Abstract
Background
Chronic lymphocytic leukemia (CLL) and other non-Hodgkin’s lymphomas (NHLs) lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. Our study analyzed antibody (Ab) seropositivity from SARS-CoV-2 vaccination in patients with these cancers.
Methods
In the final analysis, 240 patients were involved, and seropositivity was defined as a positive total or spike protein Ab.
Results
Seropositivity was 50% in CLL, 68% in WM, and 70% in the remaining NHLs. Moderna vaccination led to higher seropositivity compared to Pfizer vaccination across all cancers (64% vs. 49%; P = .022) and specifically CLL patients (59% vs. 43%; P = .029). This difference was not explainable by differences in treatment status or prior anti-CD20 monoclonal Ab therapy. In CLL patients, current or prior cancer therapy led to lower seropositivity compared to treatment-naïve patients (36% vs. 68%; P = .000019). CLL patients treated with Bruton’s tyrosine kinase (BTK) inhibitors had better seropositivity after receiving the Moderna vaccination compared to Pfizer (50% vs. 23%; P = .015). Across all cancers, anti-CD20 agents within 1 year led to a lower Ab response compared to greater than one year (13% vs. 40%; P = .022), a difference which persisted after booster vaccination.
Conclusion
Antibody response is lower in patients with indolent lymphomas compared to the general population. Lower Ab seropositivity was found in patients with a history of anti-leukemic agent therapy or those immunized with Pfizer vaccine. This data suggests that Moderna vaccination may confer a greater degree of immunity against SARS-CoV-2 in patients with indolent lymphomas.
Keywords: Non-Hodgkin’s lymphomas, chronic lymphocytic leukemia, COVID-19, vaccination, rituximab, BTK inhibitors
Chronic lymphocytic leukemia and other non-Hodgkin’s lymphomas lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. This study analyzed antibody seropositivity from SARS-CoV-2 vaccination in patients with these cancers.
Implications for Practice.
The SARS-CoV-2 virus poses a greater risk for severe disease in patients with indolent lymphomas such as CLL. Antibody seropositivity after vaccination can be used as a partial measure of immunity against viral infection. This study characterizes overall Ab response rates in patients with these diseases after vaccination and how response may differ based on cancer diagnosis, treatment history, and timing of treatment. These results have real-world implications and may suggest that the optimal vaccination schedule for these patients differs from the general population and also help predict which of these patients is at greatest risk for severe COVID-19 infection.
Introduction
Non-Hodgkin’s lymphomas (NHLs) are a group of hematologic malignancies with a diverse array of pathophysiology and severity. Chronic lymphocytic leukemia (CLL) and Waldenstrom’s macroglobulinemia (WM) are examples of indolent NHLs associated with long-term survival but nonetheless have systemic effects on the function of various organ systems.1,2 As they clonally expand, various areas of the body may become involved in these lymphomas. These diseases are associated with broad immunosuppression, thereby conferring a greater risk for infection-related morbidity and mortality.3,4 Possible mechanisms in these patients include a decrease in circulating immunoglobulin levels, impaired complement-mediated cytotoxicity, and reduced cell-mediated immunity.5-7
In 2021, there were an estimated 21 250 new cases of CLL and 81 560 new cases of other NHLs.8 The 5-year survival in CLL is approximately 87% with nearly 200 000 of these patients estimated to be living in the United States alone.9 The majority of these patients are diagnosed at an older age and often have multiple medical co-morbidities. Thus, patients with CLL and other NHLs are at risk of infection not just due to their malignancies but also their overall health profile. The COVID-19 pandemic further jeopardizes the health of an already at-risk group, affecting both patients and medical providers alike in an already burdened healthcare system.
During the SARS-CoV-2 pandemic, patients with CLL, WM, and other NHLs are more likely to progress to severe infections, particularly in those undergoing active cancer treatment.10-12 Rates of supplemental oxygen requirements, hospitalization, and death are greater when compared to cohorts without these lymphomas. Vaccination against SARS-CoV-2 generally provides protection against the complications of viral infection in the general population.13 However, published data have shown inferior antibody (Ab) response in patients with CLL and other B-cell malignancies, questioning the full effectiveness of vaccination in these groups.14-19 In addition, other studies have also shown that cancer patients being actively treated for their malignancy have lower levels of anti-SAR-CoV-2 titers compared to untreated cancer patients.20 Impaired Ab response after SARS-CoV-2 vaccination has also been demonstrated in patients with WM and other NHLs.21,22 This is consistent with other vaccine series, where these patients have shown an inferior Ab response after influenza and pneumococcal vaccinations.23-27
Seropositivity after SARS-CoV-2 vaccination is better in CLL patients who are treatment naïve or in clinical remission but worse in patients who have received disease-specific therapies.28 The use of monoclonal antibodies (mAbs) directed against the CD20 antigen that is found on the surface of malignant B-lymphocytes, such as rituximab and obinutuzumab, appears to significantly affect Ab response to vaccination. There is a critical need to better understand the effect that the type and timing of certain therapies have on seropositivity in these patients. In recent years, CLL treatments have shifted primarily to continuous Bruton’s tyrosine kinase (BTK) inhibitors or fixed-duration B-cell lymphoma-2 (BCL-2) inhibitors with or without an anti-CD20 mAb. The impact of these targeted therapies on a patient’s immunity and vaccine response have been previously studied, but data including booster doses and in larger cohorts has been lacking.29
The primary goal of this study is to analyze Ab seropositivity after the initial SAR-CoV-2 vaccination series and seroconversion after booster doses in patients with CLL, WM, and other NHLs at a single, tertiary care academic center. The secondary aims are to determine whether seropositivity varies based on disease, treatment history, or type of vaccination series and to evaluate the incidence and severity of SARS-CoV-2 infections in this cohort.
