LGL leukemia patients exhibit substantial protective humoral responses following SARS‐CoV‐2 vaccination

Abstract Large granular lymphocyte leukemia is a rare chronic lymphoproliferative disorder of cytotoxic cells. Other hematological malignancies such as CLL and multiple myeloma have been associated with poor vaccination response and markedly increased severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mortality rates, specifically in patients who have undergone immunosuppressive therapy. Given the immunosuppressive therapies often used to treat the disease, large granular lymphocytic (LGL) patients may be especially vulnerable to SARS‐CoV‐2 infection. A questionnaire was sent to all patients in the LGL Leukemia Registry at the University of Virginia (UVA) to obtain information on vaccination status, type of vaccine received, side effects of vaccination, patient treatment status before, during, and after vaccination, antibody testing, history of coronavirus disease 2019 (COVID‐19) infection, and presence or absence of booster vaccination. Antibody testing of 27 patients who had quantitative SARS‐CoV‐2 Spike Protein IgG levels determined by University of Virginia medical laboratories via the Abbott Architect SARS‐CoV‐2 IgG II assay were collected. The assay was scored as reactive at a threshold of ≥50.0 AU/mL or nonreactive with a threshold of <50.0 AU/mL. LGL patients without treatment as well as patients who held treatment prior to their vaccination have a robust humoral response to SARS‐CoV‐2 vaccines. Patients who did not hold their immunosuppressive treatments have signifigantly diminished vaccine response compared to those who held their immunosuppressive treatment. Our findings support a dual strategy of pausing immunotherapy during the vaccination window and administration of the SARS‐CoV‐2 booster to all LGL leukemia patients to maximize protective antibodies.

regimens include single agent immunosuppressives such as methotrexate, cyclophosphamide, and cyclosporine [1]. By nature of the immunosuppressive therapies and epidemiologic parameters, LGL leukemia patients may be especially vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Similar hematologic malignancies like chronic lymphocytic leukemia (CLL) have been associated with markedly increased SARS-CoV-2 mortality rates, specifically in patients who have undergone immunosuppressive therapy [3].
Weaker vaccination responses were also observed in a cohort of multiple myeloma patients [4]. Given the previously reported coexistence of T cell-large granular lymphocytic leukemia (T-LGL) leukemia with B cell dyscrasias, one must wonder whether insufficient humoral responses to SARS-CoV-2 vaccination would be observed among LGL patients [5][6][7][8][9].
About 30% of LGL leukemia patients have a concurrent autoimmune disorder, most commonly rheumatoid arthritis [1]. Notably, the therapeutic approach for LGL leukemia is often similar in autoimmune diseases. In one study of SARS-CoV-2 vaccine humoral responses on a cohort receiving methotrexate for psoriasis, patients were found to have detectable antibody titers even with concomitant immunosuppressive therapy [10]. Moreover, patients receiving methotrexate for rheumatoid arthritis demonstrated equivalent response rates to the SARS-CoV-2 vaccine versus healthy controls [11]. In both of these studies, antibody titers were specifically measured as they are directly correlated with protective immunity from SARS-CoV-2 [12].
Currently, there are no reports examining the intrinsic SARS-CoV-2 vaccine responses in LGL leukemia. Therefore, we examined vaccine titer responses in LGL leukemia patients to determine if LGL leukemia patients develop robust humoral immune response with or without concurrent immunosuppressive treatment.

METHODS
A questionnaire was sent to all patients in the large granular lym-

RESULTS AND DISCUSSION
The qualitative vaccine response rate was 83.8% (57/68) in the LGL registry's full cohort (n = 68). This included a subset of UVA patients (n = 27) with quantitative antibody titers, and 41 outside patients whose antibody titers were collected at other sites. In the full cohort, there were no known previous COVID-19 infections and nine total patients received booster shots. When patients with booster shots were excluded, the response rate was 81.3% (48/59) in the full cohort and 85.7% (18/21) in the UVA cohort for those who had available qualitative data on response rate (Table 1). Among the UVA cohort, we Seven patients with quantitative antibody data had continued their methotrexate or adalimumab treatments with vaccination, while six patients had paused methotrexate treatment before, during, and/or after vaccination ( Figure 1C). Time for stopping therapy before and after vaccination ranged from 10 days before the first vaccine to 10 days after the second vaccine. Given the variability of vaccine responses in patients with LGL leukemia as seen in Figure 1A, we asked if withholding immunosuppressive medication before, during, or after vaccination improved humoral responses to the vaccine (n = 28).
This analysis excluded those who received booster vaccines before the quantitative antibody draw and those with known COVID-19 infection.
We observed that LGL patients who withheld their medications were more likely to respond to the vaccine than those who continued their

ETHICS STATEMENT
Data collection and analysis were performed in concordance with the

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.