key: cord-0719870-q57q1tc4
authors: Pourhassan, Hoda; La Rosa, Corinna; Chiuppesi, Flavia; Puing, Alfredo; Aldoss, Ibrahim; Park, Yoonsuh; Zhou, Qiao; Karpinski, Veronica; Faircloth, Katelyn; Kaltcheva, Teodora; Johnson, Daisy; Francisco, Sandra Ortega; Zaia, John A.; Nakamura, Ryotaro; Al Malki, Monzr M.; Diamond, Don J.; Dadwal, Sanjeet Singh; Forman, Stephen J.
title: Successful outcome of pre-engraftment COVID-19 in an HCT patient: impact of targeted therapies and cellular immunity
date: 2022-01-12
journal: Blood Adv
DOI: 10.1182/bloodadvances.2021006282
sha: 8f996043ec214a0b2467846aea018a49695b270b
doc_id: 719870
cord_uid: q57q1tc4

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a global pandemic that upended existing protocols and practices, including those for allogeneic hematopoietic stem cell transplantation (HCT). Here we describe the successful clinical course and multiple key interventions administered to an acute lymphoblastic leukemia patient, who tested SARS-CoV-2 positive by RT-PCR on day -1 of matched unrelated donor (SARS-CoV-2 IgG negative) T-cell-replete HCT. This experience allowed for implementing a virologic and immunomonitoring panel to characterize the impact of SARS-CoV-2 on the recipient's nascent humoral and cellular immune response. The finding of robust, functional, and persistent levels of SARS-CoV-2 specific T-cells, starting early after transplant was unexpected, and in combination with the clinical strategy may have contributed to the favorable outcome. Additionally, it is plausible that pre-existing cross-reactive endemic coronavirus immunity in the allogeneic graft reduced recipient susceptibility to COVID-19 disease. This case supports the critical role that T-cell responses may play in mitigating SARS-CoV-2 infection, even in the context of transplant immunosuppression, in which reconstitution of humoral response is commonly delayed. Interventional approaches to transfer SARS-CoV-2-specific cellular immunity such as HCT donor vaccination and adaptive cellular therapy could be of benefit.

Immunocompromised hematology cancer patients, who receive an allogeneic hematopoietic stem cell transplant (HCT) are at enhanced risk for serious complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 Here we report favorable HCT outcome of a patient who was transplanted during active COVID-19 infection.

A 64-year-old Hispanic female with Philadelphia chromosome positive acute lymphoblastic leukemia in first remission was admitted for T-cell-replete HCT from matched unrelated donor [IgM/IgG negative for Spike (S) and Nucleocapsid (N) proteins, and S receptor-binding domain (RBD)] using reduced intensity conditioning (fludarabine/melphalan) and graft versus host disease (GVHD) prophylaxis with tacrolimus/sirolimus 7 . According to City of Hope (COH) standard procedure during the COVID-19 pandemic, a nasopharyngeal swab (NPS) was performed within 72 to 96 hours prior to hospital admission and the patient tested negative for SARS-CoV-2 ( Figure 1A ), by RT-PCR (DiaSorin Molecular Simplexa™ COVID-19 direct assay).

after completion of conditioning on day -1, NPS RT-PCR test returned positive. The patient was asymptomatic, however, a computed tomography (CT) scan of the chest showed two small foci of ground glass density with new curvilinear atelectasis. She received her cryopreserved stem cell infusion as scheduled, and a ten-day course of remdesivir was promptly started. Additionally, a single unit of high-antibody-titer COVID-19 convalescent plasma was given on day +2 per Food and Drug Administration emergency use authorization Table S1 ).

Follow up to day +365 was unremarkable, except for chronic GVHD, which was resolved on prednisone and topical steroids; and hypogammaglobulinemia, requiring immunoglobulin (IVIG) infusions. She received both doses of BNT162b2 mRNA vaccine (on days +212 and +242) without adverse events. As of the writing of this report, the patient is alive and without evidence of malignancy or COVID-19, one year after HCT.

Biospecimen collection and immunological analyses are detailed in Supplemental Materials.

Briefly, SARS-CoV-2 S and N humoral and cellular responses were characterized by performing SARS-CoV-2-specific neutralization assays based on lentiviral-pseudovirus, qualitative in house developed ELISA, longitudinal ELISPOT for the detection of IFN-γ/IL-4 cytokines and multiparameter flow cytometry T cell analyses. Patient specimens were also assessed for presence of SARS-CoV-2 S-and N-specific IgG, IgM, mucosal humoral immunity (IgA) and functional cellular immunity, with T cell memory immune phenotyping. Clinical and laboratory data were collected from electronic medical records.

