key: cord-1026487-smooxy69
authors: Herzog Tzarfati, Katrin; Gutwein, Odit; Apel, Arie; Rahimi‐Levene, Naomi; Sadovnik, Maya; Harel, Lotem; Benveniste‐Levkovitz, Patricia; Bar Chaim, Adina; Koren‐Michowitz, Maya
title: BNT162b2 COVID‐19 vaccine is significantly less effective in patients with hematologic malignancies
date: 2021-07-14
journal: Am J Hematol
DOI: 10.1002/ajh.26284
sha: 755e770a04e4fd01bb7d48145aefd7d04cc2ff88
doc_id: 1026487
cord_uid: smooxy69

Patients with hematologic malignancies have an increased risk of severe COVID‐19 infection. Vaccination against COVID‐19 is especially important in these patients, but whether they develop an immune response following vaccination is unknown. We studied serologic responses to the BNT162b2 vaccine in this population. A lower proportion of patients were seropositive following vaccination (75%) than in a comparison group (99%; p < 0.001), and median (interquartile range [IQR]) antibody titers in patients were lower (90 [12.4–185.5] and 173 [133–232] AU/ml, respectively; p < 0.001). Older age, higher lactate dehydrogenase, and number of treatment lines correlated with lower seropositivity likelihood and antibody titers, while absolute lymphocyte count, globulin level, and time from last treatment to vaccination correlated with higher seropositivity likelihood and antibody titers. Chronic lymphocytic leukemia patients had the lowest seropositivity rate followed by indolent lymphoma. Patients recently treated with chemo‐immunotherapy, anti‐CD20 antibodies, BCL2, BTK or JAK2 inhibitors had significantly less seropositive responses and lower median (IQR) antibody titers (29%, 1.9 [1.9–12] AU/ml; 0%, 1.9 [1.9–1.9] AU/ml; 25%, 1.9 [1.9–25] AU/ml; 40%, 1.9 [1.9–92.8] AU/ml; and 42%, 10.9 [5.7–66.4] AU/ml, respectively; p < 0.001). Serological response to BNT162b2 vaccine in patients with hematologic malignancies is considerably impaired, and they could remain at risk for severe COVID‐19 infection and death.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS- has spread at an alarming rate, leading to a death toll of over 3.0 million worldwide. 1 Patients suffering from hematologic malignancies are severely immunocompromised and are considered particularly vulnerable and prone to severe disease due to SARS-CoV-2 infection. Risk of death for these patients is close to 35%, which is twice that of subjects without hematologic malignancies infected with COVID-19. 2, 3 Patients diagnosed recently, those suffering from acute myeloid leukemia (AML) and those receiving active antineoplastic treatment with monoclonal antibodies (MoAbs) are at a particularly high risk. 4, 5 When compared to patients with solid tumors and healthy controls, patients with hematologic malignancies infected with SARS-CoV-2 were shown to have prolonged viral shedding and delayed seroconversion.

Some of these patients, in particular those recently treated with anti-CD20 MoAbs or stem cell transplantation (SCT), were unable to mount an antibody response at all. 6 Even when an antibody response develops, reinfection with COVID-19 is still a possibility. This was observed in healthy young individuals, seropositive for SARS-CoV-2 immunoglobulin G (IgG), at a rate as high as 10% in close quarters. Reinfection was associated with lower baseline IgG titers. 7 Efforts to develop effective vaccines against SARS-CoV-2 have led to the rapid approval of several vaccines including the BNT162b2 COVID-19 vaccine, which has been available in Israel since December 20, 2020. The company-sponsored trial in the general population, 8 as well as real-world data from Israel 9 have shown high efficacy in preventing severe clinical disease. Vaccinating patients with hematologic malignancies is especially important due to their vulnerability to severe COVID-19, but whether they develop an immune response following vaccination remains unknown. Furthermore, patients with hematologic malignancies were previously shown to have poor responses to vaccinations, such as against influenza, herpes zoster, pneumococcal infection and hepatitis B. [10] [11] [12] [13] [14] We therefore aimed to study the serological response following the recommended two-dose BNT162b2 COVID-19 vaccine in a wide range of hematologic malignancies patients.

Center in Israel, having received two doses of vaccination, were approached for participation in the study.

