Impact of SARS-CoV-2 infection on patients with hematological malignancies: a retrospective study

ABSTRACT

Objectives

This study aimed to evaluate the characteristics of patients with hematological malignancies (HM) and SARS-CoV-2 infection and analyze the risk factors of their severity and mortality.

Methods

A retrospective study including inpatients diagnosed HM and SARS-CoV-2 infection between December 2022 and February 2023 were conducted. Demographic information, medical history, comorbidities, diagnosis, treatment related information and outcomes were extracted from electronic medical database. The primary outcome of this study were the severity of SARS-CoV-2 infection and case-fatality rate. The clinical characteristic and outcomes of the patients were summarized and analyzed.

Results

A total of 74 patients with HM and SARS-CoV-2 infection were included. Out of the total cases, 85.1% (63) had a mild /moderate SARS-CoV-2 infection, and 14.9% (11) were severe/ critical infection cases. A total of 8 deaths occurred in all cases for a case-fatality rate of 10.8%. Multivariate analysis identified patients with acute myeloid leukemia (AML) (P = 0.043, OR:5.274, 95%CI:1.053-26.407), primary hematological disease in active state (P = 0.005, OR:13.905, 95%CI:2.180-88.704) were independent risk factors for the severity of SARS-CoV-2 infection and patients with AML had 11.145-fold higher risk of non-survival (P = 0.020, OR:11.145, 95%CI:1.460-85.103) in comparison to the patients with other types of HM. There were no significant differences in the severity and case-fatality rate (P > 0.05) between the patients receiving chemotherapy drugs administration waiting <14 days and ≥14 days after negative SARS-CoV-2 testing.

Conclusion

The primary hematological disease in active state may be the main risk factor for negative outcome of the patents. Waiting 14 days for chemotherapy initiation after negative SARS-CoV-2 testing is unnecessary.

KEYWORDS:

• Hematological malignancy
• SARS-CoV-2
• severity
• case-fatality rate

Introduction

Since late 2019, the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a destructive pandemic. As of 21 September 2023, there have been more than 770 million confirmed cases and 6 million death cases worldwide [1]. Patients with hematologic malignancies (HM) are more susceptibility and at a higher risk of SARS-CoV-2 infection and even developing life-threatening infections due to myelosuppression and lymphopenia, as well as cytotoxic chemotherapy regimens [2–5], which will lead to treatment delays and negative outcomes [3,6]. Studies have shown that patients with HM and COVID-19 have higher rates of severe/critical disease and mortality compared to the general population and patients with solid tumors [7–10]. This poses a huge challenge for hematologists in clinical practice and management.

On 6 December 2022, China announced the cancelation of the dynamic zero COVID-19 policy. Shortly thereafter, the Omicron variant strains of SARS-CoV-2 rapidly spread throughout the country, leading to a significant number of infections within a short period [11,12]. Hematologists are facing an imminent clinical challenge and burden in clinical practice. While data on this frail population is still limited. Never has hematologists to delineated the characteristics of the patients with HM and SARS-CoV-2 infection more urgent. In this study, we aim to delineate the characteristics and analyze the possible risk factors associated with the severity/critical and case-fatality rate of the patients so as to provide valuable references for clinic practice.

Methods

Study design and patients

This retrospective, single-center case–control study was conducted at a general hospital in Guangxi, China. The study protocol was approved by the ethics committee of the First Affiliated Hospital of Guangxi Medical University (Approval no. 2023-E306-01). Considering the retrospective nature of the study and the absence of identifiable patient data, written informed consent was waived. The study focused on inpatients admitted between December 2022 and February 2023. The inclusion criteria were as follows: inpatients aged ≥14 years old, diagnosed with hematological malignancies and confirmed SARS-CoV-2 infection. Patients with double primary cancer or a history of allogeneic or autologous hematopoietic stem cell transplantation were excluded to eliminate bias from other tumors and transplantation status. Patients who were readmitted during the observation period were considered as new subjects.

Clinical specimens and diagnosis

Clinical specimens for SARS-CoV-2 infection testing were collected through nasopharyngeal or oropharyngeal swabs or other upper respiratory tract specimen collection methods. A positive qualitative real-time reverse transcriptase-polymerase chain reaction (RT–PCR) test with ORF1ab/N RNA cycle threshold values ≤40 on the collected sample confirmed the diagnosis of SARS-CoV-2 infection.

Data collection

Demographic information, past medical history, comorbidities, diagnosis, treatment phase, chemotherapeutic regimens, medications for SARS-CoV-2 infection, and outcomes of patients with HM were extracted from the electronic medical database by an author (He Y.) and reviewed by another author (Huang Y.L.). According to Azhdari Tehrani, H. and his colleagues’ report [5], patients were divided into two categories depending on the primary malignancies state. One group were patients with primary malignancies in active state including patients in pre-induction or induction treatment phases and refractory patients. Refractory patients are usually unresponsiveness to any type of chemotherapy and even have active disease. Therefore, Patients in pre-induction, induction treatment and refractory period were classified as active disease state group. Another group were patients with primary disease in a stable state including patients in the consolidation, and maintenance phases. For patients with chronic lymphocytic leukemia (CLL) and lymphoma, induction referred to the first-time chemotherapy, and maintenance referred to the second and later rounds of chemotherapy. The severity of SARS-CoV-2 infection was identified and classified according to SARS-CoV-2 infection Diagnosis and Treatment Protocol (Trial Version 10) published by the People’s Republic of China [13]. The severity of COVID-19 was categorized as either severe/critical or mild/moderate. Patients were also classified as survivors or non-survivors. The severity of SARS-CoV-2 infection and case-fatality rate were the primary outcomes of this study. The case-fatality rate was defined as the proportion of deaths for any cause compared to the total number of patients during our observation time.

Statistical analysis

The anonymized data were abstracted, entered and processed by the main authors (HE Y. and Li Z.Q.). Statistical analysis was performed using SPSS 17.0 software (SPSS, Inc.). The clinical characteristics of the patients were summarized and analyzed. Continuous variables were presented as mean ± standard deviation, and categorical variables were presented as counts and percentages. The severe/critical, mild/moderate rate of SARS-CoV-2 infection and the case-fatality rate of the patients were calculated. Measurement data were compared using t-tests or Mann–Whitney U-tests, while categorical variables were compared using χ² or Fisher's exact tests. Variables with P < 0.3 after univariate analyses were entered into the Logistic regression model for multivariable analysis. P-value of less than 0.05 was considered statistically significant.

Results

A total of 74 patients with HM and SARS-CoV-2 infection were included. The mean age was 47.53 ± 17.0 years old (range 15∼86). The majority of patients (75.7%) were < 60 years old. The most common HM among the patients were acute myeloid leukemia (AML) (32.4%), non-Hodgkin lymphoma (25.7%), and acute lymphoblastic leukemia (ALL) (14.9%). We found that 41 patients (55.4%) had chemotherapy, and 36 patients (48.6%) received nirmatrelvir/ritonavir treatment during the hospitalization. Most patients (56.8%) had fever symptoms after SARS-CoV-2 infection. In total, 63 (85.1%) patients were mild or moderate cases, while 11 (14.9%) patients were severe or critical. Only 5(6.7%) patients required admission to the intensive care unit. A total of 8 deaths occurred in all cases for a case-fatality rate of 10.8%. Of the death cases, 2 cases were in the induction phase, 4 in pre-induction and 2 in consolidation. The highest mortality rates were observed in patients with AML (6, 75.0%), followed by patients with ALL (1, 12.5%) and CLL (1, 12.5%). The clinical characteristics, outcome of the patients with HM and SARS-CoV-2 infection and univariate analysis are presented in Table 1.

Table 1. Clinical characteristic and outcome of the patients with hematologic malignancies and SARS-Cov2 infection (n  =  74).

Items	Mild/moderate	Severe/critical	P-value	Survivor	Non-survivor	P-value
Gender, n (%)
Male	39 (86.7)	6 (13.3)	P = 0.899	41 (91.1)	4 (8.9)	P = 0.780
Female	24 (82.8)	5 (17.2)		25 (86.2)	4 (13.8)
Age range, n (%)
<60 y	48 (85.7)	8 (14.3)	P = 1.000	51 (91.1)	5 (8.9)	P = 0.629
≥60 y	15 (83.3)	3 (16.7)		15 (83.3)	3 (16.7)
Diagnosis, n (%)
AML	17 (70.8)	7 (29.2)	P = 0.063^△	18 (75.0)	6 (25.0)	P = 0.140^△
ALL	8 (72.7)	3 (27.3)		10 (90.9)	1 (9.1)
MM	8 (100)	0		8 (100.0)	0
Lymphoma	19 (100)	0		19 (100.0)	0
MDS	3 (100)	0		3 (100.0)	0
CML	2 (100)	0		2 (100.0)	0
CLL	2 (66.7)	1 (33.3)		2 (66.7)	1 (33.3)
Others	4 (100)	0		4 (100.0)	0
AML diagnosis, n (%)
Yes	17 (70.8)	7 (29.2)	P = 0.041	18 (75.0)	6 (25.0)	P = 0.020
No	46 (92.0)	4 (8.0)		48 (96.0)	2 (4.0)
Ethnicity, n (%)
Han	38 (86.4)	6 (13.6)	P = 0.579^△	40 (90.9)	4 (9.1)	P = 0.467^△
Zhuang minority	23 (85.2)	4 (14.8)		24 (88.9)	3 (11.1)
Others	2 (66.7)	1 (33.3)		2 (66.7)	1 (33.3)
Comorbidity, n (%)
No	39 (86.7)	6 (13.3)	P = 0.488^△	40 (88.9)	5 (11.1)	P = 0.344^△
Hypertension	7 (87.5)	1 (12.5)		8 (100.0)	0
Diabetes	1 (50.0)	1 (50.0)		1 (50.0)	1 (50.0)
Others	16 (84.2)	3 (15.8)		17 (89.5)	2 (10.5)
SARS-CoV-2 infection occurred during chemotherapy period, n (%)
Yes	13 (81.3)	3 (18.8)	P = 0.923	15 (93.8)	1 (6.3)	P = 0.835
No	51 (86.2)	8 (13.8)		51 (87.9)	7 (12.1)
SARS-CoV-2 infection occurred during neutropenic phase, n (%)
Yes	12 (100)	0	P = 0.255	12 (100)	0	P = 0.418
No	51 (82.3)	11 (17.7)		54 (87.1)	8 (12.9)
Primary disease states, n (%)
Active state	22 (71.0)	9 (29.0)	P = 0.010	25 (80.6)	6 (19.4)	P = 0.103
Stable state	41 (95.3)	2 (4.7)		41 (95.3)	2 (4.7)
Nirmatrelvir/ritonavir administration, n (%)
Yes	28 (77.8)	8 (22.2)	P = 0.083	31 (86.1)	5 (13.9)	P = 0.649
No	35 (92.1)	3 (7.9)		35 (92.1)	3 (7.9)
Hospitalization days, median (IQR)	11 (5–21)	23 (14–31)	P = 0.019^#	12 (5–23.5)	24 (11–44.5)	P = 0.080^#
Body-Mass Index (MBI), Mean ±SD	21.83 ± 3.37	22.04 ± 2.04	P = 0.776	21.80 ± 3.31	22.33 ± 2.23	P = 0.663
Lowest ORF1ab RNA cycle threshold values, Mean ±SD	30.47 ± 4.33	28.19 ± 3.93	P = 0.108	30.38 ± 4.27	28.03 ± 4.49	P = 0.147
Lowest N RNA cycle threshold values, Mean ±SD	30.87 ± 4.42	28.64 ± 4.14	P = 0.124	30.76 ± 4.38	28.67 ± 4.67	P = 0.208
Chemotherapy after negative SARS-CoV-2 infection (n = 23), n (%)
Waiting <14 days	15 (93.8)	1 (6.3)	P = 0.526^△	15 (93.8)	1 (6.3)	P = 1.000^△
Waiting ≥14 days	6 (85.7)	1 (14.3)		7 (100.0)	0

Notes: AML, Acute Myeloid Leukemia, ALL, Acute Lymphatic Leukemia, MM, Multiple Myeloma, CML, Chronic Myeloid Leukemia, CLL, Chronic Lymphocytic Leukemia, MDS, Myelodysplastic Syndrome. IQR, Interquartile range, SD, Standard deviation. ^△Fisher’s exact tests, ^#Mann–Whitney U-tests.

Multivariate analysis identified AML primary disease (P = 0.043, OR:5.274, 95%CI:1.053–26.407), primary disease in active state (P = 0.005, OR:13.905, 95%CI:2.180–88.704) were independent risk factors with the severity of SARS-CoV-2 infection. We also found patients with AML primary hematological disease had an 11.145-fold higher risk for non-survival (P = 0.020, OR:11.145, 95%CI:1.460–85.103) in comparison to patients with other types of HM.

