Outcome of SARS-CoV-2-Infected Polish Patients with Chronic Lymphocytic Leukemia

Simple Summary The severe acute respiratory syndrome coronavirus (SARS-CoV-2) has become the cause of a worldwide pandemic, and its clinical infection course in patients with hematological malignancies may be severe. Chronic lymphocytic leukemia (CLL) patients are among this group, and CLL-directed therapies are discussed as potential COVID-19-severity modifying agents. So far, the published data and clinical experience in treatment of COVID-19 patients with CLL are still scarce. Therefore, we aimed at retrospectively analyzing factors associated with SARS-CoV-2 infection course in patients with CLL. Abstract Background. The severe acute respiratory syndrome coronavirus (SARS-CoV-2) has become the cause of a worldwide pandemic, and its clinical infection course in patients with hematological malignancies may be severe. Methods. We performed a retrospective study on 188 chronic lymphocytic leukemia patients (CLL) with COVID-19 infection. Results. At the time of infection 51 patients (27.1%) were treated with Bruton tyrosine kinase inhibitor (BTKi), 46 (24.5%) with anti-CD20 antibodies while 37 patients (19.7%) received venetoclax. In total, 111 patients (59.0%) required hospitalization and 50 patients (26.5%) died due to COVID-19. Patients with poor performance status (ECOG >1; p = 0.02), advanced age (>65 years; p = 0.04), low hemoglobin concentration (≤10 g/dl; p = 0.0001), low platelets (<100 × 109/L; p = 0.003), and elevated lactate dehydrogenase level (LDH; p = 0.014) had an increased risk of death due to COVID-19. Neither CLL treatment status (treatment naïve vs. treated) nor the type of CLL-directed treatment had impact on the SARS-CoV-2 related risk of death. The multivariate survival analysis showed that advanced age (p = 0.009) and low platelet count (p = 0.0001) were associated with significantly shorter patients’ overall survival. Conclusions. SARS-CoV-2 infection in CLL patients is associated with poor outcome regardless of administered CLL-directed treatment.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease , has led to a significant morbidity increase worldwide since its outbreak in December 2019 in Wuhan, China [1]. The severity of the disease can vary between particular patients, however advanced age, cardiovascular comorbidities and history of cancer were shown to be associated with worse outcome [2][3][4][5]. Chronic lymphocytic leukemia (CLL) is the most common leukemia, with a median age at diagnosis reaching 72 years, and often patients at diagnosis are characterized by the presence of other comorbidities potentially affecting treatment possibilities and outcome [6]. CLL is characterized by defects of both adoptive and innate immune response, and the administered antileukemic treatment further strengthens immune defects, affecting elimination of SARS-CoV-2 leading to poor patient outcome [7,8]. A recently performed meta-analysis showed a high case fatality rate (CFR) of 34% in 3240 adult, mainly hospitalized patients with hematological malignancies [9]. Indeed, published reports indicate a closely related CFR in CLL patients which ranges from 27.3% to 35% depending on the study, rate of hospitalization (60-78%) and time from the beginning of the COVID-19 pandemic [10][11][12][13]. The observational study of Roeker et al. showed that some improvement in the management of COVID-19 patients had been made, as the CFR rate dropped from 35% at the beginning of the pandemic to 11% at later months [12].
Despite this fact, the morbidity of CLL patients infected with the SARS-CoV-2 virus remains high, and further progress is needed. Although several agents have been approved for COVID-19 treatment and dexamethasone showed a significant impact in patients requiring oxygen supplementation on overall survival (OS), the number of hematological patients in these studies was low and does not allow for translating these findings to the field of immunocompromised patients [14][15][16][17]. Interestingly, analysis of COVID-19directed therapies in CLL-hospitalized patients revealed that remdesivir treatment and convalescent fresh frozen plasma (CCP) transfusion reduced the risk of death, whereas dexamethasone and hydrochloroquine administration increased it [12].
Despite the growing number of agents being approved for the treatment of COVID-19, this disease still poses a serious clinical problem in CLL patients. In this paper, we analyze the outcome of SARS-CoV-2 infection in 188 CLL patients based on the data collected within a retrospective study conducted by the Polish Adult Leukemia Study Group (PALG).

