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2.
Viruses ; 13(10)2021 09 25.
Article in English | MEDLINE | ID: covidwho-1438747

ABSTRACT

Recently, two cases of complete remission of classical Hodgkin lymphoma (cHL) and follicular lymphoma (FL) after SARS-CoV-2 infection were reported. However, the precise molecular mechanism of this rare event is yet to be understood. Here, we hypothesize a potential anti-tumor immune response of SARS-CoV-2 and based on a computational approach show that: (i) SARS-CoV-2 Spike-RBD may bind to the extracellular domains of CD15, CD27, CD45, and CD152 receptors of cHL or FL and may directly inhibit cell proliferation. (ii) Alternately, upon internalization after binding to these CD molecules, the SARS-CoV-2 membrane (M) protein and ORF3a may bind to gamma-tubulin complex component 3 (GCP3) at its tubulin gamma-1 chain (TUBG1) binding site. (iii) The M protein may also interact with TUBG1, blocking its binding to GCP3. (iv) Both the M and ORF3a proteins may render the GCP2-GCP3 lateral binding where the M protein possibly interacts with GCP2 at its GCP3 binding site and the ORF3a protein to GCP3 at its GCP2 interacting residues. (v) Interactions of the M and ORF3a proteins with these gamma-tubulin ring complex components potentially block the initial process of microtubule nucleation, leading to cell-cycle arrest and apoptosis. (vi) The Spike-RBD may also interact with and block PD-1 signaling similar to pembrolizumab and nivolumab- like monoclonal antibodies and may induce B-cell apoptosis and remission. (vii) Finally, the TRADD interacting "PVQLSY" motif of Epstein-Barr virus LMP-1, that is responsible for NF-kB mediated oncogenesis, potentially interacts with SARS-CoV-2 Mpro, NSP7, NSP10, and spike (S) proteins, and may inhibit the LMP-1 mediated cell proliferation. Taken together, our results suggest a possible therapeutic potential of SARS-CoV-2 in lymphoproliferative disorders.


Subject(s)
COVID-19/metabolism , Lymphoma/immunology , SARS-CoV-2/immunology , Antibodies, Monoclonal/immunology , Antineoplastic Agents/pharmacology , Binding Sites , COVID-19/complications , Glycoproteins/metabolism , Glycoproteins/ultrastructure , Humans , Immunity/immunology , Lymphoma/therapy , Lymphoma/virology , Models, Theoretical , Molecular Docking Simulation , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/ultrastructure , Viroporin Proteins/metabolism , Viroporin Proteins/ultrastructure
5.
Br J Haematol ; 195(4): 523-531, 2021 11.
Article in English | MEDLINE | ID: covidwho-1341248

ABSTRACT

Haemato-oncological patients are at risk in case of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Currently, vaccination is the best-evaluated preventive strategy. In the present study, we aimed to assess serological response, predictive markers, and safety of BNT162b2 in haemato-oncological patients. A total of 259 haemato-oncological patients were vaccinated with two 30 µg doses of BNT162b2 administered 21 days apart. Serological response was assessed by ELECSYS® Anti-SARS-CoV-2-S immunoassay before vaccination, and at 3 and 7 weeks after the first dose (T1, T2). Safety assessment was performed. At T2 spike protein receptor binding domain (S/RBD) antibodies were detected in 71·4% of haematological and in 94·5% of oncological patients (P < 0·001). Haematological patients receiving systemic treatment had a 14·2-fold increased risk of non-responding (95% confidence interval 3·2-63·3, P = 0·001). Subgroups of patients with lymphoma or chronic lymphocytic leukaemia were at highest risk of serological non-response. Low immunoglobulin G (IgG) level, lymphocyte- and natural killer (NK)-cell counts were significantly associated with poor serological response (P < 0·05). Vaccination was well tolerated with only 2·7% of patients reporting severe side-effects. Patients with side-effects developed a higher S/RBD-antibody titre compared to patients without side-effects (P = 0·038). Haematological patients under treatment were at highest risk of serological non-response. Low lymphocytes, NK cells and IgG levels were found to be associated with serological non-response. Serological response in oncological patients was encouraging. The use of BNT162b2 is safe in haemato-oncological patients.