We also observed 23 patients who underwent chemotherapy after negative SARS-CoV-2 testing. There were no significant differences in the severity (P = 0.526) and case-fatality rate (P = 1.000) among the patients receiving chemotherapy drugs administration waiting <14 days and ≥14 days after negative SARS-CoV-2 testing.

Discussion

As the SARS-CoV-2 virus continues to evolve, cancer specialists, particularly hematologists, are facing huge clinical challenges and burdens due to limited data and the absence of definitive answers for clinical practice. Therefore, it is imperative to explore the clinical characteristics and outcomes of patients with HM and SARS-CoV-2 infection. Our present study revealed that the rate of severe/critical SARS-CoV-2 infection and case-fatality rate were 14.9% (11/74) and 10.8% (8/74) respectively lower than those reported in previous studies, where severe/critical COVID-19 occurred in 62% (429/691) patients with 33% (230/691) of them succumbing to the infection [9] and severe COVID-19 was also observed in 61.3% (119/194) of patients, with an overall cause-fatality rate of 47.4% (92/194) in another study [5]. Meanwhile, several studies also reported the all-cause mortality rates of patients with COVID-19 and HM ranging from 16.1% to 47% [5,9,14–20]. These discrepancies may be attributed to variations in SARS-CoV-2 strains circulating in different regions and periods.

It is known that SARS-CoV-2 has undergone mutations. These variants may exhibit different transmissibility, virulence, and immune evasion capabilities, potentially influencing the outcome of the patients. Current data also suggests the Omicron variant has a remarkably high transmission rate in humans and possesses strong immune escape potential, but it does not appear to cause more severe disease compared to other SARS-CoV-2 variants [21]. More explanations may account for the difference, such as a better understanding of SARS-CoV-2, vaccines with effective protection, and prompt Nirmatrelvir/ritonavir treatment. However, the rates of negative outcomes are falling gradually in comparison to the aforementioned reports. Future trends of the pandemic are still uncertain. Therefore, it is important to provide newly available evidence regarding the clinical characteristics of the patients in order to formulate optimal clinical management strategies.

The possible association between hematological cancer types and the severity of SARS-CoV-2 infection and mortality is an important issue. In our study, we found patients with AML had a 5.274-fold higher risk of developing severe/ critical SARS-CoV-2 infection and an 11.145-fold higher risk of non-survival in comparison to patients with other types of HM. This is in line with Acar, I.H. et al.'s findings showing the highest mortality rate among patients with AML and COVID-19 (44.3%) [14] and EPICOVIDEHA disclosing AML was the only independent factor associated with mortality among patients with HM and COVID-19 [15]. Furthermore, AML (versus non-Hodgkin lymphoma) was associated with increased mortality in patients with COVID-19 after adjusting for multiple variables [9]. What are the underlying mechanisms? AML as a type of aggressive hematological malignancy typically manifests with acute onset (<30 days), accompanied by bone marrow failure and immunocompromised status, typically presenting with symptomatic anemia, fever, and thrombocytopenic bleeding. Furthermore, blood product shortage may provoke a negative impact on the management of patients with AML or in active disease state. More importantly, we found, that of the 7 cases with AML and severe/critical SARS-CoV-2 infection, 85.7% (6/7) were in active state of primary disease, and 57.1% (4/7) delayed chemotherapy. To combine our results primary hematological disease in active state (OR:13.905) was an independent risk factor for the severity of SARS-CoV-2 infection. It aligns with a study that found an active cancer diagnosis significantly increased the mortality risk after COVID-19 infection [22]. Therefore, we hypothesize that not diagnosis but rather the active state of primary disease may be the main negative factor.

How to manage patients with HM in an active state during the COVID-19 pandemic is another critical and conflicting issue. Patients with hematological malignancies in the pre-induction, induction, and refractory phases have weaker immunity and are more susceptible to opportunistic infections, including SARS-CoV-2 [5,23]. For hematologic malignancy, patients in an active state with SARS-CoV-2 infection, immediate induction therapy has been observed to yield contrasting outcomes [5,24]. The UKCCMP cohort study provided key findings that disease control was an important factor for predicting mortality in patients with HM and SARS-CoV-2 infection [25]. The recommendations provided by the American Society of Clinical Oncology (ASCO) [26] suggested a careful assessment of factors such as the urgency of cancer treatment, the expected level of immunosuppression, SARS-CoV-2 symptoms, and the risk of infection progression should be carried out among the patients. EPICOVIDEHA provide key recommendations [27] for patients with AML and COVID-19 that all newly diagnosed AML patients and at the beginning of the next treatment cycle should undergo SARS-CoV-2 testing and young AML patients without symptoms should receive standard treatment after testing negative for COVID-19, or immediately if necessary.

