key: cord-0902166-8fjm9qzh
authors: Hallmeyer, S.; Thompson, M. A.; Fitzpatrick, V.; Liao, Y. L.; Mullane, M. P.; Medlin, S. C.; Copeland, K.; Weese, J. L.
title: Characteristics of Patients with Hematologic Malignancies Without Seroconversion Post-COVID19 Third Vaccine Dosing
date: 2022-04-16
journal: nan
DOI: 10.1101/2022.04.07.22273430
sha: ae9e4dfdc66d50850530ba00ccf5fa7bde9d3333
doc_id: 902166
cord_uid: 8fjm9qzh

Patients with hematologic malignancies (HM) are at greater risk of severe morbidity and mortality caused by COVID19 and show a lower response to a two-dose COVID19 mRNA vaccine series. The primary objective of this retrospective cohort study is to explore the characteristics of the subset of patients with HM who had little to no change in SARS-CoV-2 spike antibody titer levels after a 3rd vaccine dose (3V) (-/-). As a secondary objective, we seek to compare the cohorts of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus. A total of 625 patients with HM had two titer results at least 21 days apart pre- and post- the 3V dose. Among the participants who were seronegative prior to 3V (268), 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not. HM diagnosis was significantly associated with seroconversion status (P = .0003) with patients non-Hodgkin lymphoma 6 times the odds of not seroconverting compared to multiple myeloma patients (P = .0010). Among the cohort of patients who remained seronegative post-3V, 107 (90.0%) patients showed no reaction to 3V as indicated by pre- and post- 3V index values. This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V, providing much needed data for clinicians to target and counsel this subset of patients.

Patients with hematologic malignancies (HM) are at greater risk of severe morbidity and mortality caused by COVID19. 1, 2 Patients with HMs who are older, with more comorbidities, specific HM conditions, response statuses, and therapies are even more likely to experience adverse health effects caused by COVID19, including anywhere from 25% to 34% increased risk of death. 3, 4 This is believed to be due the high levels of immunosuppression making the effects of COVID19 more severe. 3 Among HM conditions, patients with myeloid malignancies seem to be at highest risk for COVID19 associated morbidity and mortality, but this varies greatly based on treatment type. [2] [3] [4] [5] [6] Moreover, patients with HMs show a lower response to the standard two-dose COVID19 mRNA vaccine series when compared to individuals with other immune suppressing conditions leaving them still more vulnerable to COVID19 associated morbidity and mortality to their non-HM counterparts. 7-9 A recently published metaanalysis put the pooled proportion of patients achieving a serologic response after a second dose of the vaccine around 87% but was sure to acknowledge that patients with HMs are less likely to mount a response as compared with patients with solid organ cancers (63.7% vs 94.9%), likely due to the type of HM and/or current treatments. 10, 11 Another large study, the CAPTURE study, showed that in patients with HMs, neutralizing antibodies, our current indication of vaccine effectiveness, are significantly reduced, and this appears to hold true with the most recent variant of concern (VOC), Omicron. 1,4,12, . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org /10.1101 /10. /2022 In the summer of 2021, when the "booster dose" was authorized under the United States Food and Drug Administration (FDA) Emergency Use Authorization (EUA), cancer patients were rightly prioritized for this third shot (3V). A third dose of the mRNA vaccine ('3V') has shown to be particularly beneficial for HM patients given the reduced response to the standard two dose series. 13 With the increased likelihood of seroconversion among individuals who may have been less responsive to the standard series there is added protection against COVID19 associated morbidity and mortality with 3V; however, research is emerging to show that this may not be true for all HM conditions and/or underlying treatments and responses.

This current study builds off a previous study conducted by the same team that assessed the characteristics of a large cohort of HM patients who had received a 3V dose of the mRNA COVID19 vaccine. 9 The primary objective of this study is to explore the characteristics of the subset of patient who had little to no change in SARS-CoV-2 spike protein titer levels post 3V (-/-) and compare to the cohort of patients who did seroconvert (-/+) to get a better understanding of the drivers of serostatus.

This retrospective cohort study analyzed patient data on SARS-CoV-2 spike IgG antibody titers pre-and post-3V across a large Midwestern healthcare system, which consists of 26-hospitals and over 500 sites of care. the ADVIA Centaur sCOVG assay was used to provide semi-quantitative (index value) results for the detection of IgG antibodies to the receptor-binding domain (RBD) of the S1 spike antigen of the SARS-CoV-2 virus. The assay received Emergency Use Authorization from the FDA and its performance characteristics were validated internally by ACL Laboratories. Assay . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 

This study included 625 patients who had been previously diagnosed with HM within the healthcare system between October 31, 2019 and January 31, 2022 and had received the full dose of a COVID19 mRNA vaccine, as defined by the CDC,two or more weeks prior to 3V. 15 Post 3V titers were obtained 21 days after 3V. Patients were excluded from the study if vaccine status was unknown or considered incomplete, or they had received a primary series vaccination that was not an mRNA vaccine manufactured by Moderna and/or Pfizer-BioNTech. Subjects were identified via Epic EMR database by the research analytics team and de-identified to the study team. This study was determined by IRB to be non-human subjects research due to the deidentification of data (#2021-214).