Subject(s)
Antibody Formation/drug effects , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Hematologic Neoplasms/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Immunoassay/methods , Immunoglobulin G/blood , Killer Cells, Natural/cytology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Lymphocytes/cytology , Lymphoma/immunology , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , SARS-CoV-2/genetics , Safety
6.
Am J Hematol ; 96(10): 1195-1203, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1286098

ABSTRACT

Patients with hematologic malignancies have an increased risk of severe COVID-19 infection. Vaccination against COVID-19 is especially important in these patients, but whether they develop an immune response following vaccination is unknown. We studied serologic responses to the BNT162b2 vaccine in this population. A lower proportion of patients were seropositive following vaccination (75%) than in a comparison group (99%; p < 0.001), and median (interquartile range [IQR]) antibody titers in patients were lower (90 [12.4-185.5] and 173 [133-232] AU/ml, respectively; p < 0.001). Older age, higher lactate dehydrogenase, and number of treatment lines correlated with lower seropositivity likelihood and antibody titers, while absolute lymphocyte count, globulin level, and time from last treatment to vaccination correlated with higher seropositivity likelihood and antibody titers. Chronic lymphocytic leukemia patients had the lowest seropositivity rate followed by indolent lymphoma. Patients recently treated with chemo-immunotherapy, anti-CD20 antibodies, BCL2, BTK or JAK2 inhibitors had significantly less seropositive responses and lower median (IQR) antibody titers (29%, 1.9 [1.9-12] AU/ml; 0%, 1.9 [1.9-1.9] AU/ml; 25%, 1.9 [1.9-25] AU/ml; 40%, 1.9 [1.9-92.8] AU/ml; and 42%, 10.9 [5.7-66.4] AU/ml, respectively; p < 0.001). Serological response to BNT162b2 vaccine in patients with hematologic malignancies is considerably impaired, and they could remain at risk for severe COVID-19 infection and death.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/complications , COVID-19/prevention & control , Hematologic Neoplasms/complications , Aged , Antibodies, Viral/immunology , BNT162 Vaccine , COVID-19/immunology , COVID-19 Vaccines/immunology , Female , Hematologic Neoplasms/immunology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Lymphoma/complications , Lymphoma/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Treatment Outcome
8.
Intern Med J ; 50(6): 667-679, 2020 06.
Article in English | MEDLINE | ID: covidwho-271531

ABSTRACT

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.


Subject(s)
Consensus , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Infection Control/methods , Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology , Lymphoma/physiopathology , Multiple Myeloma/physiopathology , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Australia , Betacoronavirus/immunology , COVID-19 , Comorbidity , Coronavirus Infections/immunology , Coronavirus Infections/virology , Drug Therapy , Guideline Adherence , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Lymphoma/immunology , Lymphoma/therapy , Multiple Myeloma/immunology , Multiple Myeloma/therapy , New Zealand , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Practice Guidelines as Topic , Risk Assessment , SARS-CoV-2 , Salvage Therapy/methods , Stem Cell Transplantation/methods
9.
Biol Blood Marrow Transplant ; 26(7): 1312-1317, 2020 07.
Article in English | MEDLINE | ID: covidwho-208523

ABSTRACT

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.


Subject(s)
Bone Marrow Transplantation/methods , Coronavirus Infections/epidemiology , Cryopreservation/methods , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Leukemia/therapy , Lymphoma/therapy , Myelodysplastic Syndromes/therapy , Pneumonia, Viral/epidemiology , Adult , Aged , Aged, 80 and over , COVID-19 , Cohort Studies , Cyclophosphamide/therapeutic use , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Histocompatibility Testing , Humans , Leukemia/immunology , Leukemia/mortality , Leukemia/pathology , Lymphoma/immunology , Lymphoma/mortality , Lymphoma/pathology , Male , Middle Aged , Myelodysplastic Syndromes/immunology , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/pathology , Pandemics , Siblings , Survival Analysis , Transplantation Conditioning/methods , Transplantation, Homologous , United States/epidemiology , Unrelated Donors/supply & distribution
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