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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

3A: Anti-SARS-CoV-2 spike IgG titers by different cutoffs Supplemental Table 3B: Neutralization Ab >30% threshold when using different cutoffs of anti-SARS-CoV-2 spike IgG response

50 Anti-SARS-CoV-2 spike IgG, 30 Neutralizing antibodies

Cellular therapies including allogeneic hematopoietic cell transplant (allo-HCT) and autologous hematopoietic cell transplant (auto-HCT) and chimeric antigen receptor (CAR) T-cell therapy render patients severely immunocompromised for extended periods after therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti–SARS-CoV-2 spike IgG Ab (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n = 149; auto-HCT, n = 61; CAR T-cell therapy, n = 7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity compared with 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.Significance:Identifying predictors of response to vaccination against SARS-CoV-2 in patients following cellular therapy is critical to managing this highly vulnerable patient population. To date, this is the most comprehensive study evaluating quantitative and qualitative responses to vaccination, providing parameters most predictive of response and potentially informing booster vaccination strategies.See related article by Chung et al., p. 568.This article is highlighted in the In This Issue feature, p. 549

2A- MVA for the whole cohort 2B-MVA for patients who underwent allo-HCT only

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

We describe the use of MALDI-TOF mass spectrometry in the analysis of a suspected case of gamma heavy chain disease. The patient had an abnormal serum immunofixation result where a monoclonal gamma heavy chain band was present without a corresponding light chain. Analysis by MALDI-TOF mass spectrometry revealed large peaks in the spectrum following IgG-specific purification. The m/z values of the peaks were outside the expected range for normal heavy chains or light chains. Corresponding peaks were not present in mass spectra of the kappa- or lambda-specific purifications. MALDI-TOF MS confirmed the presence of a truncated heavy chain without associated light chains. This case report demonstrates the value of mass spectrometry in interpreting challenging cases such as the identification of heavy chain disease.

Cellular therapies including allogeneic hematopoietic cell transplant (allo-HCT) and autologous hematopoietic cell transplant (auto-HCT) and chimeric antigen receptor (CAR) T-cell therapy render patients severely immunocompromised for extended periods after therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti–SARS-CoV-2 spike IgG Ab (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n = 149; auto-HCT, n = 61; CAR T-cell therapy, n = 7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity compared with 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. Significance: Identifying predictors of response to vaccination against SARS-CoV-2 in patients following cellular therapy is critical to managing this highly vulnerable patient population. To date, this is the most comprehensive study evaluating quantitative and qualitative responses to vaccination, providing parameters most predictive of response and potentially informing booster vaccination strategies. See related article by Chung et al., p. 568. This article is highlighted in the In This Issue feature, p. 549

BACKGROUND Cellular therapies (allogeneic hematopoietic cell transplantation, allo-HCT, autologous hematopoietic cell transplantation, auto-HCT, and chimeric antigen receptor T cell therapy, CAR T) render patients severely immunocompromised for extended periods post-therapy. Emerging data suggest reduced immune responses to COVID-19 vaccines among patients with hematologic malignancies, but data for cellular therapy recipients are sparse. We therefore assessed immune responses to mRNA COVID-19 vaccines among patients who underwent cellular therapies at our center to identify predictors of response. PATIENT AND METHODS In this observational prospective study, anti-SARS-CoV-2 spike IgG antibody titers and circulating neutralizing antibodies were measured at 1 and 3 months after the 1 st dose of vaccination. CD4, CD19, mitogen, and IgG levels from patient samples collected prior to initiation of vaccination in a subset of patients were used to assess immune recovery and association with response. A concurrent healthy donor (HD) cohort provided control response rates. RESULTS Allo-HCT (N=149), auto HCT (N=61), and CAR T (N=7) patients vaccinated between 12/22/2020- 2/28/2021 with mRNA vaccines and 69 HD participated in this study. At 3 months, 188 pts (87%) had a positive anti-SARS-CoV-2 spike IgG levels (median 5,379 AU/mL, IQR 451-15,750), and 139 (77%) had a positive neutralization Ab assay (median 93%, IQR 36-96%). All HD (100%) had a positive anti-SARS-CoV-2 spike IgG and a positive neutralization Ab assay with median levels of 8,011 AU/mL (IQR 4573-11,159) and 96% (IQR 78- 96%), respectively. Time from vaccination to cellular therapy was associated with response; 67% of patients vaccinated in the first 12 months post-cellular therapy (N=42) mounted a serologic response, compared with patients vaccinated between 12-24 (89%) (N=45), 24-36 (91%) (N=32) and >36 (93%) (N=98) months post-treatment, p= 0.001 (figure 1). Patients with immune parameters below the recommended threshold for vaccinations post-cellular therapies were also less likely to mount a response (figure 2): CD4+ T-cell count < 200 vs >200 cells/μL, 66% vs 87% (p=0.012); CD19+ B-cell count 50 cells/μL; 33% vs 95% (p40%, 42% vs 89% (p500 mg/dl, 71% vs 91% (p=0.003). Patient age, gender, prior COVID-19 infection, treatment with IVIG, and type of mRNA COVID-19 vaccine were not associated with the likelihood of serologic response. CONCLUSION This largest cohort to date, demonstrates that COVID-19 vaccine responses of cellular therapy recipients are reduced compared to healthy control and response varies based on time interval from cellular therapy and immune function at the time of vaccination, underscoring the importance of monitoring immune status parameters, as well as qualitative measures (neutralizing Ab) of vaccine response, in informing clinical decisions, including the indication for booster vaccines. Figure 1 Figure 1. Disclosures Politikos: Merck: Research Funding; ExcellThera, Inc: Other: Member of DSMB - Uncompensated. Vardhana: Immunai: Membership on an entity's Board of Directors or advisory committees. Perales: Equilium: Honoraria; Cidara: Honoraria; Sellas Life Sciences: Honoraria; Miltenyi Biotec: Honoraria, Other; Celgene: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Merck: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Medigene: Honoraria; Omeros: Honoraria; Servier: Honoraria; Bristol-Myers Squibb: Honoraria; Nektar Therapeutics: Honoraria, Other. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding.