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Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas

Equipe Mobile de Microbiologie Clinique, Groupe Hospitalier Paris Saint-Joseph, 75014 Paris, France
UMR 1319, Institut Micalis, Université Paris-Saclay, INRAeChâtenay Malabry, AgroParisTech, 92290 Chatenay Malabry, France
Infection Control Unit, AP-HP Hôpital Avicenne, Université Sorbonne Paris Nord, 93000 Bobigny, France
Medical Surgical Intensive Care Unit, Institut Paoli Calmettes, 13009 Marseille, France
Author to whom correspondence should be addressed.
Cancers 2023, 15(7), 1989;
Received: 24 January 2023 / Revised: 20 March 2023 / Accepted: 23 March 2023 / Published: 27 March 2023
(This article belongs to the Section Infectious Agents and Cancer)



Simple Summary

Targeted therapies have revolutionized the management of hematological malignancies and solid organ cancers. These new treatments present numerous infectious complications. We aim to present the main infectious complications related to immune checkpoint inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase inhibitors (PI3K), antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors and CAR-T cell infusion treatments. The knowledge of complications allows the physician to better identify patients at risk in order to implement diagnostic and therapeutic strategies, or to discuss the implementation of preventive measures.


Background: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Objectives: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton’s tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. Sources: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. Content: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton’s tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. Implications: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations.

1. Introduction

Over the past two decades, there has been a tremendous shift in cancer treatment from broad-spectrum cytotoxic drugs to targeted drugs. As early as 1909, Paul Ehrlich predicted that the immune system normally prevents the formation of carcinomas. Malignant neoplasms are known to downregulate major histocompatibility complex (MHC)-I molecules, preventing recognition of tumor cells by cytotoxic T lymphocytes (CTLs). Recent advances in treatment aim to provide effective immunotherapy with minimal toxicity. Therefore, cancer immunotherapy aims to harness the memory and specificity of the immune system to effectively eliminate malignant neoplasms. Current therapeutic approaches include cytokine therapy, CAR-T cell therapy and checkpoint inhibitor therapy. These new therapies are often associated with inflammatory and/or infectious complications requiring intensive care unit (ICU) admission. Among these new drugs, immune checkpoint inhibitors (ICIs), Bruton’s tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, anti-apoptotic protein BCL-2 inhibitors, Janus kinase (JAK) inhibitors, or CAR-T cell infusion have been identified as frequently associated with life-threatening side effects or infectious complications (Table 1) [1].
These adverse inflammatory effects may require the introduction of immunosuppressive drugs such as corticosteroids, thereby increasing the risk of infection. In addition, the differential diagnosis of inflammation/infection is often difficult.
In this article, we present a narrative review, from an infectious disease perspective, of the safety profile of oral and parenteral drugs used to treat solid organ and hematologic malignancies. We analyze the infectious complications associated with these innovative therapies, including ICIs, CAR T cells, BTK inhibitors, JAK inhibitors, and PI3K inhibitors (Table 2).

2. Material and Methods

A PubMed search was conducted to identify studies of agents currently used to treat solid organ and hematologic malignancies that reported infectious events. The search focused on systematic reviews, meta-analyses, clinical trials, guidelines, and case reports, with an emphasis on those agents considered most relevant to clinicians and a selection of drugs with a greater impact on the risk of infection. The selection of molecules was based on those most frequently associated with serious infectious adverse events leading to hospitalization in intensive care units, as well as our clinical experience and expertise.

3. Monoclonals Antibodies

Work on the activity of monoclonal antibodies on tumor cells began in the 1970s. Destruction of target cells by monoclonal antibodies (mAbs) can be achieved in several ways, including immune-mediated cell killing, direct antibody action (blocking of receptors or delivery of the target toxic agents), tumor environment and specific antibody action on the vascular system.