When to resume cancer treatment after a positive SARS-CoV-2 turning negative is another concern problem by clinicians. We found that the experience of some Chinese doctors adhering to a 14-day waiting period after SARS-CoV-2 turns negative before starting chemotherapy has not improved the prognosis of patients. ASCO pooled related guidelines [26] suggested resuming cancer treatment depending on symptom resolution, not only focusing on SARS-CoV-2 test results, ongoing assessment of SARS-CoV-2 infection, coinfections, persistent symptoms, and complications is crucial for effective management of these patients.

Nirmatrelvir/ritonavir as a new antiviral targeting the SARS-CoV-2 3Cl protease is widely recommended for patients exhibiting mild symptoms to prevent severe COVID-19. A report from the EPICOVIDEHA registry [28] displayed only 6.3% of patients received nirmatrelvir/ritonavir lower than 48.6% in the present study. However, the former study found the mortality rate in patients treated with nirmatrelvir/ritonavir was lower than those who did not. We did not obtain statistically significant results. These conflicting findings may be attributed to limited sample sizes. Other uncontrollable factors may also impact our results, such as insufficient drug supply and lack of awareness regarding when and how to administer nirmatrelvir/ritonavir.

We also addressed the outcome in patients with different SARS-CoV-2 viral loads. A multicenter observational study reported admission of SARS-CoV-2 viral load was highly predictive of in-hospital mortality and severity of illness/outcome of patients with and without cancer [29,30]. Another study found that the in-hospital mortality rates were 38.8%, 24.1% and 15.3% among patients with a high, medium, and low viral load of SARS-CoV-2, respectively (P < 0.001) [18]. RNAs encoding the ORF1ab and N proteins are abbreviated as ORF1ab/N RNAs. SARS-CoV-2 RNA copies and/or cycle threshold values from RT–PCR assays, with Ct values higher than 40 indicating undetectable viral loads [31]. A study published in the European Heart Journal found the coefficients of C-reactive protein levels were associated with Ct values for ORF1ab and N RNAs [31]. Meanwhile, CRP level is strongly associated with the severe/critical mortality rate in patients with COVID-19 [32]. However, in our study, no significant variation was observed in ORF1ab/N RNA cycle threshold values among survival vs non-survival and severe/critical vs mild/moderate patients (P > 0.05). Whether the ORF1ab/N RNA cycle threshold values can predict the severity and mortality of the patients requires more large-scale research.

Taken together, the study identified the clinical characteristics and risk factors associated with poor prognosis of the patients with HM and SARS-CoV-2 infection. The active state of the primary hematological disease may be the main risk factor for the negative outcome of the patients. Waiting time for chemotherapy initiation after a negative SARS-CoV-2 test may be not necessary. These findings highlight the need for individualized treatment approaches and ongoing evaluation of the risk-benefit balance for each patient with HM and SARS-CoV-2 infection. However, several key limitations should be addressed in the study. Firstly, the data was collected at the beginning of the cancelation of the dynamic zero of SARS-CoV-2 infections, which limited our experience in treating SARS-CoV-2 infection patients and resulted in incomplete laboratory parameters to miss some valuable laboratory parameters analysis. Secondly, as a retrospective study with certain drawbacks, some key statistics cannot be measured directly. We cannot control exposure or outcome assessment as to unable to determine the exact reasons behind the severity and fatality associated with SARS-CoV-2 infection. Additionally, we did not analyze the impact of different durations of SARS-CoV-2 infection on the outcomes in this population, as some patients were still positive for the infection at the time of discharge. Also, a limitation of a small sample size may affect the precision and interpretation of the results. These limitations highlight the need for further prospective studies with a larger sample size and comprehensive laboratory assessments to gain a better understanding of this issue.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Nursing Clinical Research ‘Climbing’ Program of the First Affiliated Hospital of Guangxi Medical University [grant number YYZS2020031]; Self-Funded Plan Projects of Guangxi Health Commission [grant number Z-A20220418, Z-A20220414]; and Research Fundamentals Enhancement Program for Young and Middle-aged Teachers in Guangxi Higher Education Institutions [grant number 2023KY0128].