Introduction
Chimeric antigen receptor (CAR) T cells are currently clinically used leukocytes engineered to target B-cell malignancies [1]. T cells targeting CD19 can be used in the clinic to treat malignant tumors. Favorable outcomes have been demonstrated in acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma. Adoptive immunotherapy of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells following lymphodepleting chemotherapy is an option for the treatment of patients with relapsed or refractory (R/R) B leukemia (ALL) [2,3]. This is a novel approach and yields high overall response rates in NHL and CLL, and high complete response rates in ALL, and is currently being investigated in large-scale trials in multiple large clinical centers.
There are currently 3–5 CAR-T cell therapies that have been reported clinically and have been approved by the US Food and Drug Administration for the treatment of diffuse large B-cell lymphoma, acute lymphoblastic leukemia and multiple myeloma. CAR-T-cell immunotherapy is being developed for autoimmune diseases and viral infections [4–6]. Although the results of this malignancy-targeted therapy are game-changing, they are not without a cost. Various off-target conditions are frequently observed, including morbidity and mortality that may lead to severe cytokine-related toxicity [7,8]. One of the most significant complications of this treatment includes multifactorial-related problems with infection and its sequelae affecting immunosuppression in this patient group. Most patients who received CD19 CAR-T cell immunotherapy had poor immune function due to their malignancy and the effects of previous cytotoxic therapy. Lymphoblastic chemotherapy immediately before CAR-T cell infusion may also lead to cytopenias and may compromise the mucosal barrier [9]. CAR-T cell immunotherapy reduces cytotoxicity, which may also be complicated by the induction of cytokine release syndrome (CRS) and neurotoxicity, thereby increasing the risk of infection. In most cases, CD19 CAR-T cells deplete normal CD19+ B cells, resulting in hypogammaglobulinemia in patients. Despite multiple immune impairments in patients receiving CD19 CAR-T cell immunotherapy, the infectious complications of this therapy have not been systematically studied [10,11]. In this study, the infection epidemiology of 40 leukemia patients in our hospital after CD19 CAR-T cell immunotherapy was collected to preliminarily explore the factors that lead to the high risk of infection in patients, and provide a basis for future clinical treatment.
Materials and methods
Patients
Forty patients in this study had received lymphodepleting chemotherapy and CD19 CAR-T cell therapy in a phase 1/2 open-label single-shot trial.
Monitor
Gender, age, disease type, stage and outcome after treatment were recorded (complete response, partial response, SD, disease progression, overall survival and progression-free survival after follow-up) , proportion of lymphocyte subsets in patients (if there is the best before and after treatment, if not, one time is also possible); immunoglobulin test results; other immune-related test results; post-treatment complications, adverse reactions and other specific circumstances. Immunological features and related immune and cytokines were detected in infected patients after CAR T therapy.
Severity grading of cytokine release syndrome
Neurotoxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Infection classification
Bacterial infections are classified as bacteremia or site-specific infections. Multiple positive blood cultures for different organisms on the same day are considered distinct events. If bacterial isolates were a possible skin contaminant (diphtheria, bacillus or coagulase-negative staphylococci) and were isolated in only one blood culture, they were excluded unless systemic antibiotics were given. Infections were recorded if there was a microbiologic or histopathologic diagnosis, and the date of onset of infection was defined as the date on which diagnostic testing was performed. A second event was considered if repeated positive cultures and intermediate cultures were negative >21 days after the initial diagnosis. Site-specific bacterial infection was defined as evidence of bacterial infection by the culture of a normally sterile site or culture of a nonsterile site and evidence of tissue invasion. Lower respiratory tract infection was defined as the detection of a respiratory virus in bronchoalveolar lavage fluid with new or changing pulmonary infiltrates and lower respiratory tract symptoms. Invasive mycosis may be present, and fungal infection is documented. Infections caused by respiratory viruses were classified as upper respiratory tract infections if the virus was detected in nasopharyngeal/throat washes or swabs, sinuses or sputum without symptoms or clinical evidence of lower respiratory tract infection.
