Impaired antibody response to COVID‐19 vaccination in patients with chronic myeloid neoplasms

The COVID-19 pandemic has had a severe impact on people with blood cancers. Patients with blood cancer are at an increased risk of poor outcomes after COVID-19 infection, with more severe infections and a higher case fatality rate (1-3), which may reflect immunocompromise due to their underlying disease and/or immunosuppressive treatments. As a result, regulatory approval and the subsequent rapid roll out of COVID-19 vaccines has been extremely well received by the blood cancer community.

The COVID-19 pandemic has had a severe impact on people with blood cancers. Patients with blood cancer are at an increased risk of poor outcomes after COVID-19 infection, with more severe infections and a higher case fatality rate, [1][2][3] which may reflect immunocompromise due to their underlying disease and/or immunosuppressive treatments. As a result, regulatory approval and the subsequent rapid roll out of COVID-19 vaccines has been extremely well received by the blood cancer community. However, the registry trials of the currently approved vaccines largely excluded patients with blood cancers. Immune responses in this diverse group therefore require urgent study to ensure that these vulnerable patients are adequately protected from severe COVID-19 infection.
A recent study demonstrated substantially reduced seroconversion rates post-COVID-19 vaccination in oncology patients, when compared to healthcare worker (HCW) controls, following a single dose of the Pfizer-BioNTech BNT162b2 vaccine. Response rates were >90% in HCWs but <40% in patients with solid cancers, and strikingly low (<15%) in the 56 patients studied with haematological malignancy. 4 Impaired immunity and reduced seroconversion are unsurprising in a heavily treated patient group, those with aggressive disease, marked cytopenias, and those with B-cell neoplasms. This study only included three patients with myelodysplastic syndrome (MDS)/myeloproliferative neoplasms (MPNs) and myelofibrosis (MF) and none with chronic myeloid leukaemia (CML). Responses in patients with chronic myeloid neoplasms, many of whom are minimally treated and have normal or only mildly deranged blood counts, might be expected to be less severely impaired, and therefore warrant specific study.
We therefore sought to gather real-world data by measuring anti-SARS-CoV-2 IgG spike (S) antibody levels, more than two weeks following a single dose of either BNT162b2 or the AstraZeneca-Oxford ChAdOx1 nCoV-19 (AZD1222) vaccines in patients with CML, essential thrombocythemia (ET), polycythaemia vera (PV), MF and MDS attending the Churchill Hospital Myeloid Clinic, Oxford University Hospital, UK. Patients with clinical or laboratory evidence of prior COVID-19 infection were excluded from the study. As part of routine clinical blood sampling, quantitative anti-S antibody titres were measured using the EU compliant (CEmarked) Abbott SARS-CoV-2 IgG II Quant Assay (Maidenhead, UK) (positive threshold: ≥ 50 AU/ml) and anti-nucleocapsid (N) antibodies (indicative of past infection) were measured using the Abbott SARS-CoV-2 IgG assay. Leucocyte immunophenotyping (T/B/NK cell subsets) and serology to other previous immunizations (tetanus and pneumococcus) were also measured. Deidentified data on HCWs was used as a comparative cohort, obtained from the Infections in Oxfordshire Research Database (Research Ethics Committee, Health Research Authority and Confidentiality Advisory Group approvals: 19/SC/0403, 19/CAG/0144).
There was no difference in the median time from vaccine to anti-S testing in the patients with positive anti-S antibodies compared to those without [positive anti-S: median 34Á5 days (IQR 28-56); negative anti-S median 32 days (IQR 23Á5-62Á5)], suggesting that the lower rate of seroconversion in the patients with myeloid neoplasms compared to the HCWs was not due to a decline in antibody levels over time.
Tetanus and pneumococcal serology were available for 27 patients and demonstrated immunity in all but one patient. In addition to a complete blood count differential, detailed lymphocyte subset analysis by flow cytometry was performed in 39/59 patients, of whom 15% (6/39) were lymphopenic (lymphocyte count <1Á0 9 10 9 /l). Among the lymphopenic patients, 4/6 had a reduction in both absolute CD19 and CD3 cell counts (Table SI). No association was found between absolute lymphocyte count and anti-S seroconversion [positive anti-S: median lymphocyte count 1Á74 9 10 9 /l (IQR 1Á46-2.2); negative anti-S median lymphocyte count 1Á5 9 10 9 /l (IQR 1Á1-1.
There is a clear need to protect patients with haematological disorders from COVID-19 infection and its complications, and to design effective vaccination programmes. This analysis demonstrates that seroconversion rates in patients with chronic myeloid neoplasms are higher than those reported in more aggressive blood neoplasms or those on intensive treatments, 4 or studies in patients with B-cell neoplasms. 6,7 We observed here reasonably high seroconversion rates following a single vaccine dose in patients with CML and in MPN patients receiving interferon, but humoral responses in certain MPN and MDS patients, especially those in patients receiving ruxolitinib and hydroxycarbamide, were found to be substantially impaired as compared to responses in healthy adults of a similar age group. T-cell-mediated immunity was not assessed, which may have slightly underestimated the functional response rates to vaccination. Nonetheless, these findings clearly demonstrate an impairment of humoral response. The mechanism for this is not yet known, but is suggestive of both disease-and treatment-mediated immune dysfunction. Although our data show almost ubiquitous presence of anti-tetanus and pneumococcus antibodies, previous studies in patients with MPNs have also suggested reduced B-and T-cell-mediated immune responses following vaccination against influenza A strains. 8,9 The poor seroconversion rates in a group of patients with chronic blood cancers, including those who are not on cytoreductive treatments, those who are in complete haematological remission or major molecular response, suggest a clear need for detailed study and careful interrogation of COVID-19 vaccination regimens in potentially vulnerable patient groups. 10,11 Further study with longer-term follow-up is required to determine responses to booster vaccine doses, and whether the observation of reduced seroconversion following first vaccine dose will be associated with higher rates of COVID-19 infection. While it is expected that a higher proportion of patients will respond following booster vaccine doses, the suboptimal responses observed here to the first vaccine dose highlight an unexpected and potentially important immunocompromise in this patient group, which will be informative for planning our ongoing response to this evolving pandemic.