Disease- and Therapy-Specific Impact on Humoral Immune Responses to COVID-19 Vaccination in Hematologic Malignancies

Abstract

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.

Figure 1.

Quantitative antibody responses to COVID-19 vaccines. Anti–SARS-CoV-2 spike IgG antibody titers were measured at 1 and 3 months after initial COVID-19 vaccination and summarized using scatter plots with median and interquartile range. Note: “1 month” time point = 3 weeks from the first BNT162b2 vaccine and 4 weeks from the first mRNA-1273 vaccine. mo, month. A, Patients with hematologic malignancy (Heme; red dots) compared with healthy controls (HC; gray dots), excluding those with previous COVID infection. B, Heme and HC with history of COVID-19 infection. C, Heme off (open circles) and on (filled red circles) cancer treatment. D, Heme responses after receiving BNT162b2 (orange circles) and mRNA-1273 (blue circles). E, Heme responses by gender (male = filled teal circles; female = open teal circles). F, Heme responses by age. For all plots, green dashed line denotes the threshold for a positive result (50.0 AU/mL), orange dashed line denotes the median value at 1 month for HC (886 AU/mL), and red dashed line denotes the median value at 3 months for HC (7,720 AU/mL). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns = not significant. n = number of individuals per category.

Figure 2.

Disease-specific antibody responses to COVID-19 vaccines. Anti–SARS-CoV-2 spike IgG antibody titers measured at 1 and 3 months after initial COVID-19 vaccination grouped by disease subtype and summarized using scatter plots with median and interquartile range. Note: “1 month” time point = 3 weeks from the first BNT162b2 vaccine and 4 weeks from the first mRNA-1273 vaccine. A, Patients with leukemia (Leuk), lymphoma (Lymph), and multiple myeloma (MM). mo, month. B, Patients with leukemia on observation (Obs) and patients receiving BTK inhibitors (BTKi), venetoclax (ven), and other therapies. C, Patients with lymphoma on Obs and patients receiving BTKi, phosphoinositide 3-kinase (PI3K) inhibitors, anti-CD19/CD20–directed therapies (αCD19/20), and other therapies. D, Patients with multiple myeloma on Obs and patients receiving immunomodulatory agents (IMiD), anti-CD38–directed therapy (αCD38), anti–B-cell maturation antigen-directed therapies (αBCMA), and other therapies. For all plots, green dashed line denotes the threshold for a positive result (50.0 AU/mL), orange dashed line denotes the median value at 1 month for healthy controls (886 AU/mL), and red dashed line denotes the median value at 3 months for healthy controls (7,720 AU/mL). n = number of individuals per category.

Figure 3.

Neutralizing antibody levels after COVID-19 vaccines. Circulating neutralizing antibodies against SARS-CoV-2 were assessed at 1 and 3 months after initial COVID-19 vaccination. Note: “1 month” time point = 3 weeks from the first BNT162b2 vaccine and 4 weeks from the first mRNA-1273 vaccine. A, Violin plots comparing patients with hematologic malignancy (Heme; red fill) with healthy controls (HC; gray fill). Green dashed line denotes the threshold for a positive result (30% inhibition). ****, P < 0.0001. mo, month; n = number of individuals per category. B, Scatter plot of anti–SARS-CoV-2 spike IgG antibody titers and neutralizing antibodies assessed at 1 and 3 months after initial COVID-19 vaccination. Red horizontal line denotes threshold for the positive neutralizing result (30% inhibition). Red vertical line denotes threshold for the positive antibody result (50.0 AU/mL). Q1 = negative antibody titer and negative neutralizing activity. Q2 = positive antibody titer and negative neutralizing activity. Q3 = positive antibody titer and positive neutralizing activity.