Methods
A total of 398 patients with hematologic malignancies were evaluated in a single indolent lymphoma clinic with a primary focus on CLL and WM. Patients seen between January to October 2021, prior to the availability of prophylactic SARS-CoV-2 Ab infusions, were screened for inclusion. All patients were seen at Northwestern Memorial Hospital in Chicago, Illinois and were followed until their most recent clinic visit, telemedicine contact, or hospitalization. This study was reviewed and approved by the Northwestern University Institutional Review Board. SARS-CoV-2 Ab titers were obtained prospectively and all additional data were collected via the electronic medical record.
Inclusion criteria were age ≥18 years, diagnosis of CLL, WM, or other NHLs via flow cytometry of peripheral blood or confirmation biopsy of an involved site, and full completion of an initial vaccination series and subsequent Ab testing. Exclusion criteria were any aggressive malignancy at diagnosis, the transformation from an indolent lymphoma to an aggressive lymphoma, incomplete vaccination series, or lack of serum Ab testing.
Clinical data were collected via chart review by 2 independent reviewers. Patient demographics, underlying medical co-morbidities, cancer diagnosis, time of diagnosis, cancer treatment, vaccination information, and Ab results were all collected. Follow-up data were collected to the present day. Adverse events were recorded based on reported symptoms documented in the electronic medical record. Relevant cancer treatment history included whether a patient was receiving treatment, the treatment agent, and the timing of the treatment relative to vaccination and Ab testing.
SARS-CoV-2 Ab titers against the total Ab, spike protein IgG and IgM Ab, and nucleocapsid IgG Ab were obtained as part of the clinic’s standard of care model to better assess humoral immune function in this immunocompromised population. Antibody testing was performed 0.5-6 months after the completion of an initial vaccination series with Pfizer (New York, NY, USA), Moderna (Cambridge, MA, USA), Johnson & Johnson (New Brunswick, NJ, USA), or heterologous brands.30-32 Beckman Coulter (Indianapolis, IN, USA) SAR-CoV-2 assays were used to determine seropositivity for each measured Ab.33 Seropositivity was defined as a positive total Ab (>1.00 binding Ab units [BAU]/mL) or spike protein Ab (>0.80 BAU/mL) and aligns with the World Health Organization International Standard. Any additional Ab testing that occurred after obtaining a booster vaccination was also included. Serum Ab titer values were collected for all total Ab results and only for positive spike protein and nucleocapsid results. The sensitivity of reported titer values was limited to a maximum value of 10 BAU/mL for the total protein, 200 BAU/mL for the spike Ab, and 20 BAU/mL for the nucleocapsid Ab.
Information on which patients tested positive for the SARS-CoV-2 virus was also collected, and the severity of their infection was graded based on the National Institutes of Health Clinical Spectrum of SARS-CoV-2 Infection.34 The severity of the disease ranges from asymptomatic infection to critical illness and incorporates clinical symptoms, oxygen saturation (SpO2), and radiographic imaging for grading.
Clinical characteristics were summarized for the full cohort. Wherever applicable, values were reported as median ± CI. Seropositivity responses were then compared based on cancer diagnosis, treatment regimen, and vaccine manufacturer. Comparisons between groups were performed using chi-squared tests for categorical variables or t-tests for continuous variables, wherever applicable. Univariate logistic regression models were performed to assess the association between risk factors and seropositivity responses, followed by a multivariate regression model including significant factors selected from the univariate models, for which odds ratio (OR) with CI was reported. A P-value of < .05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism software and R version 4.2.2 for the logistic regression analysis. Tables and figures were created using Microsoft Word and Excel software.
Results
A total of 240 patients with post-vaccination SARS-CoV-2 Ab results were included in the study (Fig. 1). The most common reason for exclusion was a lack of Ab testing after vaccination, followed by aggressive lymphomas (de novo or transformed), and not completing vaccination. Baseline clinical characteristics for the cohort are outlined in Table 1. CLL was the most common diagnosis (75%; 181/240), followed by WM (9%; 22/240), and several other NHLs. The breakdown of diagnoses is found in Supplemental Fig. S1, with marginal zone lymphoma and follicular lymphoma comprising a plurality of the other NHLs. The status of treatment is as follows: 42% (100/240) of cohort patients had not yet received any prior disease-specific therapies, 21% (52/240) were under surveillance after completing treatment, and 37% (88/240) were actively undergoing therapy. In the CLL sub-group, nearly half of the patients (44%; 79/181) had not been treated for their disease while the rest were actively undergoing treatment or had previously been treated (56%; 102/181).
Figure 1.
Flowchart of patients with indolent lymphomas vaccinated against SARS-CoV-2. Chart describing initial cohort of patients with hematologic malignancies that were screened for inclusion, including exclusion criteria and number of patients who received the booster dose or were infected with SARS-CoV-2.
Table 1.
