Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality.In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41.Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations.A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution.The Netherlands Organisation for Health Research and Development and Amsterdam UMC.
Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT. The process of selection of feasibility for transplant in myelofibrosis (MF) is determined by several factors such as age, disease stage, comorbidities, performance status, and donor availability.1 The Myelofibrosis Transplant Scoring System (MTSS) has emerged as a valuable tool for selecting suitable candidates for transplant in MF. By incorporating patient-, transplant-, and donor-specific variables, the MTSS has proven its effectiveness in stratifying patients at varying risks of non-relapse mortality (NRM) and overall survival (OS). More recently, a CIBMTR/EBMT score has been identified as an effective tool for MF transplant candidates' prognostication. However, it should be noted that the prognostic ability of both scores may be reduced by a lack of information on the presence of comorbidities and body mass index (BMI) prior to the transplant, which was not available in these analyses.2 In order to assess the role of comorbidities and BMI in MF patients undergoing transplantation the Chronic Malignancies Working Party (CWMP) of the EBMT performed a retrospective study with the aim to provide more comprehensive and reliable data on the impact of these factors on transplant outcomes and to identify potential areas for improvement in current MF transplantation protocols. The policy of such study is consistent with that previously published.3 Inclusion and exclusion criteria, definitions, and methodology are available in the supplemental material. Overall, 4086 patients were included in the final analysis. Patients' characteristics are available in Table S1. Out of 3157 patients with fully reported comorbidity data, 1701 patients (54%) had at least one comorbidity, with pulmonary conditions being the most prevalent (12.7% moderate and 6.8% severe), as documented also in other transplant scenarios.4 Other comorbidities present in more than 5% of cases were cardiac disorders (8.6%), diabetes (5.7%) and prior-solid tumor (5.4%). An overview of all comorbidities is available in Figure S1. Concerning the HCT-CI, 1701 (54%) patients had a low (0), 762 (24%) intermediate (1, 2) and 694 (22%) high-risk (≥3) score, respectively. Table S2 reports the clinical characteristics stratified according to different HCT-CI classes. As expected, higher risk class did correlate with increased use of RIC regimens (high risk with 70% vs. 69% and 62% in intermediate, and low risk, respectively), decreased KPS (KPS <80 in 11% vs. 8.1 and 5%). Moreover, the proportion of the splenectomised patients was higher for the high-risk HCT-CI category (14% vs. 9% and 6% in high, intermediate, and low HCT-CI categories, respectively), leading to a lower prevalence of massive splenomegaly (≥15 cm) (17% vs. 22% and 28%). Compared to previous cohorts in which the HCT-CI had been developed and subsequently validated,5 the prevalence of comorbidities was higher in our study. Overall, these differences underscore a significant shift in the characteristics of the transplant population over time, as transplantation is increasingly considered in older patients with comorbidities. By univariable analysis, both NRM and OS were statistically associated with HCT-CI risk categories. The 5-year expected NRM was 27% (25%–30%), 33% (29%–36%), and 36% (32%–40%) in low, intermediate, and high-risk HCT-CI groups (p < .001), respectively. The 5-year estimated OS was 58% (55%–61%), 52% (47%–56%), and 46% (42%–51%) for the low, intermediate, and high HCT-CI scores, respectively (p < .001) (Figure S2). No statistical differences were observed in relapse incidence (p = .22), and incidence of grade 2–4 acute GVHD (p = .056) or chronic GVHD (p = .46) depending on the HCT-CI. Table S3 details the causes of NRM. After adjusting for other variables well known to be associated with NRM and OS in MF, high-risk HCT-CI was strongly associated with both NRM (HR 1.32, 95% CI 1.12–1.55, p < .001) and OS (HR 1.27, 95% CI 1.11–1.46, p < .001), relative to patients with a low-risk HCT-CI (score of 0) (Figure S3). Also, splenectomy status did not appear to affect NRM in the context of high HCT-CI class (p = .95). Therefore, the presence of comorbidities continues to play a negative prognostic role on allo-HCT outcomes and should be integrated into the selection process for MF patients undergoing transplantation along with the existing MTSS and CIBMTR/EBMT tools. A total of 2679 patients had information on BMI at time of transplant: 50 patients were classified as underweight (1.9%), 1318 as normal weight (49.2%), 964 as overweight (36%), and 347 as grade 1 to 3 obese (13%). Median BMI was 24.9 (range, 12.1–46.1). The high prevalence of overweight and obese individuals suggested that patients with robust