Infection severity classification
The severity of the infection is classified as mild, moderate, severe, life-threatening or fatal. Mild infections do not require treatment. Moderate infections require oral treatment only. Serious infections requiring intravenous antimicrobial therapy or associated with other clinical conditions are considered serious, except for bacteremia due to possible skin contamination and fever without systemic symptoms (classified as moderate). Life-threatening infections can be complicated by symptoms that are considered life-threatening.
Data collection and statistical considerations
Patient information was extracted from medical records and databases. Infections were retrospectively identified from the day of the first CAR-T cell infusion day 0–day 90 post-infusion.
Risk factor analysis
To identify baseline clinical characteristics that modulate infection density, we used univariate and stepwise multivariable regression with an offset to account for days at risk. To assess risk factors for infection after CAR-T cell infusion, we performed univariate and stepwise multivariate Cox proportional hazards regression. Standard follow-up of at least 28 days was performed, and infections that occurred between CAR-T cell infusion and day 28 were analyzed. Stepwise multivariate models were constructed using entry and exit criteria of P < 0.1. Statistical significance was defined as 2-sided P < 0.05. Analyses were performed using SAS version 9.4 (SAS Institute) and Prism 7.
Statistical analysis
Each experiment was performed in triplicate and the data were recorded as mean ± SD. The IC50 value was defined as the final concentration of 50% radical inhibition (relative reducing power or chelating effect). Statistical comparisons were made by one-way ANOVA to detect significant difference using SPSS 13.0 (SPSS Inc., Chicago, Illinois, USA) for windows. P < 0.05 was considered to be statistically significant.
Results
Patient and treatment characteristics
Forty adult patients with R/R CD19+ B-cell malignancies were included in the study, 20 (50%) with ALL, 10 (25%) with chronic lymphocytic leukemia (CLL) and 10 (25%) with NHL. Patient and treatment characteristics are shown in Table 1. Patients received a median of 4 regimens before lymphodepletion and CD19 CAR-T cell immunotherapy. Twenty patients (50%) had previously undergone autologous or allogeneic hematopoietic cell transplantation (HCT). Before lymphodepleting chemotherapy, 25% of patients had serum IgG <400 mg/dl, 20% had neutrophil count (ANC) <500 cells/mm3 and 80% had absolute lymphocyte count (ALC) <200 cells/mm3. The median time to neutrophil recovery to ±500 cells per mm3 after CAR-T cell infusion was 6 days. Six patients (15%), including two with preexisting neutropenia before lymphodepleting chemotherapy, had no neutrophil recovery on day 28 or before the examination, and four patients (10%) were in CAR – never had ANC <500 cells/mm3 infusion after T cell therapy. Thus, this cohort had previously received multiple immunosuppressive therapies and had severe immunodeficiency before CAR-T cell infusion.
Table 1 -
Patient and treatment characteristics
| Characteristics |
ALL (20) |
CLL (10) |
NHL (10) |
Total (40) |
| Age, years |
41.2 ± 10.6 |
40.6 ± 8.9 |
42.6 ± 10.8 |
43.2 ± 9.4 |
| Pre-lymphodepletion |
| ANC <500 |
8 |
1 |
1 |
10 |
| ALC <200 |
16 |
5 |
8 |
29 |
| CAR-T cell dose |
| level 1 |
10 |
2 |
1 |
13 |
| level 2 |
8 |
8 |
7 |
23 |
| level 3 |
1 |
1 |
2 |
4 |
| CRS grade |
| 0 |
10 |
6 |
6 |
22 |
| 1–3 |
4 |
1 |
2 |
7 |
| 4–5 |
6 |
3 |
2 |
11 |
ALL, acute lymphoblastic leukemia; ALC, absolute lymphocyte count; ANC, neutrophil count; CAR-T, chimeric antigen receptor-modified T; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome; NHL, non-hodgkin's lymphoma.