Baseline characteristics and overview of vaccination data of patients with indolent lymphomas that received SARS-CoV-2 vaccination
| Patient characteristics | All patients (n = 240) | CLL (n = 181) | WM (n = 22) | Other NHLs (n = 37) |
|---|---|---|---|---|
| Male | 64% (153/240) | 67% (122/181) | 50% (11/22) | 51% (19/37) |
| Age (years) | 60 ± 1 | 60 ± 2 | 62 ± 4 | 64 ± 4 |
| Race | ||||
| Non-Hispanic White | 84% (202/240) | 86% (155/181) | 91% (20/22) | 73% (27/37) |
| Non-Hispanic Black | 10% (24/240) | 10% (18/181) | — | 16% (6/37) |
| Hispanic | 2% (5/240) | 2% (4/181) | — | 3% (1/37) |
| Asian | 4% (9/240) | 2% (4/181) | 9% (2/22) | 8% (3/37) |
| Rai stage at diagnosis | ||||
| Not stated | 20% (37/181) | |||
| 0 | 32% (57/181) | |||
| I | 27% (49/181) | |||
| II | 9% (17/181) | |||
| III | 3% (6/181) | |||
| IV | 8% (15/181) | |||
| Lymphadenopathy | 33% (78/240) | 37% (66/181) | — | 32% (12/37) |
| Splenomegaly | 15% (35/240) | 16% (29/181) | — | 16% (6/37) |
| Treatment status | ||||
| Observation | 42% (100/240) | 44% (79/181) | 18% (4/22) | 46% (17/37) |
| Surveillance | 21% (52/240) | 15% (27/181) | 45% (10/22) | 41% (15/37) |
| Active treatment | 37% (88/240) | 41% (75/181) | 36% (8/22) | 14% (5/37) |
| CLL treatment type | ||||
| Anti-CD20 | 38% (68/181) | |||
| BTK inhibitor | 42% (76/181) | |||
| BCL-2 inhibitor | 17% (30/181) | |||
| Anti-CD20 & BTK inhibitor | 24% (43/181) | |||
| Anti-CD20 & BCL-2 inhibitor | 14% (25/181) | |||
| All three classes | 6% (10/181) | |||
| Quantitative Ig levels (mg/dL) | ||||
| IgM | 32 ± 98 | 36 ± 40 | 410 ± 503 | 43 ± 276 |
| IgG | 695 ± 47 | 695 ± 51 | 534 ± 122 | 792 ± 149 |
| Vaccination series | ||||
| Johnson & Johnson | 0.5% (1/240) | — | — | 3% (1/37) |
| One dose | 100% (1/1) | — | — | 100% (1/1) |
| Moderna | 36% (87/240) | 39% (70/181) | 41% (9/22) | 22% (8/37) |
| Two doses | 9% (8/87) | 10% (7/70) | 25% (1/4) | — |
| Three doses | 68% (59/87) | 70% (49/70) | 75% (3/4) | 75% (6/8) |
| Four doses | 23% (20/87) | 20% (14/70) | — | 25% (2/8) |
| Pfizer | 49% (118/240) | 47% (85/181) | 50% (11/22) | 59% (22/37) |
| Two doses | 8% (10/118) | 8% (7/85) | — | 14% (3/22) |
| Three doses | 73% (86/118) | 74% (63/85) | 73% (8/11) | 68% (15/22) |
| Four doses | 19% (22/118) | 18% (15/85) | 27% (3/11) | 18% (4/22) |
| Heterologous | 14% (34/240) | 14% (26/181) | 9% (2/22) | 16% (6/37) |
| Three doses | 15% (5/34) | 12% (3/26) | — | 33% (2/6) |
| Four doses | 85% (29/34) | 88% (23/26) | 100% (2/2) | 67% (4/6) |
| Ab titer levels (BAU/mL) | ||||
| Total index | ||||
| No treatment | 5.4 ± 0.9 | 3.6 ± 1.0 | 10.0 ± 3.6 | 7.7 ± 1.9 |
| Any treatment | 0.4 ± 0.7 | 0.3 ± 0.8 | 2.4 ± 2.3 | 7.1 ± 2.2 |
| Spike IgM | ||||
| No treatment | 8.4 ± 9.5 | 8.4 ± 9.5 | — | — |
| Any treatment | 2.7 ± 11.4 | 25.6 ± 14.2 | — | 2.2 ± 0.2 |
| Spike IgG | ||||
| No treatment | 9.4 ± 4.3 | 10.9 ± 5.0 | 13.2 ± 13.9 | 3.8 ± 9.5 |
| Any treatment | 14.4 ± 5.4 | 8.0 ± 6.0 | 15.7 ± 8.9 | 37.6 ± 13.0 |
| Anti-nucleocapsid | ||||
| No treatment | 8.1 ± 2.5 | 9.2 ± 3.0 | 10.4 | 3.7 ± 4.5 |
| Any treatment | 20 ± 3.7 | 4.4 ± 4.5 | 20 ± 7.3 | 20 |
SARS-CoV-2 vaccination with Pfizer and Moderna were the 2 most common vaccinations, in that order. Only a single patient received the Johnson & Johnson vaccination for their initial series. Ninety-two percent (222/240) of patients received at least one booster dose, while 8% (18/240) of patients only finished the initial vaccination series. Some patients in the latter group received multiple booster doses, largely consistent with Centers for Disease Control and Prevention (CDC) recommendations for elderly and/or immunocompromised persons. The majority of patients reported few to no symptoms after vaccination. The most common symptoms were soreness at the injection site, fever, mild fatigue, and lymphadenopathy. One patient required hospitalization given concern for angioedema.
