Kinetics of cellular and humoral immunogenicity and effectiveness of SARS-CoV-2 booster vaccination in hematologic neoplasms.

Data on the effect of booster SARS-CoV-2 vaccination are mainly focused on humoral immunogenicity, while the kinetics of vaccine-induced cellular response and its correlation with effectiveness in hematologic patients are less explored. Our aim was to evaluate the longitudinal cellular and humoral immunogenicity induced by two and three doses of the mRNA-1273 SARS-CoV-2 vaccine in 270 patients with hematologic malignancies, and its relationship with the severity of breakthrough SARS-CoV-2 infection. Results indicate that at 23 weeks after the second dose, the seroconversion rate declined from 68.5% to 59.3%, with a reduction in median anti-S titers from 1577 to 456 BAU/mL, mainly in patients over 65 years of age or chronic lymphocytic leukemia (CLL) patients undergoing active therapy. Cellular immunogenicity, however, remained positive in 84.4% of cases. A third vaccine dose seroconverted 42.7% (41/96) and triggered cellular response in 36.7% (11/30) of previously negative patients. Notably, only 7.2% (15/209) of patients failed to develop both humoral and cellular response. Active therapy, anti-CD20 antibodies, lymphopenia, hypogammaglobulinemia, and low CD19+ cell count were associated with poor humoral response, while active disease, GvHD immunosuppressive therapy, lymphopenia, and low CD3+ , CD4+ , CD56+ cell count determined an impaired cellular response. After 13.8 months of follow-up, the incidence of SARS-CoV-2 infection was 24.8% (67/270), including 6 (9%) severe/critical cases associated with a weaker cellular (median interferon gamma (IFN-γ) 0.19 vs. 0.35 IU/mL) and humoral response (median anti-S titer <4.81 vs. 788 BAU/mL) than asymptomatic/mild cases. In conclusion, SARS-CoV-2 booster vaccination improves humoral response and COVID-19 severity is associated with impaired vaccine-induced immunogenicity.

Emergence of Delta and Omicron variants carrying resistance-associated mutations in immunocompromised patients undergoing sotrovimab treatment with long-term viral excretion.

OBJECTIVES: To monitor the early emergence of genetic mutations related to reduced susceptibility to monoclonal anti-body (mAb)-based treatment in immunocompromised patients with long-term viral excretion using whole-genome sequencing at a tertiary university hospital in Barcelona, Spain. METHODS: Serial severe acute respiratory syndrome coronavirus 2-positive samples (mid-December 2021-mid-March 2022) from eight immunosuppressed, fully vaccinated patients (for solid-organ transplantation or haematologic malignancies) with long-term viral excretion despite undergoing mAb therapy (sotrovimab) for coronavirus disease 2019 were selected. Whole-genome sequencing was performed following the ARTIC, version 4.1, protocol on the MiSeq platform. Mutations in the coding sequence of the spike protein with a frequency of ≥5% were studied. RESULTS: A total of 37 samples from the studied cases were analysed. All the cases, except one, were confirmed to have the Omicron variant BA.1; one had Delta (AY.100). Thirty-four different mutations were detected within the receptor-binding domain of the spike protein in 62.5% of patients, eight of which were not lineage related and located in the sotrovimab target epitope (P337L, E340D, E340R, E340K, E340V, E340Q, R346T and K356T). Except for P337L, all changes showed a significant increase in frequency or fixation after the administration of sotrovimab. Some of them have been associated with either reduced susceptibility to mAb therapy, such as those at position 340, or the acquisition of a new glycosylation site (346 and 356 positions). CONCLUSIONS: This study highlights the importance of monitoring for early in vivo selection of mutations associated with reduced susceptibility to mAb therapy, especially in immunocompromised patients receiving anti-viral drugs, whose immune response is not able to control viral replication, resulting in long-term viral shedding, and those receiving selective evolution pressure. Virologic surveillance of genetically resistant viruses to available anti-viral therapies is considered a priority for both patients and the community.

