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1.
JAMA Oncol ; 2022 Aug 11.
Article in English | MEDLINE | ID: covidwho-1990392

ABSTRACT

Importance: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. Objective: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Design, Setting, and Participants: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities. Exposures: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and Measures: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients. Results: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody. Conclusions and Relevance: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial Registration: EudraCT Identifier: 2021-001072-41.

2.
J Infect Dis ; 2022 Aug 04.
Article in English | MEDLINE | ID: covidwho-1973177

ABSTRACT

The aim of this randomized, controlled trial is to determine whether anti-SARS-CoV-2 hyperimmune globulin protects against severe COVID-19 in severely immunocompromised, hospitalized, COVID-19 patients. Patients were randomly assigned to receive anti-SARS-CoV-2 hyperimmune globulin (COVIG) or intravenous immunoglobulin without SARS-CoV-2 antibodies. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven out of eight (88%) in the IVIG control group (p = 0.015, Fisher's exact test). COVIG may be a valuable treatment in severely immunocompromised, hospitalized, COVID-19 patients and should be considered when no monoclonal antibody therapies are available. The trial was registered at www.trialregister.nl (#NL9436).

3.
Blood Adv ; 6(5): 1537-1546, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1666615

ABSTRACT

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG ≥ 300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >50% of patients obtained S1 IgG ≥ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG ≥ 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer-cell number, and number of immunosuppressants predicted S1 IgG ≥ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553.


Subject(s)
COVID-19 , Hematology , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2 , Vaccination
4.
Roeker, Lindsey E.; Scarfo, Lydia, Chatzikonstantinou, Thomas, Abrisqueta, Pau, Eyre, Toby A.; Cordoba, Raul, Muntañola Prat, Ana, Villacampa, Guillermo, Leslie, Lori A.; Koropsak, Michael, Quaresmini, Giulia, Allan, John N.; Furman, Richard R.; Bhavsar, Erica B.; Pagel, John M.; Hernandez-Rivas, Jose Angel, Patel, Krish, Motta, Marina, Bailey, Neil, Miras, Fatima, Lamanna, Nicole, Alonso, Rosalia, Osorio-Prendes, Santiago, Vitale, Candida, Kamdar, Manali, Baltasar, Patricia, Österborg, Anders, Hanson, Lotta, Baile, Mónica, Rodríguez-Hernández, Ines, Valenciano, Susana, Popov, Viola Maria, Barez Garcia, Abelardo, Alfayate, Ana, Oliveira, Ana C.; Eichhorst, Barbara, Quaglia, Francesca M.; Reda, Gianluigi, Lopez Jimenez, Javier, Varettoni, Marzia, Marchetti, Monia, Romero, Pilar, Riaza Grau, Rosalía, Munir, Talha, Zabalza, Amaya, Janssens, Ann, Niemann, Carsten U.; Perini, Guilherme Fleury, Delgado, Julio, Yanez San Segundo, Lucrecia, Gómez Roncero, Ma Isabel, Wilson, Matthew, Patten, Piers, Marasca, Roberto, Iyengar, Sunil, Seddon, Amanda, Torres, Ana, Ferrari, Angela, Cuéllar-García, Carolina, Wojenski, Daniel, El-Sharkawi, Dima, Itchaki, Gilad, Parry, Helen, Mateos-Mazón, Juan José, Martinez-Calle, Nicolas, Ma, Shuo, Naya, Daniel, Van Der Spek, Ellen, Seymour, Erlene K.; Gimeno Vázquez, Eva, Rigolin, Gian Matteo, Mauro, Francesca Romana, Walter, Harriet S.; Labrador, Jorge, De Paoli, Lorenzo, Laurenti, Luca, Ruiz, Elena, Levin, Mark-David, Šimkovič, Martin, Špaček, Martin, Andreu, Rafa, Walewska, Renata, Perez-Gonzalez, Sonia, Sundaram, Suchitra, Wiestner, Adrian, Cuesta, Amalia, Broom, Angus, Kater, Arnon P.; Muiña, Begoña, Velasquez, César A.; Ujjani, Chaitra S.; Seri, Cristina, Antic, Darko, Bron, Dominique, Vandenberghe, Elisabeth, Chong, Elise A.; Lista, Enrico, García, Fiz Campoy, Del Poeta, Giovanni, Ahn, Inhye, Pu, Jeffrey J.; Brown, Jennifer R.; Soler Campos, Juan Alfonso, Malerba, Lara, Trentin, Livio, Orsucci, Lorella, Farina, Lucia, Villalon, Lucia, Vidal, Maria Jesus, Sanchez, Maria Jose, Terol, Maria Jose, De Paolis, Maria Rosaria, Gentile, Massimo, Davids, Matthew S.; Shadman, Mazyar, Yassin, Mohamed A.; Foglietta, Myriam, Jaksic, Ozren, Sportoletti, Paolo, Barr, Paul M.; Ramos, Rafael, Santiago, Raquel, Ruchlemer, Rosa, Kersting, Sabina, Huntington, Scott F.; Herold, Tobias, Herishanu, Yair, Thompson, Meghan C.; Lebowitz, Sonia, Ryan, Christine, Jacobs, Ryan W.; Portell, Craig A.; Isaac, Krista, Rambaldi, Alessandro, Nabhan, Chadi, Brander, Danielle M.; Montserrat, Emili, Rossi, Giuseppe, Garcia-Marco, Jose A.; Coscia, Marta, Malakhov, Nikita, Fernandez-Escalada, Noemi, Skånland, Sigrid Strand, Coombs, Callie C.; Ghione, Paola, Schuster, Stephen J.; Foà, Robin, Cuneo, Antonio, Bosch, Francesc, Stamatopoulos, Kostas, Ghia, Paolo, Mato, Anthony R.; Patel, Meera.
Blood ; 136(Supplement 1):45-49, 2020.
Article in English | PMC | ID: covidwho-1338959