Median time from completion of the initial vaccination series to Ab testing in the entire cohort was 2 ± 0.3 months (range: 0.5-7.5 months). By histology, follow-up after the initial vaccine series was 2.3 ± 0.2 months in the CLL cohort, 1.9 ± 0.5 months in the WM cohort, and 2.3 ± 0.4 months in the patients with other NHLs. Seropositivity after the initial 2-dose vaccination series was 50% in CLL, 68% in WM, and 70% in other NHLs (Table 2). For CLL patients (n = 181), there was a significant difference in seropositivity when receiving the Moderna series (59%) compared to Pfizer (43%) after the initial vaccination series (P = .029). This difference trended toward significance in the WM patients but not in the other NHLs group. There was no difference between the Moderna and Pfizer vaccines in the proportion of patients under observation (43%; 40/92 vs. 41%; 60/147), surveillance (23%; 21/92 vs. 20%; 30/147), or active treatment (34%; 31/92 vs. 39%; 57/147). There were no differences in timing from last anti-CD20 mAb treatment to the initial vaccine dose between Moderna and Pfizer patients.
Table 2.
Antibody seropositivity in CLL, WM, and other NHLs after initial SARS-CoV-2 vaccination series.
| Malignancy | All patients | Moderna | Pfizer | P-value |
|---|---|---|---|---|
| All patients (n = 240) | 55% (131/240) | 64% (59/92) | 49% (72/147) | .02 |
| CLL (n = 181) | 50% (90/181) | 59% (44/74) | 43% (46/107) | .03 |
| • No treatment (n = 79) | 68% (53/79) | 71% (25/35) | 64% (28/44) | .46 |
| • Any treatment (n = 102) | 36% (37/102) | 49% (19/39) | 29% (18/63) | .04 |
| BTK inhibitor (n = 76) | 33% (25/76) | 50% (14/28) | 23% (11/48) | .02 |
| Anti-CD20 mAb (n = 68) | 31% (21/68) | 40% (10/25) | 26% (11/43) | .21 |
| Anti-CD20 mAb < 1 year (n = 26) | 19% (5/26) | 36% (4/11) | 7% (1/15) | .06 |
| Chemo-immunotherapy (n = 21) | 24% (5/21) | 25% (2/8) | 23% (3/13) | .92 |
| BCL-2 inhibitor (n = 30) | 37% (11/30) | 46% (6/13) | 29% (5/17) | .35 |
| WM (n = 22) | 68% (15/22) | 89% (8/9) | 54% (7/13) | .08 |
| • No treatment (n = 5) | 100% (5/5) | 100% (2/2) | 100% (3/3) | — |
| • Any treatment (n = 18) | 61% (11/18) | 86% (6/7) | 45% (5/11) | .09 |
| BTK inhibitor (n = 7) | 71% (5/7) | 100% (2/2) | 60% (3/5) | — |
| Anti-CD20 mAb (n = 13) | 62% (8/13) | 80% (4/5) | 50% (4/8) | — |
| Anti-CD20 mAb < 1 year (n = 3) |
33% (1/3) | - | 33% (1/3) | — |
| Chemo-immunotherapy (n = 7) | 71% (5/7) | 75% (3/4) | 67% (2/3) | .81 |
| BCL-2 Inhibitor (n = 0) | — | — | — | — |
| Other NHLs (n = 37) | 70% (26/37) | 78% (7/9) | 70% (19/27) | .67 |
| • No treatment (n = 17) | 88% (15/17) | 100% (4/4) | 85% (11/13) | .81 |
| • Any treatment (n = 20)* | 55% (11/20) | 67% (4/6) | 54% (7/13) | .60 |
| BTK inhibitor (n = 1) | 100% (1/1) | — | 100% (1/1) | — |
| Anti-CD20 mAb (n = 20)* | 55% (11/20) | 67% (4/6) | 54% (7/13) | .60 |
| Anti-CD20 mAb < 1 year (n = 8)* |
0% (0/8) | 0% (0/1) | 0% (06) | — |
| Chemo-immunotherapy (n = 13)* | 54% (7/13) | 67% (2/3) | 56% (5/9) | .74 |
| BCL-2 inhibitor (n = 1) | 0% (0/1) | - | 0% (0/1) | — |
Over half of the patients (52%; 124/240) were tested for the nucleocapsid IgG Ab, which is thought to be a marker of prior exposure to and immunity from the SARS-CoV-2 virus.35 Few patients in the cohort tested positive for the nucleocapsid IgG Ab (21%; 51/240), and in every instance, there was also an accompanying positive total Ab or spike protein IgM/IgG Ab. The median titer for patients who tested positive for the nucleocapsid IgG Ab was 8.4 ± 2.1 BAU/mL. However, only 4 of these patients had a documented SARS-CoV-2 infection prior to their nucleocapsid IgG Ab testing. In patients with a positive nucleocapsid Ab, the spike protein IgG titer was 8.0 ± 5.1 BAU/mL, higher than those with a negative nucleocapsid Ab in whom the spike protein IgG titer was 1.3 ± 4.2 BAU/mL (P = 0.01). There were some occasions where a positive total Ab resulted in tandem with a negative spike protein IgM/IgG Ab, and the opposite was seen as well.
