key: cord-0733104-colrl8we authors: Mori, Akio; Onozawa, Masahiro; Tsukamoto, Shihori; Ishio, Takashi; Yokoyama, Emi; Izumiyama, Koh; Saito, Makoto; Muraki, Haruna; Morioka, Masanobu; Teshima, Takanori; Kondo, Takeshi title: Humoral response to mRNA‐based COVID‐19 vaccine in patients with myeloid malignancies date: 2022-03-14 journal: Br J Haematol DOI: 10.1111/bjh.18138 sha: aabc23957a3a7be89595fcd1268f10e085084192 doc_id: 733104 cord_uid: colrl8we Data on the response to the COVID‐19 vaccine in patients with myeloid malignancy, who are at severe risk in case of infection, have not emerged. In a study of 69 patients with myeloid malignancies, including 46 patients with acute myeloid leukaemia (AML) and 23 patients with myelodysplastic syndrome (MDS), anti‐spike SARS‐CoV‐2 antibody titres were measured 3 months after the second mRNA‐based vaccination. Seroconversion rates for AML and MDS were 94.7% and 100% respectively, with no significant difference from healthy controls (HCs). Patients with MDS showed a significantly lower antibody titre than that in HCs or AML patients. In AML patients, the antibody titres were comparable to those in HCs when treatment was completed, but lower in patients under maintenance therapy. The response to COVID‐19 vaccine appears to be related to disease and treatment status. Patients with myeloid malignancies may be more responsive to vaccines than patients with lymphoid malignancies. The end of the SARS-CoV-2 pandemic, the virus responsible for COVID-19, is not foreseen. Vaccination using two subtypes of mRNA-based vaccines, BNT162b2 or mRNA-1273, is an effective public health measure to reduce the risk of infection and severe complications from COVID-19. 1-3 However, patients with haematological malignancies were excluded from pivotal trials. 1, 2, [4] [5] [6] Therefore, data for COVID-19 vaccine responses in patients with haematological malignancies, particularly in patients with myeloid malignancies including acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), are limited. Unfortunately, recent studies revealed that patients with haematological malignancies were at the greatest risk of COVID-19-related mortality. [7] [8] [9] [10] [11] [12] [13] [14] However, recent preliminary studies have suggested a low seroconversion rate in vaccinated patients with haematological malignancies compared with that in healthy controls (HCs). [15] [16] [17] [18] [19] [20] [21] While a serological response is not the only predictor of immunity, it has been used as a surrogate marker of vaccine efficacy in many vaccination studies in patients with haematological malignancies because a low serological level could make this population more vulnerable to COVID-19. [15] [16] [17] [18] [19] [20] [21] [22] [23] In Japan, the national policy encourages all applicants who wish to receive COVID-19 vaccine including patients with malignancies to be vaccinated. In this study, we investigated the antibody titres of COVID-19 in patients with myeloid malignancies who received two doses of the mRNA-based COVID-19 vaccine and compared them with the antibody titres in HCs. Previously treated, currently treated, and newly diagnosed AML or MDS patients were included in this study. All patients were vaccinated with two doses of the mRNA-based COVID-19 vaccine (either BNT162b2 or mRNA-1273) and visited the Blood Disorders Center at Aiiku Hospital between 17 August and 31 December 2021. BNT162b2 and mRNA-1273 were administered 21 and 28 days apart, respectively. Individuals with a known history of COVID-19 were excluded from the cohorts of patients and the HCs. The response criteria in patients with AML and MDS were defined according to European Leukemia Net recommendations 24 and the modified International Working Group (IWG) 2006 response criteria for MDS, 25 respectively. Disease status was determined at the time of the second vaccination. Considering the age distribution of patients with myeloid malignancies, we recruited health-care workers aged ≥ 50 years at Aiiku Hospital who had received two doses of the BNT162b2 vaccine. They had minimal risk of SARS-CoV-2 transmission from inpatients as our hospital did not accept COVID-19 patients. This study was a prospective observational study (UMIN 000045150) and conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Aiiku Hospital. Informed consent was obtained from all participants in the study. Serum samples were obtained 3 months ± SD 2 weeks after the second vaccine dose and were evaluated for anti-spike (S) SARS-CoV-2 antibodies using Elecsys Anti-SARS-CoV-2S immunoassay, performed on the Cobas e411 fully automated analyser (Roche Diagnostics, Basel, Switzerland) to the antibody targeting the SARS-CoV-2 S protein receptor-binding domain. 