ABSTRACT

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020;Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects.Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts.CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. <6), CLL treatment history, details regarding COVID-19 course, management, and therapy, and vital status were collected.The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies;univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx).Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98);31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2).Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L;27% vs. 21%), and lymphocytopenia (ALC <1.0 x 109/L;18% vs. 28%), while others varied between Co1 and Co2 (p<0.0001), including cough (61% vs. 93%), dyspnea (60% vs. 84%), fatigue (13% vs. 77%).Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p<0.0001). Figure 1 depicts OS in each cohort. Univariable analyses demonstrated that age and CIRS ≥6 significantly predicted inferior OS in both cohorts, while only age remained an independent predictor of inferior OS in multivariable analyses (Table 2). Prior treatment for CLL (vs. observation) predicted inferior OS in Co1 but not Co2.Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including thera eutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts;COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented.

5.
Blood ; 137(10): 1365-1376, 2021 03 11.
Article in English | MEDLINE | ID: covidwho-1127679

ABSTRACT

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.


Subject(s)
Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Gene Frequency , Gene Rearrangement , Humans , Somatic Hypermutation, Immunoglobulin
6.
Blood Adv ; 5(3): 913-925, 2021 02 09.
Article in English | MEDLINE | ID: covidwho-1072925

ABSTRACT

Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton's tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.


Subject(s)
Adaptive Immunity , COVID-19/pathology , Hematologic Neoplasms/drug therapy , Immunity, Innate , Protein Kinase Inhibitors/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Cytokines/metabolism , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/metabolism , Hematologic Neoplasms/complications , Hematologic Neoplasms/pathology , Humans , SARS-CoV-2/isolation & purification
7.
Leukemia ; 34(9): 2354-2363, 2020 09.
Article in English | MEDLINE | ID: covidwho-638239

ABSTRACT

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.


Subject(s)
Betacoronavirus , Coronavirus Infections/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pneumonia, Viral/pathology , Adenine/analogs & derivatives , Age Factors , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Pandemics , Piperidines , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Prognosis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Surveys and Questionnaires
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