L-MIND: Safety and Efficacy of Tafasitamab in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma on Treatment for at Least 2 Years

Context: Durable responses with the immunotherapy tafasitamab+lenalidomide were previously reported in ASCT-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in the Phase II L-MIND trial (NCT02399085). Based on L-MIND, tafasitamab+lenalidomide received accelerated approval (US) and conditional approval (EU and other countries) in this setting. Objective: To describe the long-term efficacy and safety of tafasitamab+lenalidomide in L-MIND patients who received treatment for ≥2 years. Methods: Ongoing, multicenter, open-label, single-arm Phase II study. Eligibility: ≥18 years old, histologically confirmed DLBCL, and 1–3 prior systemic therapies for DLBCL, including ≥1 anti-CD20 therapy. Tafasitamab: twelve 28-day cycles (12 mg/kg IV) QW during Cycles 1–3, with a loading dose on Cycle 1 Day 4;Q2W Cycles 4–12. Lenalidomide: 25 mg PO Cycles 1–12 Days 1–21. Cycle 13+ tafasitamab monotherapy Q2W until disease progression. Time-to-event, treatment response, and safety endpoints were assessed. Results: Of 80 patients in the full analysis set, 27 (34%) received treatment for ≥2 years (median: 4.3 years). At data cut-off (February 15, 2022), 23 of 27 patients were confirmed alive, one was lost to follow-up, one died with unknown cause, and two died following adverse events (AEs) unrelated to study treatment. Thirteen patients remained on treatment, including six with treatment ≥5 years. Fourteen patients discontinued tafasitamab after ≥2 years due to progressive disease (n=4), patient/physician's decision (n=8), and non-treatment-related fatal AEs (n=2: one each, COVID-19 and cardiovascular AE). Among the 27 patients who received treatment for ≥2 years, the AE analysis for patients receiving tafasitamab+lenalidomide combination therapy (Cycles 1–12) and tafasitamab monotherapy (Cycles 13–24) by exposure-adjusted incidence revealed lower incidence of AEs during tafasitamab monotherapy compared with combination therapy. The majority of AEs were Grade 1–2. The most common AEs (≥1 event/patient-year) were neutropenia and diarrhea during combination (incidence, all-grade/Grade ≥3 AEs: 3.87/1.91 and 1.04/0.04, respectively) and following monotherapy (incidence, all-grade/Grade ≥3 AEs: 0.87/0.45 and 0.32/0.0, respectively). Conclusions: Tafasitamab+lenalidomide followed by tafasitamab monotherapy provided durable responses, with long-term treatment efficacy in those patients who received tafasitamab for up to 5 years. The adverse event burden decreased as patients transitioned from combination therapy to tafasitamab monotherapy. Funding: MorphoSys AG.

Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies.

Recent studies have shown a suboptimal humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients diagnosed with hematologic malignancies; however, data about cellular immunogenicity are scarce. The aim of this study was to evaluate both the humoral and cellular immunogenicity 1 month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by using the Elecsys and LIAISON anti-SARS-CoV-2 S assays, and T-cell response was assessed by using interferon-γ release immunoassay technology. Overall, 76.3% (184 of 241) of patients developed humoral immunity, and the cellular response rate was 79% (184 of 233). Hypogammaglobulinemia, lymphopenia, active hematologic treatment, and anti-CD20 therapy during the previous 6 months were associated with an inferior humoral response. Conversely, age >65 years, active disease, lymphopenia, and immunosuppressive treatment of graft-versus-host disease (GVHD) were associated with an impaired cellular response. A significant dissociation between the humoral and cellular responses was observed in patients treated with anti-CD20 therapy (the humoral response was 17.5%, whereas the cellular response was 71.1%). In these patients, B-cell aplasia was confirmed while T-cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients undergoing immunosuppressive treatment of GVHD, whereas only 52.4% had a cellular response. The cellular and humoral responses to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematologic malignancies are highly influenced by the presence of treatments such as anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.

Spanish Society of Hematology and Hemotherapy expert consensus opinion for SARS-CoV-2 vaccination in onco-hematological patients.

In the midst of the COVID-19 pandemic, different vaccines in front of SARS-CoV-2 have been approved and administered in different vulnerable populations. As patients with cancer were excluded from pivotal trials of vaccination, little is known on their immunogenic response to these vaccines, particularly in patients with severely impaired immune system. In response to that uncertainty, the Spanish Society of Hematology and Hemotherapy launched an initiative aimed to provide recommendations for vaccination of the main hematological conditions. This document is based on the available information on COVID-19 outcomes, prior knowledge on vaccination in hematological patients, recent published data on serological response in oncohematological patients and expert opinions. New information about SARS-CoV-2 vaccination will be gathered in the near future, providing new scientific grounds to delineate the most adequate management of vaccination in patients with hematological diseases. The current limited data on SARS-CoV-2 vaccines in hematological patients represents a major limitation of this expert consensus opinion. In fact, the speed in which this field evolves may reduce their validity in the near future.