Incidence of infections in the first 28 days after CAR-T-cell infusion
We analyzed 40 patient-day risk during the first 28 days after CAR-T cell infusion. Figure 1 shows the cumulative incidence curve of time to the first infection for any bacterial, viral and fungal infection. The first infection was identified within a median of 6 days after CAR-T cell infusion; 80% of first infections occurred within the first 10 days. The infection density in the first 28 days after CAR-T cell infusion was 1.19 infections per 100 days. During this period, 8 of 40 patients (20%) developed multiple infections (Table 2). Bacterial infection was the most common, occurring in six patients (15%). In total 10 patients developed respiratory viral infections, of which two patients developed lower respiratory tract disease. One of these patients was diagnosed with an invasive fungal infection. Three patients had concurrent CRS and infection. The median time to onset of CRS was 2 days before infection, and only three patients developed CRS before infection.
Table 2 -
Incidence of infections in the first 28 days after chimeric antigen receptor-modified T-cell infusion
| Type of infection |
ALL (20) |
NHL (10) |
CLL (10) |
Total (40) |
| Bacterial infections |
5 |
2 |
1 |
8 |
| Viral infections |
2 |
1 |
1 |
4 |
| Fungal infections |
1 |
1 |
1 |
3 |
| Any infection |
6 |
2 |
2 |
10 |
ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; NHL, non-hodgkin's lymphoma.
;)
Figure 1: Cumulative incidence curves of first bacterial, viral, and fungal infections.
Incidence of bacterial, viral and fungal infections after CAR-T cell infusion
CD19 CAR-T cell immunotherapy leads to the depletion of endogenous B cells, which may lead to infection 28 days after CAR-T cell infusion. Of the 40 patients evaluated, 36 (90%) developed B-cell depletion within 28 days of CAR-T cell infusion. By day 90, only 8 (20%) of 40 patients evaluated had evidence of endogenous B-cell recovery. We assessed 40 patients at 30-day risk of infection between days 29 and 90. During this period, 4 of 40 patients (10%) developed 23 infections. Viral infections were the most common, with 13 infections in four patients (10%). Three patients developed upper respiratory tract viral infection, and 1 (11%) patient developed lower respiratory tract disease. One patient without a history of HCT had nonrespiratory viral infections including cytomegalovirus (CMV), BK polyomavirus cystitis and CMV pneumonia by plasma PCR. Bacterial infections were second with eight events in two patients (5%). One of the bacterial infections was bacteremia, one of which was caused by an intrinsically fluoroquinolone-resistant gram-negative bacteria.
Severity of infection after CD19 CAR-T cell immunotherapy
To understand the clinical significance of infection, we assessed the severity of infection. Between days 0 and 90 after CAR-T cell immunotherapy, mild or moderate infections accounted for 33 (50%) of 66 events in 8 patients (20%). In four patients (10%), serious infections accounted for 16 of 66 events (40%). Life-threatening infections accounted for four events in one patient (2.5%). Infection is the leading cause of death from acute pulmonary hemorrhage due to invasive A. niger tracheobronchitis in patients with CLL without neutropenia 90 days after CAR-T cell infusion. Infection is a factor in fatal CRS and death in neutropenic patients with ALL complicated by severe C. One of 4 life-threatening infections may appear before lymphatic clearance and progress after CAR-T cell infusion (invasive fungal sinusitis and species undetermined). Grade ≥4 CRS occurred in two patients who developed life-threatening infections. Both lethal infections occurred de novo after infusion of CAR-T cells in patients with grade ≥4 CRS. These data suggest that most infections are mild to moderate and that life-threatening or fatal infections are uncommon after CD19 CAR-T cell immunotherapy.