Data were collected between February 7 and April 8, 2021, and compared with an age-matched group of subjects with no hematologic malignancy (comparator group). Participants with solid cancer or immune diseases were not excluded. All participants completed a questionnaire pertaining to possible exposure to COVID-19, prior PCR testing for COVID-19 and results thereof, concurrent medical conditions and immunosuppressive therapy. Data regarding hematologic diagnoses, as well as current and prior treatments were retrieved from the electronic medical records.

Blood samples for COVID-19 serology were collected between 30 and 60 days following the second vaccine dose. Patients with prior COVID-19 infection were excluded from the study, as were patients having serology testing done within 14 days of vaccination. The study was approved by the local institutional review board and all participants signed an informed consent form.

Serologic testing for SARS-Cov2 IgG was performed using the Liaison SARS-CoV-2 S1/S2 IgG test (DiaSorin, Saluggia, Italy), a chemiluminescence immunoassay for the quantitative determination of anti-S1-and anti-S2-specific IgG antibodies to SARS-CoV-2 in human serum or plasma samples. Clinical sensitivity and specificity of this assay are 97.4% and 98.5%, respectively. Samples were considered negative for antibody titers <12 AU/ml. 15 

Serologic samples were collected from 427 individuals. Four subjects were excluded due to an interval of less than 14 days between vaccination and sampling (three patients and one control). Therefore, 423 subjects are included in this analysis: 315 patients with hematologic malignancies and 108 in the comparison group. Characteristics of study subjects are given in Table 1 . The median (IQR) age of the study cohort was 70 (61-77) years, with no significant difference in age between patients and the comparison group. The patient cohort included more males and more patients with renal disease compared with the comparison group (p = 0.026 and 0.046, respectively). The time period from the second vaccine to serology testing did not differ between the two groups (p = 0.61).

In all, 74.6% of patients with hematologic malignancies developed a positive humoral response (seropositivity) with a median (IQR) antibody titer of 85 (10.7-172) AU/ml as opposed to the comparison group in whom 99.1% were seropositive following vaccinations, with a median antibody titer of 157 (130-221) AU/ml (p < 0.001 for both comparisons).

In case-matched analysis, 69 patients/comparison group paired for age, gender, comorbidities, and time from vaccination to serology assay were analyzed (Table 1) . COVID-19 seropositivity developed in 75% of patients and 99% of the matched comparison group, with median (IQR) antibody titers of 90 (12.4-185.5) and 173 (133-232) AU/ml, respectively (p < 0.001 for both), much the same as for the entire cohort.

Features of hematologic malignancies as well as serologic data are presented in Table 2 Hodgkin lymphoma (94%) had the highest rates (p < 0.001) (Table 2; Figure 2 ). At the time of vaccination, 59% of patients with hematologic malignancies had active disease and 52% were receiving treatment. Patients who had never received treatment were more likely to obtain seropositivity than those receiving one, or two or more therapeutic lines (95% compared with 73% and 63%, respectively; p = 0.001). Time from end of treatment to COVID-19 vaccination influenced the rate of seropositivity, with patients receiving treatment 0-6 months prior to vaccination having the lowest rate of seropositivity (66%, p < 0.001 compared with no treatment). Type of treatment at vaccination significantly affected the rate of seropositivity. Patients receiving chemo-immunotherapy (CIT), single-agent anti-CD20 therapy, BCL2 inhibitors, BTK inhibitors, as well as JAK2 inhibitors had the lowest rate of seropositivity (29%, 0%, 25%, 40%, and 42%, respectively). Type of treatment also remained significant when comparing between treatments given up to 6, 24 and 60 months prior to vaccination (p < 0.001 for comparison of seropositive proportions between treatment types at each time point). Patients who underwent auto-SCT had the same rate of seropositivity as those who did not undergo SCT (p = 0.48). 

We Table 2) .

