary Follow-up After Hematopoietic Cell Transplantation During the COVID-19 Pandemic: Prospective Pilot Study.

BACKGROUND: Patients who have recently received a hematopoietic cell transplant (HCT) are at higher risk of acute complications in the first weeks after discharge, especially during the COVID-19 pandemic. OBJECTIVE: The aim of this study was to test the use of a telehealth platform for the follow-up of HCT patients during the first two weeks after discharge. METHODS: In total, 21 patients who received autologous or allogeneic HCT for hematological malignancies were screened from April 30, 2020, to July 15, 2020. The telehealth platform assisted in the daily collection of vital signs as well as physical and psychological symptoms for two weeks after hospital discharge. The required medical devices (oximeter and blood pressure monitor) were given to patients and a dedicated smartphone app was developed to collect this data. The data were reviewed daily through web-based software by a hematologist specializing in HCT. RESULTS: Only 12 of 21 patients were able to join and complete the study. Technological barriers were the most frequent limiting factor in this study. Among the 12 patients who completed the study, adherence to data reporting was high. The patients' experience of using such a system was considered good. In two cases, the system enabled the early recognition of acute complications. CONCLUSIONS: This pilot study showed that telehealth systems can be applied in the early posttransplant setting, with evident advantages for physicians and patients for both medical and psychological aspects. Technological issues still represent a challenge for the applicability of such a system, especially for older adult patients. Easier-to-use technologies could help to expand the use of telehealth systems in this setting in the future.

The direct and indirect effects of COVID-19 pandemic in a real-life hematological setting.

BACKGROUND: Clinical outcomes of novel coronavirus 2019 disease (COVID-19) in onco-hematological patients are unknown. When compared to non-immunocompromised patients, onco-hematological patients seem to have higher mortality rates. AIMS: We describe the characteristics and outcomes of a consecutive cohort of 24 onco-hematological patients with COVID-19 during the first month of the pandemic. We also describe variations in healthcare resource utilization within our hematology department. METHODS AND RESULTS: Data from patients between the first month of the pandemic were retrospectively collected. Clinical and logistic data were also collected and compared with the average values from the prior 3 months of activity. Prevalence of COVID-19 in our hematological population was 0.4%. Baseline characteristics were as follows: male sex: 83%, lymphoid diseases: 46%, median age: 69 (22-82) years. Median follow-up in survivors was 14 (9-28) days and inpatient mortality rate was 46%. Average time to moderate/severe respiratory insufficiency and death were 3 (1-10) and 10 (3-18) days, respectively. Only 1 out of every 12 patients who developed moderate to severe respiratory insufficiency recovered. Upon univariate analysis, the following factors were associated with higher mortality: age ≥ 70 years (P = .01) and D-dimer ≥900 mcg/L (P = .04). With respect to indirect effects during the COVID-19 pandemic, and when compared with the prior 3 months of activity, inpatient mortality (excluding patients with COVID-19 included in the study) increased by 56%. This was associated with a more frequent use of vasoactive drugs (+300%) and advanced respiratory support (+133%) in the hematology ward. In the outpatient setting, there was a reduction in initial visits (-55%) and chemotherapy sessions (-19%). A significant increase in phone visits was reported (+581%). CONCLUSION: COVID-19 pandemic is associated with elevated mortality in hematological patients. Negative indirect effects are also evident within this setting.