Baseline characteristics associated with increased infection density after CD19 CAR-T cell immunotherapy
Identifying patient and treatment characteristics that increase the risk of subsequent infection will help identify those who may benefit from broader antimicrobial prophylaxis. In a univariate Poisson model, receiving ≥4 prior antitumor regimens, ANC <500 cells/mm3 before CAR-T cell infusion, and a CAR-T cell dose of 2 × 107 cells/kg were associated with significant increased associated infection densities (Table 3). In a stepwise multivariate model, ALL patients, those receiving ≥4 prior antitumor regimens, and those receiving 2 × 107 CAR-T cells/kg had higher infection densities (Table 3). These findings suggest that patients receiving more intensive antitumor therapy and higher CAR-T cell doses have a higher risk of infection following CAR-T cell immunotherapy.
Table 3 -
Baseline characteristics associated with increased infection density after
CD19 chimeric antigen receptor-modified T cell immunotherapy
| CAR-T cell infusion variables |
Ratio of infection densities (95% CI) |
P value |
| Age |
0.93 (0.47–1.85) |
0.69 |
| Disease type |
2.03 (1.02–3.95) |
4.44 (2.06, 9.55) |
| Prior auto or allo HCT |
0.73 (0.35–1.34) |
0.26 |
| Prior antitumor treatment regimens ≥4 versus <4 |
2.27(1.10–4.57) |
0.018 |
| ALC <200 cells/mm3
|
0.75 (0.38–1.48) |
0.48 |
| ANC <500 cells/mm3
|
1.84 (0.88–3.84) |
0.12 |
| CAR-T cell dose |
3.06 (1.36–6.90) |
0.02 |
ALC, absolute lymphocyte count; ANC, neutrophil count; CAR-T, chimeric antigen receptor-modified T; CI, confidence interval; HCT, hematopoietic cell transplantation.
Factors associated with increased risk of infection after CAR-T cell infusion
Given the higher incidence of infections in patients receiving higher CAR-T cell doses, which were associated with increased risk of CRS and neurotoxicity, we used Cox proportional hazards regression to determine the first increase in CAR-T cell infusion infection risk factors. In addition to baseline patient characteristics, the analysis included the following time-related variables: ANC <500 cells/mm3 on the day of infection, maximal CRS and neurotoxicity grade, tocilizumab or corticosteroid treatment and ICU admission. In univariate analysis, higher CAR-T cell dose levels, more severe CRS or neurotoxicity, tocilizumab treatment and ICU admission were associated with an increased risk of infection (Table 4). When the ANC was less than 500 cells/mm3, the risk of infection increased but did not reach statistical significance (P > 0.05). In total 74 and 91% of infections occurred in patients with ANC <500 and <1000 cells/mm3, respectively. After stepwise variable selection in the multivariate model, CRS severity was the only factor associated with infection, with each increase in the CRS severity category increasing the risk of infection by 3.4 (P < 0.001). Immunological features and related immune and cytokines were detected in infected patients after CART. Patients receiving CRS or neurotoxicity received a median of 1 dose of tocilizumab and 2 days of corticosteroids, with a median daily prednisone-equivalent dose of 1.2 mg/kg. No corticosteroid treatment was associated with infection, and there were insufficient events to determine whether the duration or dose of tocilizumab or corticosteroids independently increased risk. Overall, the data showed that most infections occurred during neutropenia, with more severe CRS patients at higher risk of infection.
Table 4 -
Factors associated with increased risk of infection after chimeric antigen receptor-modified T cell infusion
| CAR-T cell infusion variables |
Unadjusted HRa(95% CI) |
P value |
| ICU admission |
4.37(1.78–10.44) |
0.02 |
| Corticosteroid use |
1.54 (0.45–5.25) |
0.52 |
| Tocilizumab use |
3.45 (1.23–9.44) |
0.018 |
| 0 versus 1–2 versus 3–5 |
1.73 (1.14–2.75) |
0.016 |
| 0 versus 1–3 versus 4–5 |
3.35(1.99–5.74) |
0.001 |
| 2 × 107 vs. 2 × 105
|
3.15 (1.08–9.59) |
0.037 |
| 2 × 107 vs. 2 × 106
|
3.14 (1.24–8.43) |
0.015 |
aData shown are from the univariate model only.