Patients
The study was conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The data were acquired retrospectively by the Polish Adult Leukemia Group (PALG) sites by identifying patients from their local registries. CLL patients with SARS-CoV-2 infection confirmed by a positive test result using rapid antigen detection or real-time polymerase chain reaction (PCR) test were included in the analysis. Treatment indications and response assessments were based on the 2018 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and performed by the enrolling physicians.
Data were collected between 25 March 2020 and 7 May 2021. Vaccines against SARS-CoV-2 in Poland became available at the end of December 2020, first for the medical staff, then for the subsequent age groups, starting from octogenarians. SARS-CoV-2 vaccination became available for oncological patients only in March 2021, which means that at the time of analysis, most patients were not immunized against SARS-CoV-2.

Statistical Analysis
The data were analyzed in Statistica 13.3 (Dell Inc., StatSoftPolska Sp. z o.o., Cracow, Poland), Graph Pad Prism 9 (La Jolla, CA, USA) and SAS software (SAS Institute Inc., Cary, NC, USA). For univariate analysis Kruskal-Wallis, Mann-Whitney U, Fisher's exact and chi-squared tests were employed. The overall survival (OS) was defined as the time from positive SARS-CoV-2 test to death and was analyzed with a log-rank test. Multivariate analysis of OS was performed using the Cox proportional hazard model. The level of statistical significance was set at p < 0.05.

Analysis of the Hospitalized Subgroup
Data of hospitalized patients are summarized in Table 1

Analysis of the Hospitalized Subgroup
Data of hospitalized patients are summarized in Table 1