Data gathered in this study included: age, race, ethnicity, COVID19 mRNA vaccine type, COVID19 infection history prior to 3V of COVID19 vaccine, days between the second and third dose of COVID19 vaccine, HM diagnosis, up to four SARS-CoV-2

IgG antibodies results between August 28, 2021 and January 31, 2022, and days between the third dose of COVID19 vaccine and each IgG result. Age values below 90 were collected as continuous and "Age 90 or older" was recoded as 90. Sex included male and female. Race was collapsed into White, Black, Asian/Pacific Islander, and multi-racial (two or more races). Ethnicity included Hispanic/Latino and non-. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) infection. IgG level values "<0.50" and ">100.00" were recoded to 0.50 and 100.00, respectively.

Diagnosis was collapsed into lymphoid leukemia, non-Hodgkin lymphoma (NHL), multiple myeloma and other plasma cell neoplasms, Hodgkin lymphoma, myeloid leukemia, other, and multiple conditions (Table 1) .

Descriptive statistics are reported as count (percent) for categorical variables and as median (IQR) for continuous variables. Demographics and baseline variables are also reported by IgG antibody status before/after receiving 3V dose.

To assess the association between each individual characteristics and seroconversion status, patients were placed into two groups based on IgG antibody status pre-and post-the 3V dose, (-/+) and (-/-). Categorical variables were compared using a Chi-squared test or a Fisher's exact test, as appropriate, and continuous variables using a Mann-Whitney U test. P-value less than 0.05 as an indicator of statistical significance. For categorical variables with more than two levels, p-values were calculated for both the global and the pairwise comparisons. Odds ratios are displayed as measures of association for all categorical variables. Logistic regressions were used to measure the association between HM condition and seroconversion.

Three models were run to assess significant associations. Logistic regression model 1:

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 16, 2022. 

For original data, please contact andrew.marek@aah.org.

A total of 625 patients with HM had two titer results at least 21 days apart preand post-the 3V dose. Overall, 14 patients were excluded for not having two titers results at least 21 days apart and an additional 25 patients were excluded for not having the 3V dose between the two titers. Four patients were excluded from the Race category and seven patients were excluded from the Ethnicity category for missing/unknown values. The median (range) age was 71 (64-78) years, 323 (51.7%) were male, 578 (93.1%) were White, and 605 (97.9%) were non-Hispanic/Latino (Table   2 ). Three hundred ninety-one (62.6%) received the Pfizer-BioNTech and 234 (37.4%) received Moderna vaccine as the 3V dose. A total of 21 (3.4%) patients had a COVID19 infection prior to receiving the 3V dose. The median (range) days between second and third doses of vaccine was 199 (177 -224). In the overall sample, the top three . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.07.22273430 doi: medRxiv preprint conditions were 28% were diagnosed with NHL, 18.2% diagnosed with LL, 12.2% diagnosed with multiple myeloma (Table 2) .

The following analyses are only comparing the subgroup of HM patients who had a negative serostatus pre-3V, given the lower likelihood of seroconversion as compared with non-HM counterparts. Among the participants who were seronegative prior to 3V, 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not (Table 3) .

Results show the median days between dose 2 and dose 3 was significantly higher in patients who seroconverted compared to those who did not (P = .0171). Additionally, HM condition was significantly associated with seroconversion status (P = .0003). NHL (Table 4) .

Among the cohort of patients who did not seroconvert, 107 (90.0%) patients showed no reaction to 3V as indicated by pre-and post-3V index values. This subgroup had a pre-3V index value and a post-3V index value difference of <0.05 AU/ml. The . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

This study focuses on an important subset of HM patients who did not seroconvert after the COVID mRNA 3V. This study compares the cohort of patients who did not seroconvert (-/-) to the cohort of patients who did seroconvert (-/+) to get more insight into the differences between these two groups. Analysis shows that seroconversion is not driven by patient demographics or vaccine type. Seroconversion is however driven by HM diagnosis type and days between dose 2 and 3V -with seroconversion more likely with patients who had more days between dose 2 and 3.

showed that patients with NHL have 6 times the odds of not seroconverting compared to multiple myeloma patients. Additionally, NHL patients have approximately 14 times the odds of not seroconverting compared to patients diagnosed with the Other HM condition group (Table 1 for "other" conditions).

Perhaps most interesting is that the analysis showed very little to no reaction to 3V among the -/-cohort, raising interesting clinical questions about how to counsel this group of patients and whether this group may or may not benefit from a fourth dose.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 0

Due to this study data being obtained from a standard of care internal program it lacked T-cell function or neutralizing antibody functional measurements. Additionally, as part of real-world data the patients were not a homogeneous population with the same treatment schedules, however this data may complement such data sets. Future studies should dive more deeply into individual HM patient characteristics as seroconversion may also be a function of disease and/or treatment.

This study focuses on HM patients who are not seroconverting after the COVID mRNA 3V, suggesting a prioritized population for continued increased behavioral precautions, additional vaccination efforts, including a fourth dose of an mRNA COVID vaccine, as well as passive immunity boosting through monoclonal and or polyclonal antibodies.

This study received no external funding support. This study was funded by the healthcare system in which patients were used for analysis. Additionally, Christopher Blumberg and Benzon Salazar from our research analytics team supported this study by working with the research team to gather data from our EMR system. Anne Rivelli helped with data visuals, and Robert Citronberg, MD, Tulio Rodriguez, MD, Karen Gordon, Katie Cleland, and Amy Bock, helped with conceptualization and implementation of the internal clinical project in which a group of oncologists proactively asked their patients to draw titers.

. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.07.22273430 doi: medRxiv preprint

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All authors declare no competing financial interests.