17, 26, 27 This assay has a minimum measurement value of 0.4 U/ml, with a concentration of ≥ 0.8 U/ml considered as a positive result. For individuals with an antibody titre < 0.4 U/ml, it was calculated as 0.4 U/ml for convenience. The Mann-Whitney U test was used to compare medians of antibody titres. Spearman's rank correlation coefficient was used to assess the relationship between two variables. Differences between two groups of categorical data were analysed using Fisher's exact test. A two-sided p < 0.05 was considered to indicate statistical significance. All statistical analyses were performed with EZR (Jichi Medical University, Saitama, Japan). 28 A total 69 patients with myeloid malignancies, including 46 patients with AML and 23 patients with MDS, were enrolled in this study. The characteristics of the patients are shown in Table 1 . HCs included 43 individuals with a median age of 56.0 years (range 50-72) and with a female predominance (69.8%). Patients with MDS showed a significantly lower antibody titre than that in HCs: [median 157.0 U/ml [interquartile Figure 1A ). There were 18 patients who were receiving active treatment including five patients in non-CR who were receiving treatment, one patient in CR who was receiving consolidation chemotherapy, and 12 patients in CR who were receiving maintenance therapy. In the 12 patients receiving maintenance therapy, hypomethylating agent (HMA) was administered to nine patients, Am80 in two patients, and FLT3 inhibitor in one patient. The antibody titre in patients undergoing maintenance therapy was significantly lower than that in patients under treatment-free observation Figure S1B) . Furthermore, Spearman's correlation coefficient and p values were calculated to assess the relationship between duration from diagnosis to vaccination and antibody titres in all of the patients, and a significant correlation was confirmed (r = 0.63, p < 0.0001,) ( Figure S1C ). The seroconversion rate at 3 months after the second vaccination for MDS patients was 100%. In contrast to patients with AML, certain treatments were continued in all the MDS patients in CR, and both MDS patients in non-CR and in CR showed significantly lower antibody titres than HCs This study showed high seroconversion rates in patients with AML and MDS at 3 months after the second vaccination (94.7% and 100%, respectively), in contrast to recent studies showing lower seroconversion rates (39.5-76.0%) in vaccinated patients with haematological malignancies. [15] [16] [17] [18] [19] [20] [21] These studies focused mainly on lymphoid malignancies. B-cell depleting therapies such as anti-CD20 antibody agents are known to reduce vaccine efficacy. 18, 20, 29 In our study of myeloid malignancies, seroconversion rates after vaccination were comparable to healthy individuals. Therefore, patients with myeloid malignancies may have less diseaserelated immune dysfunction than patients with lymphoid malignancies. 21 This is one of the first studies on the effect of COVID-19 vaccines focusing on patients with AML and MDS and provides several new findings. First, in AML patients who completed treatment, the antibody titres were comparable to those in HCs. There was a positive correlation between antibody titres and the period from diagnosis to vaccination, indicating that off-therapy AML patients who were in longterm CR regain sufficient humoral immune responses. Such a good vaccine response has not been reported in other haematological malignancies. Second, the antibody titre in CR patients with AML receiving maintenance therapy was significantly lower than that in CR patients under treatment-free observation. Although several studies have shown that patients with haematological malignancies receiving active treatment had lower antibody titres after vaccination than those in offtreatment patients, 16, [19] [20] [21] 27 there are insufficient data on the impact of maintenance therapy on vaccine efficacy. In lymphoid malignancies, maintenance therapy with anti-CD20 antibody drugs, Bruton's tyrosine kinase inhibitors, and venetoclax reduced antibody titres. 16, 20, 24 On the other hand, tyrosine kinase inhibitors do not impair the vaccine response in patients with chronic myeloid leukaemia. 19 Myeloma patients under maintenance therapy with immunomodulatory agents had relatively intact serological responses. 17, 21 In our study, there was a significant difference in the period from diagnosis to vaccination between AML patients in CR under treatment-free observation and those receiving maintenance therapy ( Figure S1B ), and that difference seemed to contribute to the difference in antibody titres. Besides, 75% of the AML patients undergoing maintenance therapy received HMA in our cohort, and lymphopenia is known as an adverse event of HMA. 30 In view of these findings, careful consideration should be given to the positive and negative effects of maintenance therapy in patients with haematological malignancies with regard to COVID-19. 