Type of treatment also significantly influenced post-vaccination antibody titers, when comparing between types of treatment given in the last 6, 24, and 60 months (data not shown). Classification trees were applied in an attempt to identify subgroups of patients who are at risk for seronegativity following vaccination with the BNT162b2 COVID-19 vaccine. Figure 2 demonstrates a classification tree incorporating age, type of current treatment, and diagnosis. As seen, the first division for dis- A second classification tree shown in Figure 3 

All study participants were approached via a telephone call at the end of shown that the majority of solid organ transplant recipients failed to mount an appreciable antibody response to the first dose of mRNA-based COVID-19 vaccine. 19 Herishanu et al. 20 results. This is also consistent with a low rate of seroconversion F I G U R E 3 Classification tree for seronegativity using current treatment, absolute lymphocyte count and treatment in the past 60 months. The first division for discriminating patients is based on current treatment. The second division is based on the absolute lymphocyte count. The third division for patients with a lymphocyte count ≤0.885 is based on treatment given in the previous 60 months. MoAb, monoclonal antibodies; PIs, proteasome inhibitors; IMIDs, immune modulatory drugs; TKI, tyrosine kinase inhibitors; CIT, chemo-immunotherapy; BCL2, B-cell lymphoma 2; JAK2, janus kinase 2; BTK, bruton tyrosine kinase reported in CLL patients with PCR-positive SARS-CoV-2 infection, more than half of whom were on active treatment with either BCR inhibitors or a combination of a BCL2 inhibitor and anti CD20

MoAb. 21 In a recently published cohort of MM patients, seropositivity was demonstrated at a rate of 56% following the first dose of COVID-19 vaccine, with patients not in complete response or very good partial response at a higher risk for seronegativity as well as those with immunoparesis and more prior treatment lines. Any therapy but no specific treatment was associated with seronegativity. 22 Comparably we demonstrated seropositivity in 76% of MM patients following vaccination with two doses.

Of special interest, treatment with ruxolitinib, the main JAK2

inhibitor used in our patient cohort, was associated with one of the lowest seropositivity rates and low antibody titers (42% and 10.9

[IQR: 5.7-66.4] AU/ml, respectively). This JAK1/JAK2 inhibitor has broad anti-inflammatory activity. As the severe respiratory disease due to COVID-19 has features consistent with cytokine release syndrome, ruxolitinib was studied in these patients. Treatment with ruxolitinib in severely ill COVID-19 patients led to a reduction in COVID hyperinflammation scores and clinical improvement, although it was not statistically significant in a randomized control trial. 23, 24 Therefore, it is plausible that ruxolitinib treatment could blunt the immune response following COVID-19 vaccination, leading to seronegativity of treated patients. shown that exposure to SARS-COV-2 can induce a cellular immune response without seroconversion. 27 Also, most participants in the early BNT162b2 COVID-19 vaccine trials mounted a virus-specific CD4+ and CD8+ T-cell immune response, which could convey longlasting memory immunity against COVID-19, in addition to a robust serological response. 28 Such responses were demonstrated in SARS-CoV-1 survivors lasting 6-11 years. 29 Thus, it is plausible that patients diagnosed with hematologic malignancies may still benefit from vaccination through a cellular immune response, even when seronegative for antibodies to SARS-CoV-2.

Newer approaches to vaccinate patients with reduced immunological responses could include different vaccine design or dosing schedules, 30 as well as combining different coronavirus vaccines, 31 and these should be further studied.

Limitations of the current study include relatively small patient subgroups in some disease and treatment categories, which could lead to a confounding effect of diagnosis and treatment type. The distribution of antibody titers was extremely skewed, resulting in difficult to perform linear regression even after natural log transformation, and very large CI. Finally, post-vaccination follow-up of the study cohort was very short and we could not demonstrate a correlation between seronegativity or low antibody titers and clinical disease.

To conclude, older patients, those diagnosed with CLL, NHL, and MM, and those receiving CIT, single-agent anti-CD20 therapy, BCL2

inhibitors, BTK inhibitors, as well as JAK2 inhibitors are at risk for seronegativity following vaccination and thus are potentially still susceptible to COVID-19 infection.

We thank Dr Tomer Ziv-Baran for statistical analysis support.

All authors declare there are no relevant disclosures or conflicting financial interests.

Katrin Herzog Tzarfati and Maya Koren-Michowitz initiated and designed the study, collected, and analyzed data, and wrote the paper. Odit Gutwein, Arie Apel, Naomi Rahimi-Levene, Maya

Sadovnik, and Lotem Harel participated in data collection. Adina

Bar Chaim and Patricia Benveniste-Levkovitz were responsible for serological testing.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Maya Koren-Michowitz https://orcid.org/0000-0002-7223-328X

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