We then investigated the impact of lymphoma treatment on vaccine response. In the CLL cohort, current or prior cancer-directed therapy at any point correlated with a lower rate of Ab response to the COVID-19 vaccines compared to treatment-naïve patients (36% vs. 68%; P = 0.000019). Interestingly, for patients treated with BTK inhibitors such as ibrutinib, Moderna vaccination led to a significantly higher seropositivity rate compared to Pfizer vaccination after the initial two-dose series (50% vs. 23%; P = .015). A history of prior anti-CD20 mAb therapy was also studied as a potential confounder in this comparison group. In patients treated with BTK inhibitors that had negative SARS-CoV-2 Ab testing after the initial series, there was no difference in the rate of prior anti-CD20 mAb therapy between those who received the Moderna (64%; 9/14) and Pfizer vaccines (65%; 24/37) (P = .97). Lower levels of the total Ab were noted in patients with any history of anti-cancer therapy compared to those just under observation across all compared groups: 0.4 ± 0.7 BAU/mL vs. 5.4 ± 0.9 BAU/mL in the entire cohort, 0.3 ± 0.8 BAU/mL vs. 3.6 ± 1.0 BAU/mL in CLL, 2.4 ± 2.3 BAU/mL vs. 10.0 ± 3.6 BAU/mL in WM, and 7.1 ± 2.2 BAU/mL vs. 7.7 ± 1.9 BAU/mL in the other NHLs (Table 1).
Although a similar trend of seropositivity was observed in those treated with anti-CD20 mAb and BCL-2 inhibitors after the initial series, the difference was not significant. However, a correlation between the timing of treatment and seropositivity rates was also found. Regardless of vaccination type, a lower rate of seropositivity after the initial series was seen in those who received anti-CD20 agents amongst all lymphoma diagnoses within one year from the first vaccine dose compared to those who had these therapies more than one year prior (13% vs. 40%; P = .022). In CLL patients specifically, this difference in seropositivity was also observed (19% vs. 38%; P = .23). This difference persisted in those patients who underwent repeat Ab testing after the initial booster vaccination (25% vs. 59%; P = .034). No significant difference in anti-CD20 mAb treatment history was found between the cohorts of patients who received the Moderna (39%; 36/92) or Pfizer vaccines (44%; 64/147) (P = .50).
Of the 17% (41/240) of patients who had a prior history of immunochemotherapy, no difference in spike Ab seropositivity was observed between the Moderna and Pfizer vaccines (Table 2). One patient was treated with a combination of ipilimumab and nivolumab for concurrently diagnosed metastatic melanoma. In addition, there was a remote history of CLL vaccine in a clinical trial setting in 2 patients and a history of chimeric antigen receptor T-cell (CAR-T) treatment in one patient, all occurring several years prior to SAR-CoV-2 vaccination.
A multivariate logistic analysis of Ab response after the initial vaccination series only was then conducted using the following variables: age at diagnosis, gender, race, history of prior SARS-CoV-2 infection, cancer diagnosis and cancer treatment history with BTK inhibitors, and BCL-2 inhibitors or anti-CD20 mAb (Table 3). Initial vaccination with the Pfizer series was statistically less likely to produce an Ab response compared to the Moderna vaccination (OR 0.47, 95% CI [0.26, 0.86], P = .02). The other variable which strongly correlated with a decreased Ab response within this model was a history of anti-CD20 mAb agents within one year of the first vaccine dose (OR 0.11, 95% CI [0.03, 0.38], P < .001). Conversely, having an Other NHL diagnosis correlated to an improved Ab response (OR 4.15, 95% CI [1.48, 13.4], P = .012).
Table 3.
Multivariate logistic model after initial SARS-CoV-2 vaccination.
| Univariate logistic | Multivariate logistic | |||||
|---|---|---|---|---|---|---|
| Characteristic | OR1 | 95% CI | P value | OR | 95% CI | P-value |
| Vaccine type (after two doses only) | ||||||
| Moderna | — | — | — | — | ||
| Pfizer | 0.54 | 0.31, 0.91 | .02 | 0.47 | 0.26, 0.86 | .02 |
| Diagnosis | .03 | .02 | ||||
| CLL | — | — | — | — | ||
| Other NHL | 2.39 | 1.14, 5.31 | .03 | 4.15 | 1.48, 13.4 | .01 |
| WM | 2.17 | 0.87, 5.91 | .11 | 2.43 | 0.73, 9.11 | .20 |
| Age | 1.01 | 0.98, 1.03 | .60 | |||
| Gender | ||||||
| Female | — | — | ||||
| Male | 0.83 | 0.49, 1.41 | .50 | |||
| Race | ||||||
| White | — | — | ||||
| Other | 1.17 | 0.58, 2.40 | .70 | |||
| Prior COVID infection (via PCR) | ||||||
| No | — | — | ||||
| Yes | 0.94 | 0.44, 2.06 | .90 | |||
| Prior COVID infection (via nucleocapsid-Ab) | ||||||
| No | — | — | ||||
| Yes | Inf | 0.00, Inf | NA | |||
| Not tested | 2.32 | 1.26, 4.36 | .008 | |||
| Prior/current cancer treatment | ||||||
| No | — | — | — | — | ||
| Yes | 0.28 | 0.16, 0.49 | <.001 | 0.68 | 0.20, 2.42 | .50 |
| BCL-2 inhibitor ever? | ||||||
| No | — | — | — | — | ||
| Yes | 0.43 | 0.19, 0.94 | .04 | 1.51 | 0.54, 4.26 | .40 |
| BTK inhibitor ever? | ||||||
| No | — | — | — | — | ||
| Yes | 0.27 | 0.15, 0.47 | <.001 | 0.51 | 0.17, 1.42 | .20 |
| CD20 mAb ever? | ||||||
| No | — | — | ||||
| Yes | 0.35 | 0.20, 0.58 | <.001 | |||
| Chemo and anti-CD20 ever? | ||||||
| No | — | — | — | — | ||
| Yes | 0.53 | 0.26, 1.04 | .07 | 0.70 | 0.26, 1.83 | .50 |
| CD20 mAb within 1 year of first vaccine dose? | <.001 | <.001 | ||||
| Never | — | — | — | — | ||
| Not within 1 year | 0.60 | 0.33, 1.09 | .10 | 0.83 | 0.30, 2.25 | .70 |
| Yes | 0.10 | 0.04, 0.25 | <.001 | 0.11 | 0.03, 0.38 | <.001 |
Abbreviation: OR, odds ratio.