CAR-T, chimeric antigen receptor-modified T; CI, confidence interval; HR, hazard ratio.
Incidence and severity of infections in patients receiving Cy/Flu-based lymphodepletion and optimized CD19 CAR-T cell doses
Our data suggest a higher risk of infection following CD19 CAR-T cell immunotherapy in patients who received higher doses of CAR-T cells and developed more severe CRS or neurotoxicity. We previously identified a preferred regimen consisting of cyclophosphamide and fludarabine (Cy/Flu)-based lymphodepletion, followed by an optimized CAR-T cell dose based on disease type and tumor burden, which was associated with reduced risk of severe CRS and equivalent antitumor activity. At an infection density of 0.69 among 90 patients receiving the preferred regimen, eight patients (20%) developed only 10 infections during the first 28 days after CAR-T cell therapy, lower than those receiving the nonpreferred regimen (RR, 0.30; P < 0.001). Median time to ANC ≥500 cells/mm3 was similar in patients receiving the preferred or nonpreferred regimen. There are no fatal infections. These data suggest that patients who received an optimized regimen to reduce the severity of CRS had less severe infections after CAR-T cell infusion compared to patients who did not receive the optimized regimen.
Discussion
A total of 40 patients in this study received lymphodepleting chemotherapy and CD19 CAR-T cell therapy, which can be divided into R/R ALL, CLL and NHL, cohort study, the results demonstrate more prior antitumor therapy, ALL patients, increasing the -cell dose, can obtain the higher risk of CAR-T infection and worse CRS. Receiving an optimized CD19 CAR-T cell immunotherapy regimen reduces serious CRS infections and reduces the risk of life-threatening or fatal infections.
The incidence, distribution and severity of infections in this study and those previously reported are similar to those observed in clinical trials of salvage or primary treatment of patients with R/R or advanced ALL, CLL and non-hodgkin's lymphoma (NHL). In this study, three infections were reported in ALL patients with CTCAE grade ≥34–52%, 21–25% of CLL patients, and 23–24% of NHL patients. Infections in patients following CD19 CAR-T cell immunotherapy were significantly lower than the rates of infection after myeloablative HCT observed in unrelated donors during the first 100 days and between days 101 and 180. Consistent phenomena were observed between both early and late specific infection classes following CAR-T cell immunotherapy after HCT in unrelated donors. Although comparisons with other studies are limited by differences in patient characteristics and observation periods [12,13], the results obtained in this study show that the risk of infection after CAR-T cell immunotherapy is comparable to the risk after a number of other treatments. However, the incidence of bacterial infection may have been overestimated in this study because patients who received a single-bacterial positive blood culture were included, and these patients may have skin contaminants that could not distinguish infection from CRS as a cause of fever.
Most of the infections in this study were caused by bacteria typical of patients with hematological malignancies undergoing chemotherapy. Viremia is caused by viral infection mainly by double-stranded DNA viruses (such as herpes virus, adenovirus and BK virus), mainly respiratory viruses, but the results of viral infection are rarely detected by clinical trials in other studies [14–16]. Invasive fungal infections are the least common infections, but they were reported in 5% of patients in this study and should also be considered. All patients with fungal infections had previous HCT or severe CRS requiring immunosuppressive therapy. Despite the high net immunosuppression status of the patient cohort before initiation of lymphodepleting chemotherapy, with only one infection being the primary or secondary cause of death, infections that currently occur following CAR-T cell infusion are rarely life-threatening or serious. Among patients with severe, life-threatening or fatal infections, two infections existed before receiving lymphodepletion and progressed after CAR-T cell infusion. Although delaying CAR-T cell immunotherapy to resolve infection may be the first choice, it may increase the risk of malignancy progression [17,18]. Further exploration of the risks of immunotherapy in the setting of confirmed infection is warranted.