nutritional reserves were more often considered suitable for transplantation, while cachectic or sarcopenic patients may have had their transplant deferred due to a general tendency among physicians to avoid transplantation in such conditions, generally associated with worse transplant course. As compared to under-normal weight patients (1368, 51.1%), overweight/obese patients were more frequently males (69% vs. 57%), and had been more frequently exposed to ruxolitinib (40% vs. 34%). Continuous BMI was weakly correlated with all other comorbidities. Aside from a correlation of 0.11 with diabetes, correlations with any other comorbidity did not exceed ±0.07 (Table S4). Despite differences in comorbidities and patient characteristics between different BMI classes, on univariable analysis, no significant differences were found across the BMI groups in terms of NRM (p = .5), OS (p = .3), grade II-IV acute GVHD (p = .73), or chronic GVHD (p = .6). By contrast, a modest difference was found regarding relapse incidence (p = .031). Furthermore, within a multivariable model that accounted for other variables known to correlate with NRM and OS in MF, including weight loss before allo-HCT, BMI was determined to have no significant impact on either NRM (p = .59) or OS (p = .41). Figure 1A,B show the hazard ratio plots of BMI (relative to a reference BMI of 21.75) on OS and NRM respectively, and highlight the very limited impact of BMI on OS and NRM. Likelihood ratio tests also confirm the lack of non-linear effects on both OS (p = .25) and NRM (p = .33). These findings contrast with the original HCT-CI data, which identified a BMI >35 as a risk factor in both NRM and OS after allo-HCT.5 In this context, it seems evident that overweight and obese MF patients should not be excluded from a potentially curative life-saving procedure. In MF, overweight or obesity can be associated with milder disease activity, resulting in better nutritional status and suggesting a greater likelihood of improved survival. On the other hand, even patients with lower BMIs can derive benefits from a transplant procedure. Importantly, evidence of weight loss >10% within 6 months prior to allo-HCT was significantly associated with higher risk of NRM (HR 1.19, 95% CI 1.01–1.39, p = .042), and a trend toward shortened OS (HR 1.19, 95% CI 0.96–1.46, p = 0.108). Therefore, it seems to be vital to consider transplantation not when the disease is already symptomatic with ongoing weight loss. In this case, the optimization of nutritional status where possible should be considered. The major strengths of this study rely on the novelty of this information in the largest sample of MF transplant patients, with comprehensive assessment of comorbidities and BMI and significant follow-up. These numbers permit a comprehensive identification of factors associated with allo-HCT outcomes. Nevertheless, it's important to acknowledge some limitations in this study. First, despite adjusting for weight-loss prior to allo-HCT, the conclusions regarding the effect of BMI on mortality were likely also affected by selection effects that could not be modeled. In particular, patients with BMI >35 (i.e., for whom one would expect a clear negative impact on mortality) in this study may have been selected for allo-HCT based on other more favorable disease characteristics or lack of other comorbidities. Second, the study lacks detailed information regarding specific treatments administered for the management of comorbidities and weight loss before transplantation, which could potentially impact allo-HCT results; additionally, the definition of comorbidities lacks an understanding of their functional impact, and there is a current suggestion to include concomitant frailty assessment in cancer patients.4 Third, the amount of missing data for both main variables and important adjustment factors was substantial. We chose not to exclude patients on the basis of unavailable comorbidity and BMI information (which may have rendered the cohort less representative), and instead made use of the observed information in the data in order to multiply impute the missing values, thereby potentially enhancing the robustness of the study results. However, the authors believe that despite these limitations, the significance of the topic, which pertains to an ever-growing number of MF patients over the years, outweighs these concerns. In conclusion, this study, for the first time in a robust fashion, highlights the prognostic significance of HCT-CI in MF patients undergoing allo-HCT. Additionally, it suggests that BMI at the time of transplantation has a limited impact on transplant outcomes in this patient population. These findings enhance our understanding of risk factors and can guide clinical decision-making for MF patients considering allo-HCT. Nevertheless, future research should aim to validate these findings and explore the possibility of integrating comorbidity assessment alongside existing scoring systems and splenomegaly evaluation3, 6 to develop effective tools for selecting MF patients as candidates for transplantation. NP, DM, JCH, TC, GB conceived and designed the research. NP, EB, LdW, LK, DM, JCH, TC, GB, KR, MR, JD, LA, DR analyzed and interpreted the data. NP and EB wrote the manuscript. NMK, TS, RPL, JP, KS, AB, AC, PD, DB, IYA, SLP, JF, PC, GH, WR, SS enrolled patients in the study and collected data. All authors reviewed the manuscript before submission. The authors declare no conflicts of interest. Each patient provided consent for the collection of data by the EBMT. The EBMT only releases de-identified datasets that comply with all relevant global regulations regarding privacy and confidentiality. The data underlying this publication will be made available upon written request to the corresponding author. