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Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti–SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20–directed therapies, and anti-CD38/B-cell maturation antigen–directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not. Significance: Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population. See related article by Tamari et al., p. 577. This article is highlighted in the In This Issue feature, p. 549

Cellular therapies including allogeneic and autologous hematopoietic cell transplant (allo-HCT, auto-HCT) and chimeric antigen receptor T cell therapy (CAR T) render patients severely immunocompromised for extended periods post-therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti-SARS-CoV-2 spike IgG antibody (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n=149, auto HCT n=61, and CAR T n=7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity, compared to 100% for both in 54 concurrent healthy controls. Time from cellular therapy to vaccination and immune recovery post-cellular therapy were associated with response. Vaccination against COVID-19 is an important component of post-cellular therapy care, and predictors of quantitative and qualitative response are critical in informing clinical decisions about optimal timing of vaccines and the requirement for booster doses.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.