It has been reported that most infections occur in the early stage after CAR-T cell infusion [19]. In the present study, analyzed by Poisson regression modeling, the baseline variables associated with increased infection density were ALL diagnosis and more prior antitumor regimens, which is consistent with the severity of immune compromise leading to increased disease risk [20–23]. Higher CAR-T cell doses are also associated with an increased risk of infection, but with both the development and severity of CRS [24,25]. In this study, the influencing factors after CAR-T cell infusion were analyzed, and the development of CRS was the most important predictor of infection through Cox regression model analysis. Most infections occur after the onset of CRS and rarely induce or exacerbate CRS. Further support for the risk posed by CRS is that we observed fewer infections and no deaths directly related to infection in 40 patients by receiving CAR-T cell therapy to effectively alleviate disease and tumor burden in CRS. It is unclear whether immunosuppressive therapy, high cytokine levels or aggressive supportive care and ICU management increase the risk of severe CRS or infection in neurotoxic patients [26–28]. An increased incidence of possible infection risk has been reported in patients receiving long-term treatment of tocilizumab for rheumatic disease, but the risks associated with certain doses are unknown. Our analysis suggests that neutropenia may also contribute to an increased risk of infection after CAR-T cell infusion, but this study was unable to assess the effect of the intensity of lymphatic depletion after CAR-T cell infusion on infection risk. Future studies will need to identify lymphodepleting regimens with limited hematopoietic toxicity to enable the development of robust CAR-T cell transplantation regimens.
Data from this study will guide the development of improved supportive care plans and related programs. Antibacterial prophylaxis regimens for CD19 CAR-T cell receptors need to be standardized [28,29], and we modeled on autologous HCT guidelines through clinical practice of 40 cases. Antibiotic prophylaxis and intravenous immune globulin supplementation to prevent infection have yielded favorable results and can be considered effective treatments. However, patients who have previously received autologous or allogeneic HCT or who have developed life-threatening CRS or neurotoxicity are at increased risk of developing invasive fungal infections, and the results also suggest that broader preventive measures can be considered in selected high-risk patients to reduce the incidence of infection. The results also suggest an association between the infection that occurs before lymphodepletion and infection that occurs after CAR-T cell infusion, similar to the approach developed for allogeneic HCT, which will aid in the development of infection prevention protocols.
The difference and advantage of this study from other studies is the inclusion of a large cohort of CAR-T cell recipients with three disease types, all of whom established baselines, received standardized supportive care measures, closely monitored infections and received CAR-T cells. The risk of infection after T cell infusion was assessed and influencing factors were analyzed. A cohort study of 40 patients was included in this study, and potential biases requiring follow-up beyond 28 days limit the interpretation of late event rates. However, the infection data that occurred between days 28 and 90 was the infection status after CAR-T cell treatment, which provided important information for further epidemiological analysis and summary.
In conclusion, the incidence of infection after CD19 CAR-T cell immunotherapy is influenced by multiple factors, and studies suggest that the type of infection is consistent with that in patients with R/R B-cell malignancies who received salvage chemoimmunotherapy. Patients with greater immunosuppression and CAR-T cell-related toxicity are at the highest risk of infection. This study identifies a target population that requires improved prevention strategies. Can be used to improve patient outcomes following CAR-T cell immunotherapy, and since life-threatening or fatal infections are rare in this clinical profile, the findings may provide evidence of efficacy in preventing infections in immunocompromised hosts that have been established in other settings. clinical strategy.
Acknowledgements
This study was approved by the Research Ethics Committee at the Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University. Written informed consent was obtained from the patient.
All the data generated or analyzed during this study are included in this published article. The data is available upon reasonable request.
The authors sincerely appreciate the consideration of our article and look forward to receiving comments from the reviewers. The authors authorize your publication.
Conflicts of interest
There are no conflicts of interest.
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