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Illness after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous variants. Data on the disease burden in immunocompromised patients are lacking. We investigated the clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 (COVID-19) caused by Omicron.Organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients infected with the Omicron variant were included. Characteristics of consenting patients were collected and patients were contacted regularly until symptom resolution. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed.114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received 3 mRNA vaccinations. While only 1 patient died, 23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2 immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL) at diagnosis, being older, being a lung transplant recipient, having more comorbidities, and having a higher frailty score were associated with hospital admission (all P < .01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of these patients, and 1 died.While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. In addition to vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.
Background: Patients with hematologic malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality.Methods: In this cohort study we quantified SARS-CoV-2-specific antibody concentration and neutralizing activity in SARS-CoV-2 naive, immunocompromised patients with hematologic malignancies who received 4 COVID-19 mRNA vaccinations.Findings: 414 patients with hematologic malignancies were included in our analyses. Although S1 IgG concentrations significantly improved after the fourth dose, they remained significantly lower compared to those obtained by age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralizing antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in some patient groups with persistent immunodeficiencies. 19% of patients did not seroconvert despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralizing capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations.Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a hematologic malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution.Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC.Declaration of Interest: None of the authors declare competing financial interests.Ethical Approval: Study protocols were approved by the Institutional Review Board of Amsterdam UMC location Vrije Universiteit and participating centers (COBRA-KAI study) and Utrecht University (VITAL cohort). All patients provided written informed consent.
Biomarkers measured in blood chemistry before allogeneic hematopoietic stem cell transplantation (HSCT) may reflect patients' physiological status. We hypothesized that selected markers are predictive for nonrelapse mortality (NRM) following transplantation and could contribute to risk assessment. We investigated the value of pre-HSCT albumin, estimated glomerular filtration rate (eGFR), and alkaline phosphatase (AlkP) in predicting NRM. We retrospectively analyzed clinical and laboratory data from 1217 patients receiving a first HSCT in 2 European centers between 2003 and 2015. Transplantation indications and conditioning regimens were diverse. Patients had a median age of 55 years and hematopoietic cell transplantation comorbidity index (HCT-CI) scores of 0 (24%), 1 to 2 (39%), and ≥3 (37%). Cutoffs of eGFR <60 mL/min, albumin <3.5 g/dL, and AlkP >180 IU/L corresponded with 8.8%, 8.3%, and 6.5% of the patients, respectively. eGFR and albumin were associated with increased risk and higher cumulative incidence of day-100, 1-year, and 2-year NRM, both as continuous or categorized variables. A similar pattern was observed for AlkP, except for day-100 NRM. In multivariable analyses, eGFR and albumin were consistently among the top risk factors for early and late-term NRM, abrogating the role of age. Prediction models for day-100, 1-year, and 2-year NRM based only on HCT-CI resulted in c-statistics of .565, .575, and .577, respectively. Addition of both biomarkers increased c-statistics for day-100, 1-year, and 2-year NRM to .651, .633, and .624, respectively. Albumin and eGFR are prognostic biomarkers for NRM after HSCT and improve the discriminative power of the HCT-CI.