29 However, continuation of HMA maintenance therapy for AML and MDS is often essential. Therefore, maintenance therapy should be continued for patients with myeloid malignancies, with strict measures for preventing infection. Our study has several limitations. This study included a heterogeneous patient population and the number of patients was small, which made it difficult for us to perform sub-analysis for certain subgroups. Although this study focused on myeloid malignancies, myeloproliferative disorders were not included. This study evaluated only humoral immunity not T-cell immunity nor certain clinical factors that are also important in preventing a severe course of COVID-19. 3, [31] [32] [33] Although the serological response is used as a surrogate marker of vaccine efficacy in many vaccination studies, preventive antibody titres against SARS-CoV-2 infection are unknown. [15] [16] [17] [18] [19] [20] [21] [22] Furthermore, the protective impact of vaccination and its ability to prevent SARS-CoV-2 infection or clinically significant COVID-19 was not studied. In conclusion, the response to COVID-19 vaccine appears to be related to disease and treatment status. Myeloid malignancies may have less impact than lymphoid malignancies on the vaccine response. AML patients under treatment-free observation in CR could be expected to have a vaccine effect that is comparable to that in healthy individuals. In contrast, since the response to vaccination might be insufficient in AML patients undergoing maintenance therapy, maintenance therapy should be continued with strict measures for prevention of infection even after vaccination. The authors thank the nursing and medical staff at Aiiku Hospital who looked after the patients, with special thanks to Ms. Yuko Fujimaki, the nursing manager and Mr. Masayuki Kudo, the vice general manager. We thank Dr. Hajime Senjo at Hokkaido University for guiding the statistical analysis. The authors declare that they have no conflict of interest. Akio Mori designed the study, analysed the data, and wrote the manuscript. Masahiro Onozawa revised the manuscript. Shihori Tsukamoto, Takashi Ishio, Emi Yokoyama, Koh Izumiyama, Makoto Saito and Masanobu Morioka performed recruitment and treatment of patients and provided a critique of the manuscript. Haruna Muraki performed experiments and provided a critique of the manuscript. Takanori Teshima revised and approved the manuscript. Takeshi Kondo designed and supervised the study and approved the manuscript. All authors read and approved the final manuscript. Mori https://orcid.org/0000-0002-2064-2145 Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting Interim findings from first-dose mass COVID-19 vaccination rollout and COVID-19 hospital admissions in Scotland: a national prospective cohort study Safety and efficacy of NVX-CoV2373 Covid-19 vaccine Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak Case fatality rate of cancer patients with COVID-19 in a New York hospital system COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study Outcomes of COVID-19 in patients with CLL: a multicenter international experience COVID-19 infections and clinical outcomes in patients with multiple myeloma in new York City: a cohort study from five academic centers Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set Outcomes of COVID-19 in patients with cancer: report from the National COVID Cohort Collaborative (N3C) Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia Humoral response rate and predictors of response to BNT162b2 mRNA COVID19 vaccine in patients with multiple myeloma Humoral serologic response to the BNT162b2 vaccine is abrogated in lymphoma patients within the first 12 months following treatment with anti-CD2O antibodies Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma Disease-and therapy-specific impact on humoral immune responses to COVID-19 vaccination in hematologic malignancies Immunogenicity, safety, and tolerability of 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine in recipients of allogeneic hematopoietic stem cell transplant aged 2 years: an open-label study A randomized trial of two 2-Dose influenza vaccination strategies for patients following autologous hematopoietic stem cell transplantation Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia Antibody responses to BNT162b2 mRNA COVID-19 vaccine and their predictors among healthcare workers in a tertiary referral hospital in Japan Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients Investigation of the freely available easy-to-use software 'EZR' for medical statistics A third anti-SARS-Cov2 mRNA dose does not overcome the pejorative impact of anti-CD20 therapy and/or low immunoglobulin levels in patients with lymphoma or chronic lymphocytic leukemia Online ahead of print Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes Vaccines for SARS-CoV-2: lessons from other coronavirus strains Human immunopathogenesis of severe acute respiratory syndrome (SARS) COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses Additional supporting information may be found in the online version of the article at the publisher's website.