Discussion
In this paper, we confirm that COVID-19 poses a serious threat to CLL patients with a CFR of 26.5% observed in the whole cohort. An even more dismal outcome was noted in patients requiring hospitalization due to COVID-19 infection in whom CFR rate reached 38.7%. Our data are comparable in this case to other so-far published national and international multicenter studies, where CFRs ranged from 27.3% to 35% [10][11][12][13]. The data gathered in this study stem from the second and third waves of the COVID-19 pandemic in Poland, when experience in the treatment of COVID-19 disease was very limited and the SARS-CoV-2 vaccination program was at the earliest phase of its development. Therefore, the data generated in our observational study should be compared mostly to the first observational COVID-19 study reports, as the development of new SARS-CoV-2-directed agents and gains in clinical experience based on the observations of Roeker et al. led to outcome improvement in CLL patients by reducing the CFR from 35% to 11% [12].
In the analyzed cohort, 59% of patients required hospitalization, and overall 99 (89.1%) patients required oxygen supplementation, whereas mechanical ventilation was necessary in 22 (20.0%). Although we did observe a slightly lower number of hospitalized patients in our cohort compared to other studies, the severity of the infection in the hospitalized patients seems to be comparable to the data presented in other observational studies [10][11][12][13]. It is noteworthy that some studies underline that introduction of dexamethasone, remdesivir and gains in clinical experience helped to reduce the CFR, as shown in the studies of Roeker et al. and Blixt et al. [12,19]. Interestingly, in the study of Roeker et al., in the later phase of the pandemic a reduced number of hospitalizations for CLL patients with COVID-19 was observed (85% vs. 55%) as well as ICU admissions (32% vs. 15%), and this also could have the beneficial effect on the observed lower mortality in the later phase of the pandemic [12]. In contrast, in the study of Blixt et al., no significant difference in the hospitalization rates was noted (86% vs. 71%). However, the observed reduction in deaths from 32% to 18% could be related to the increasing clinical experience and broader use of remdesivir and dexamethasone in the later period of the pandemic in Sweden (5% to 41% and 47% to 78%) [19]. On the other hand, the largest analysis of CLL patients with COVID-19 did not show any improvement between outcomes of subsequent waves of SARS-CoV-2 infection [10]. Considering the variable drug availability, heterogenous populations, and differences in local treatment protocols, a strict comparison of patient outcomes between these studies is not possible.
We observed the increased risk of death in patients with advanced age. In our study, we confirmed that advanced age is a significant factor for poor outcomes with COVID-19, which corroborates the results of other observational studies [3,4,10,13]. Interestingly we also noted that low hemoglobin and platelet levels were associated with the patient's increased risk of death, which to our knowledge has not been reported so far. In our opinion, this observation may reflect CLL disease activity and severity, and therefore could additionally increase patients' risk of death. In the whole cohort, the median OS was not reached; however, in terms of the analyzed factors, only advanced age and low platelet count were associated with shorter OS. Although the impact of advanced patient age on shorter OS was well-described in the previous studies, the impact of low platelet levels should be regarded with caution due to limitations in the observational nature of our study [3,4,10,13].
Low hemoglobin and platelet levels, in addition to the presence of 17p deletion, elevated LDH and anti-CD20 antibody treatment, were factors significantly associated with the need for hospitalization, and therefore they potentially contribute to the increased mortality, mirroring the severity of COVID-19. Although, the use of anti-CD20 antibodies was not shown to impact the patient risk of death or OS in the multivariate analysis, our data indicate that the use of such agents may lead to a more severe COVID-19 clinical course. Our data partially confirm the observation from the large multicenter study performed in 941 CLL patients, which showed that the use of anti-CD20 antibodies alone or in combination led to the shorter OS when compared to untreated patients [10]. However, we did not observe any impact of the previous administration of CLL-directed treatment or the impact of venetoclax or BTK inhibitors on the patient risk of hospitalization.
Interestingly we found that low platelet counts were associated with poor outcome in the whole and hospitalized patient cohort. Platelets have been discussed to modify course of the disease in various cancers, including CLL [20,21]. It was shown that thrombocytopenia was associated with poor outcome of COVID-19 patients in intensive care units [22]. These results are also corroborated by two independently performed meta-analyses which point to poor outcomes in patients with low platelet counts [23,24]. We also showed that thrombocytopenia was associated with increased risk of hospitalization in CLL COVID-19 patients; however, a recently published report does not corroborate our finding as platelet count did not affect the SARS-CoV-2 infection outcome in hospitalized patients [25].
In this study, we could not address the issue of COVID-19-directed treatment due to the retrospective nature of the study and data heterogeneity. The roles of remdesivir and CCP administration have shown beneficial effects in some studies, however their efficacy in CLL patients is questionable [1,12,17,26,27]. In the hospitalized cohort, we did not observe any impact of CLL treatment status history or impact of potential agents (anti-CD20 antibodies, BTKi and venetoclax), although some studies suggest the protective role of BTK inhibitors or increased severity during venetoclax therapy [11,13,28,29]. It must be stressed that the data presented in this analysis have several limitations, and assessment of the effectivity of particular agents, COVID-19-or CLL-directed, was not the primary aim of our observational study. Furthermore, the treatment of COVID-19 was administered in accordance with local guidelines, not within clinical trials. In addition, due to the time-dependent availability, particular agents (e.g., remdesivir or CCP) could not have been administered in a timely manner dependent on the disease severity.
Besides the abovementioned limitations due to testing policy in Poland, in the second and third waves of COVID-19 we potentially could have missed some asymptomatic patients. Another limitation of this study is the lack of detailed assessment of patient comorbidities. In our analysis, we assessed patient performance on the ECOG scale, however, proper assessment of patient disease burden based on the type of comorbidity or its precise definition severity using the Cumulative Illness Rating Scale (CIRS) was not possible. We acknowledge that these data would be of utmost importance in assessing factors associated with COVID-19 outcome.

Conclusions
In view of the presented results, SARS-CoV-2 infection in patients with CLL is associated with poor outcome regardless of administered CLL-directed treatment. Due to the retrospective nature of the study and collection of data outside clinical trial regulations we could not assess COVID-19-directed treatments. This issue should be addressed within clinical trials to assess the potential clinical benefit of COVID-19-directed therapies in immunocompromised CLL patients.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/cancers14030558/s1, Table S1: Association of analyzed factors with risk of death; Table  S2: Overall survival of all analyzed patients; Table S3: Characterization of treatment-naïve chronic lymphocytic leukemia patients diagnosed in the years 2010-2014 at the Institute of Hematology and Transfusion Medicine; Table S4: Association of analyzed factors with risk of hospitalization; Figure S1: Kaplan-Meier overall survival curves of the whole analyzed cohort in relation to clinicopathological parameters; Figure S2 Institutional Review Board Statement: Ethical review and approval were waived for this study, due to the retrospective nature of this study.