To our knowledge, this is the first reported case of successful allogeneic HCT in a patient with active COVID-19 infection detected at day -1 of HCT. Prompt intervention with remdesivir ( Figure 1A ) did not appear to have an adverse effect on regimen-related organ toxicities.

Neutrophil engraftment occurred at day +21 with clinical features of engraftment syndrome/cytokine release syndrome (CRS) associated with pulmonary infiltrates and high fevers ( Figure 1A We observed no significant increase in detectable antibodies against SARS-CoV-2 antigens after COVID-19 convalescent plasma 19 , while casirivimab/imdevimab IgG1 monoclonal antibodies were detectable for prolonged duration ( Figure 2B, S2) . The very high levels of S, S RBD-IgG1 and neutralizing antibody 20 , and the concomitant absence of N-specific and of SARS-CoV-2-specific IgM/IgA/IgG3 suggest that SARS-CoV-2 seropositivity early posttransplant was due to casirivimab/imdevimab 20 , rather than to de-novo immunoglobulin production. However, low levels of S IgG3 and N-specific IgG started to be measurable post vaccination with BNT162b2. These findings are consistent with known delay in B cell functional reconstitution and adaptive humoral immune recovery after HSCT 21 In B, the plot shows the longitudinal levels (x axis, HCT day) of C-reactive protein (CRP, blue line; y axis, mg/L), interleukin 6 (IL-6, orange line; y axis, pg/mL), D-dimer (purple line; y axis, mg/L), procalcitonin (PCT, red line; y axis, ng/mL) inflammatory markers; and HCT day of administration for tocilizumab (red arrow) and methylprednisolone (green arrow). In C, the plot shows the longitudinal levels of lactic dehydrogenase (LDH, blue line; y axis, U/L), ferritin (orange line; y axis, ng/mL) and triglycerides (grey line; y axis, mg/mL) inflammatory markers; and HCT day (x axis, HCT day) of administration for tocilizumab (red arrow) and methylprednisolone (green arrow). 

COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey

Clinical experience of coronavirus disease 2019 in hematopoietic cell transplant and chimeric antigen receptor T-cell recipients

COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

Immune reconstitution and severity of COVID-19 among hematopoietic cell transplant recipients

Impact of SARS-CoV-2 in

Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Recipients

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia

Association of inflammatory markers with the severity of COVID-19: A meta-analysis

Effective treatment of severe COVID-19 patients with tocilizumab

Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases

SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

CD8(+) T cells contribute to survival in patients with COVID-19 and hematologic cancer

Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation

Targets of T Cell Responses to SARS-CoV-2

Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Initial High Viral Load Is Associated with Prolonged Shedding of Human Rhinovirus in Allogeneic Hematopoietic Cell Transplant Recipients

Prolonged Shedding of Human Coronavirus in Hematopoietic Cell Transplant Recipients: Risk Factors and Viral Genome Evolution

Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer

Duration and key determinants of infectious virus shedding in hospitalized patients

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with COVID-19

Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection

A Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19

Adaptive immunity to SARS-CoV-2 and COVID-19

SARS-CoV-2-specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein

Efficacy of donor vaccination before hematopoietic cell transplantation and recipient vaccination both before and early after transplantation

empty symbols and segmented line) specific for SARS-CoV-2 entire epitome (Proteome, P 15mer peptide library); red square symbols and lines activated CD4 (filled symbols and line) and CD8 T-cells (empty symbols and segmented line) specific for SARS-CoV-2 Spike (S, S 15mer peptide library); blue diamond symbols and lines activated CD4 (filled symbols and line) and CD8 T-cells (empty symbols and segmented line) specific for SARS

BNT162b2 mRNA vaccine) are represented by icons. Scatter dots indicate absolute neutrophil counts (ANC, 2.0-7.3 K/µl normal range), and bars absolute lymphocyte counts (ALC, 0.8-3.1 K/µl normal range) measured after HCT. Percentage of lymphocytes started to be consistently within range by day 22 after HCT. (B) Binding antibodies to S, S receptor binding domain (RBD), and N were detected by ELISA at the indicated time points. Neutralizing antibodies were measured using SARS-CoV-2 pseudovirus (pv) with S D614G mutation. Shown is the serum dilution that neutralized 90% of the pv (NT90)