Paired Ab test results were available in 52% (124/240) of patients both after receiving the primary 2-dose series and after a booster dose of a SARS-CoV-2 vaccine. The median time between the booster dose and repeat Ab testing was 2.0 ± 0.3 months in CLL, 1.6 ± 1.0 months in WM, and 2.6 ± 1.0 months in the other NHLs. Fourteen percent (34/240) of patients in the cohort received either their first or second booster from a different manufacturer than their initial series. Five patients who initially received the Moderna primary series got a booster with either the Johnson & Johnson or Pfizer vaccines. Twenty-nine patients received the primary immunization with the Pfizer vaccine and booster with the Moderna vaccine. The rest of the patients received the same brand of vaccine for the booster as the primary series. Fig. 2 depicts pre-booster seropositivity and post-booster seroconversion rates based on vaccination type only in those with three vaccine doses across all malignancies (n = 124). Total Ab and spike protein IgG Ab titers are also shown, with the Moderna vaccine producing a higher median level of titer relative to the Pfizer vaccine in both Ab’s after the initial series and the booster.
Figure 2.
Antibody response after initial vaccination and subsequent booster against SARS-CoV-2. Graphs depict the rate of positive Ab in patients with any lymphoma who received all of the following: initial vaccination series, booster vaccinations, and antibody testing both after the initial series and after the booster dose (n = 124), and patients missing any of this data were excluded (A). Subsequently, only patients with a prior history of cancer treatment or who were actively receiving a cancer therapy were included (B). Patients in either the Moderna or Pfizer categories received three doses (initial series and booster) from the same manufacturer. Patients in the Heterologous category received vaccines from difference manufacturers for their booster dose(s) compared to their initial series. Paired absolute titer levels for the total index and spike protein IgG are subsequently reported for this group, separated by both vaccine manufacturer and whether titers were drawn after the initial vaccination series or after the booster (C). The upper limit of detection for the total index is 10 BAU/mL, and any value above this was reported as 10 BAU/mL in the graph. Horizontal bars represent median values.
There were 4 patients with positive Ab titers after the initial series that had negative titers after the booster dose. Borderline seropositivity was noted in each instance, with the total Ab measuring <2.5 BAU/mL or the spike protein IgG Ab measuring ≤1.0 BAU/mL in each case. Furthermore, 3 of these 4 patients did not have total Ab testing done after the booster dose due to limited availability of the test assay. The time from vaccination to Ab testing was between 0.5 and 2 months after the initial series but 1-5 months between the booster dose and repeat Ab testing.
Among the 45% (109/240) of patients who had negative Ab titers after the primary vaccination series, 11% (27/240) had seroconversion and 18% (44/240) remained negative on repeat Ab testing after the booster dose. The remainder of these patients did not have Ab testing after their booster dose. Among those with seroconversion, 30% (8/27) had previously undergone treatment but were currently under surveillance. Seroconversion regardless of treatment status was higher in patients who received the 3 Moderna doses compared to 3 Pfizer doses, although this was not statistically significant. A small number of patients in this cohort received a 2nd booster dose, equating to a 4th overall dose in the vaccination series, however seroconversion in this group was rare.
The incidence of confirmed SARS-CoV-2 virus infection via nasopharyngeal polymerase chain reaction (PCR) testing based on chart review was 13% (30/240). There were several patients with signs and symptoms consistent with COVID-19 infection but were not included in this calculation due to a lack of a positive PCR or antigen test. The majority of patients had a mild to moderate disease course (70%; 21/30; Table 4). The remainder had a more severe course of illness, and there were 2 deaths from the COVID infection. Common treatments included anti-COVID monoclonal antibody infusions, remdesivir, dexamethasone, and other supportive measures. About 23% (7/30) of COVID-19 infections occurred prior to the development of SARS-CoV-2 vaccines, 3% (1/30) were infected between their first and second doses, 23% (7/30) were infected after completing their initial vaccination series, and 50% (15/30) were infected after receiving their booster dose. One patient with a COVID-19 infection experienced seroconversion after testing positive between their initial vaccine series and the booster dose. The majority of severe and critical cases (63%; 5/8) occurred prior to receiving any vaccine dose. The 2 COVID-19 deaths occurred in 1 patient that received 2 vaccine doses, who did not have Ab seropositivity, and another who received 3 doses, who had seropositivity after the initial 2-dose series but negative Ab testing after the booster dose.
Table 4.
Severity of COVID-19 infection in patients with CLL and other indolent NHLs.
| NIH clinical spectrum | All patients (n = 30) | CLL (n = 22) | WM and other NHLs (n = 8) |
|---|---|---|---|
| Asymptomatic infection | 3% (1/30) | — | 13% (1/8) |
| Mild/moderate illness | 70% (21/30) | 77% (17/22) | 50% (4/8) |
| Severe illness | 17% (5/30) | 14% (3/22) | 25% (2/8) |
| Critical illness | 10% (3/30) | 9% (2/22) | 13% (1/8) |
| COVID-19 deaths | 7% (2/30) | 9% (2/22) | — |
Exposure to anti-CD20 mAb therapy was analyzed as a possible risk factor for more severe disease in the patients with COVID-19 infections. An anti-CD20 mAb agent was used to treat the malignancy in 57% (17/30) of infected patients, and the rate of moderate to critical disease was 53% (9/17) in those who received anti-CD20 mAb treatment at any point in the disease as compared to 31% (4/13) in those who did not (P = 0.22).. There was a statistically significant difference in the rate of moderate to critical COVID-19 infection among patients who last received anti-CD20 therapy within 1 year (44%; 4/9) compared to those greater than 1 year (0%; 0/8) from their COVID infection (P = .03). Fig. 3 provides additional context on the timing of COVID-19 infection, anti-CD20 mAb treatment, and vaccination response in all relevant patients illustrated as a Swimmer’s plot.
Figure 3.
Swimmer’s plot of vaccinated patients infected with SARS-CoV-2. Representation of all patients who were infected with the SARS-CoV-2 virus in the cohort. The follow-up period starts in January 2020, which is the approximately time of when the first COVID-19 cases were reported in the United States and ends at the most recent follow-up. Patient cases 1, 2, 19, 20, 24, 26, 29, and 30 received their most recent dose of anti-CD20 mAb therapy prior to the start date in the figure and thus are not marked with the designated symbol.
Discussion
Our study summarizes seropositivity and seroconversion after SARS-CoV-2 vaccination in patients with indolent NHLs, confirming previously reported findings in a large cohort while also uncovering clinically relevant differences in these patients. Key findings in this study include lower rates of Ab seropositivity in patients with indolent lymphomas such as CLL and WM compared to the general population and a higher rate of Ab seropositivity in patients receiving the Moderna vaccination compared to Pfizer vaccination in CLL and WM patients. Furthermore, in the CLL cohort, BTK-treated patients who received the Moderna vaccine were more likely to have a positive Ab response compared to those who received the Pfizer vaccine. We also found differences in patients treated with anti-CD20 agents, with higher rates of Ab seropositivity in those treated greater than one year from the first SARS-CoV-2 vaccination dose.
Seropositivity was 55% (131/240) after the primary vaccination among all patients. These results are consistent with earlier findings that patients with these malignancies have a lower seropositivity rate after SARS-CoV-2 vaccination compared to the general population and myeloid leukemia patients.36-39 We also discovered significantly higher levels of the spike protein IgG titer in patients with a positive nucleocapsid Ab than in those without, which may point to a synergistic effect on measured Ab titers in patients with a prior, undocumented infection and after initial vaccination. However, interpretation of this data should be limited since the nucleocapsid Ab titers were only measured after administration of the initial vaccine series.
Our findings also help confirm that SARS-CoV-2 vaccination is generally safe in patients with lymphoid malignancies, although a higher rate of anaphylaxis of approximately 1:750 doses was found in this study.14,38,40 A total of 109 patients had negative Ab testing after the initial vaccine series, and 38% (27/71) of those retested had seroconversion after the booster, supporting the efficacy of at least 1 booster vaccine dose in patients with indolent lymphomas. The lack of significant seroconversion between the first and second booster doses in this study may suggest a sort of diminishing returns after three mRNA vaccine doses in this patient population.
There was a difference in seropositivity after the initial series of Moderna vaccination compared to Pfizer vaccination across all studied histologies of lymphoma. To control for confounding factors in our cohort of patients, we did a multivariate analysis, and the difference in vaccine efficacy after the primary series remained statistically significant. This is different compared to the general population, where there is no difference in Ab titers between the 2 vaccinations after completion of the initial series.41 A previously reported study in hematologic malignancies has also not shown any difference between the Moderna and Pfizer vaccines, although this study is with a smaller sample size, the inclusion of more aggressive malignancies such as diffuse large B-cell lymphoma and fewer patients without any prior history of anti-cancer therapy.
18 Further study with ideally larger sample sizes and more standardized data collection can help clarify this discrepancy. One possible explanation is the higher dose of the Moderna vaccine (50 μg) compared to the Pfizer vaccine (30 μg).42 Although not statistically significant, there was also a greater percentage of patients with positive Ab titers after the first Moderna booster compared to after the first Pfizer booster dose, suggesting that this difference in efficacy may persist beyond the initial 2-dose series. Given the risk of potential confounding bias, further research via multivariate analyses is needed to reproduce these differences and to better understand their clinical utility.
Previously untreated CLL patients had a worse response to the initial COVID vaccine series compared to the general population, indicating the negative impact on humoral immune function by the lymphoid malignancy itself. Any prior or active lymphoma-directed treatment caused further compromise on humoral immune response to the vaccine, with a significantly lower seropositivity rate compared to previously untreated patients (36% vs. 68%; P = .000019). Consistent with prior literature,43 our data also confirmed that treatment with BTK inhibitors negatively affects the production of Abs after SARS-CoV-2 vaccination. In CLL patients treated with BTK inhibitors, the Ab response rate to the Moderna vaccine was significantly higher than that for the Pfizer vaccine (50% vs. 23%, respectively, P = .015). Among patients with negative SARS-CoV2 Ab titers, there was no difference in the history of anti-CD20 mAb therapy in the Moderna and Pfizer groups (P = .97).
Timing of anti-CD20 mAb therapies was also shown to affect COVID vaccine response, which has been previously shown to prevent robust Ab production even after multiple vaccine doses.44 Receiving these agents within 1 year vs. more than 1 year from the dose significantly affected seropositivity across all studied malignancies both after the initial series (13% vs. 40%; P = .022) and after the booster dose (25% vs. 59%; P = .034). Having anti-CD20 mAb within a year of the first COVID vaccine remained a significant factor in our multivariate analysis. This finding suggests a temporal association between lymphoma treatment and the body’s ability to produce detectable Ab after vaccination. More data is needed on whether there is a significant difference in seroconversion after multiple booster doses in patients who have received these treatments.
SARS-CoV-2 infection was commonly found during the follow-up interval, occurring in 13% of patients. The case fatality rate (CFR), defined as deaths from disease divided by disease cases, was 7% (2/30) in this study, higher than the global CFR of 0.5%-3% in the general population.45 Although only 23% (7/30) of patients caught COVID-19 prior to being vaccinated, they accounted for a disproportionate proportion of severe and critical cases (63%; 5/8). Despite the limited sample size, this information suggests that vaccination is at least partially effective in preventing severe disease. An alternative explanation is that patients with asymptomatic to moderate disease were more commonly infected with the Omicron SARS-CoV-2 variant and had prophylactic mAb treatments available to them, given that most of the positive tests happened from late 2021 to early 2022. This variant is suspected to cause a more indolent disease course despite its greater infectivity.46
Our data also suggest that lack of discernable SARS-CoV-2 Abs in treated CLL patients is correlated with more severe infection. Patients treated with anti-CD20 mAb therapy within 1 year from vaccination, who had lower rates of seropositivity, also were statistically more likely to have a moderate to critical COVID-19 infection (44% vs. 0%; P = .03). It should be noted that both deaths from the virus occurred in vaccinated patients, however, given the minute sample size for this subgroup, conclusions cannot be drawn with respect to the relation between vaccination status and mortality from COVID-19 in this cohort. Other studies have shown similar findings, with the SARS-CoV-2 vaccines conferring differing levels of protection to cancer patients compared to the general population, particularly when considering timing of vaccination.47
There are some limitations to this study. There was a relatively small sample size of patients with WM or other NHLs compared to CLL. There was variability in treatment strategy, timing of vaccination, and timing of Ab testing after vaccination. There also was no baseline Ab seropositivity measurement in the cohort prior to the administration of the initial SAR-CoV-2 vaccination series. Moreover, many patients did not yet have antibody testing after the completion of booster doses, limiting our analysis of the comparison between seropositivity rates before and after the booster. The statistically significant difference in seropositivity between the Moderna and Pfizer vaccinations after the initial series was not observed after the first booster dose. The significant dropout of patients from the statistical analysis may have obfuscated any differences that were initially discovered. Also, the total Ab assay was no longer available at the study institution for most patients after they had received the booster dose, thus having to rely on the spike protein Ab alone. Additionally, we did not measure cellular responses to vaccines, which have been documented to be present even without seropositivity and confirm protection against more severe infections.
Conclusion
This study provides data from a large cohort of patients with CLL, WM, and other NHLs on Ab response to SARS-CoV-2 vaccination and booster series. Insight is provided on which SARS-CoV-2 vaccines can provide greater seropositivity in select indolent lymphomas depending on disease, treatment agent, and timing of treatment from vaccination. A significant difference in seropositivity rates after Moderna SARS-CoV-2 vaccination in treated CLL patients compared to other vaccination series was discovered. Booster doses were effective in producing positive Ab titers after repeat testing. More study is needed to determine whether the difference in seropositivity between the Moderna and Pfizer vaccinations persists after a booster dose and yields a clinical benefit that may alter treatment practices. Although detailed insight into the humoral immune response was uncovered, data on cellular (T cell) response is lacking and should be further explored to better understand the full picture of immunity in these patients.
Supplementary Material
Contributor Information
Peter G Doukas, Department of Medicine, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Frederique St. Pierre, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Reem Karmali, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Xinlei Mi, Department of Preventive Medicine and Biostatistics, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Jennifer Boyer, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Mariana Nieves, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Michael G Ison, Divisions of Infectious Diseases and Organ Transplantation, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Jane N Winter, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Leo I Gordon, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Shuo Ma, Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
Conflict of Interest
Reem Karmali received research funding from BeiGene, Kite, BMS/Celgene, and Takeda, advisory honorarium from BeiGene, Kite, Morphosys, Karyopharm, BMS/Celgene, Genentech, Roche, Janssen, Calithera, Pharmacyclics, and AstraZeneca, and speaker honorarium from AstraZeneca, BeiGene, Kite, and Morphosys. Michael G. Ison received research funding, paid to Northwestern University, from GlaxoSmithKline and Pulmocide; paid consultancy from Adagio, AlloVir, Celltrion, Cidara, Genentech, Roche, Janssen, Shionogi, and Viracor Eurofins; and is also a paid member of DSMBs from Allovir, CSL Behring, Janssen, Merck, Sequiris, and Takeda. Shuo Ma received research funding from AbbVie, AstraZeneca, BeiGene, Juno, Loxo, Pharmacyclics, and TG Therapeutics, advisory honorarium from Abbvie, AstraZeneca, BeiGene, Janssen, Genentech, Pharmacyclics, and TG Therapeutics, and speaker honorarium from AstraZeneca, BeiGene, Janssen, and Pharmacyclics. The other authors indicated no financial relationships.
Author Contributions
Conception/design: P.G.D., F.S.P., S.M. Provision of study material or patients: R.K., J.N.W., L.I.G., S.M. Collection and/or assembly of data: P.G.D., F.S.P., J.B., M.N. Performed statistical analyses and created figures and tables: P.G.D., X.M. Enrolled patients for antibody testing at clinic appointments: J.B., M.N. Data analysis and interpretation: P.G.D., F.S.P. Manuscript writing: All authors. Final approval of manuscript: All authors.
Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.