Immune Checkpoint Inhibitors

Checkpoint inhibitor immunotherapies (also known as immune checkpoint inhibitors (ICIs)) are immunomodulatory antibodies used to boost the immune system. Over the past decade, the development of immune checkpoint blockade antibodies, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), has shown great results in the treatment of melanoma and other cancers making it a reference treatment for melanoma and other cancers. The anti-CTLA-4 antibody ipilimumab was the first immune checkpoint antibody approved for the treatment of patients with advanced melanoma [2,26,27].
The first marketed human IgG4 anti-PD-1 checkpoint inhibitor antibodies were pem-brolizumab and nivolumab. Their main indication was the treatment of refractory and unresectable melanoma [28,29,30]. ICIs are now indicated as first-line treatment for these pathologies [31,32,33,34]. Phase 2 randomized controlled trials evaluating the safety of CTLA-4-targeted agents [2,3,4] or (PD)-1 and (PD-L1)-targeted agents in patients with advanced melanoma did not suggest an increased risk of infection.
However, the use of immune checkpoint blockade drugs is associated with the occurrence of numerous adverse events related to the stimulation of the immune system. These side effects affect many organs (lungs, pancreas, liver, etc.). Treatment of these side effects is based on symptomatic treatments for benign forms and low or high dose corticosteroids or even the use of tumor necrosis factor alpha (TNF-α) inhibitors (infliximab), azathioprine and mycophenolate mofetil. Among patients taking anti-CTL4 agents, 70% develop adverse events, 20% of which are severe [35]. In addition, 30% of patients treated with anti-CTLA-4 develop an infectious complication [36]. In patients treated with anti-PD-1 or anti-PD-L1, 80% develop adverse events, 8% of which are severe [35]. The safety profile of PD-1/PD-L1 targeted agents appears to be better than that of CTLA-4 targeted molecules, with a lower proportion of exposed patients developing severe irAEs. Indeed, irAEs appear to be less common in patients exposed to PD-1/PD-L1 targeted agents. However, the common combination of ipilimumab and a PD-1 inhibitor carries a higher risk of irAEs than either agent alone [26,37].
Adverse events occur primarily during the first 4 months of treatment with a median of 6 weeks for anti-CLTA-4 and 2.5 months for anti-PD-1/anti-PD-L1. Seventy percent of adverse events resolve with discontinuation of ICIs with a median of 4–8 weeks after discontinuation [38].
In a study of 740 patients treated with ICIs (73% anti-CTLA-4), 54 (7.3%) presented with a serious infectious episode (n = 58), mostly lower respiratory tract infections [39]. Of these, 46% received concomitant corticosteroid therapy and 16% received anti-TNF-alpha therapy. The most common infectious agents isolated in the included patients were bacterial (79.3%), fungal (10.3%), viral (8.6%) and parasitic (1.7%). Two cases of invasive pulmonary aspergillosis, three cases of Pneumocystis jirovecii pneumonia, one case of candidemia and one case of strongyloidiasis were reported. Serious infectious events were significantly more frequent in patients treated with corticosteroids (85% vs. 43%, p < 0.0001; OR = 7.71 (3.71–16.18)) or infliximab (24% vs. 6%, p < 0.0001; OR = 4.74 (2.27–9.45)).
In addition, there are several case reports that have also highlighted opportunistic infections with a variety of pathogens, including Aspergillus fumigatus [40,41,42,43,44,45], Pneumocystis jirovecii [41,46,47,48], John Cunningham (JC) virus [49,50,51], CMV [41,52,53] and Campylobacter [54]. These reports highlight the need to have a threshold for investigation of opportunistic infections after treatment of immune-related adverse events and consideration of Pneumocystis jirovecii prophylaxis. Indeed, Pneumocystis jirovecii prophylaxis should be considered when secondary immunosuppression is given for at least four weeks [55,56].
Tuberculosis reactivation was one of the first infections associated with immune checkpoint inhibitors to be described. Indeed, the PD-1/PD-L1 pathway plays a substantial role in tuberculosis physiopathology. PD-1/PD-L1 deficiency has been associated with an increase in TNF-α, IL-1 and IFN-γ and dysregulation of the innate immune system [27,28,29,30]. Thus, two mechanisms explain the risk of tuberculosis in patients treated with ICIs: (1) downregulation of the PD-1/PD-L1 pathway induces an exacerbated inflammatory response; (2) treatment of irAEs with corticosteroids and TNF- inhibitors favors the development of active tuberculosis [31,32]. In a recent study, patients treated with PD-1/PD-L1 inhibitors had an increased risk of active tuberculosis (OR = 1.79 (95% CI 1.42–2.26; p < 0.0001)). In addition, a Japanese study of 297 lung cancer patients treated with PD-1/PD-L1 inhibitors showed a 1.7% incidence of Mycobacterium tuberculosis reactivation. The infection developed between 22 and 398 days after the start of immune checkpoint inhibitor therapy. A recently published study prospectively evaluated the value of the interferon-gamma release assay (IGRA) in patients treated with ICIs for lung cancer. The test was performed prior to ICI and at 6 and 12 months. Of the 178 patients enrolled, 3 had IGRA reversal during immunotherapy and 4 had IGRA reversal. One of the four patients with IGRA conversion developed active tuberculosis. Physicians should be aware of the potential development of tuberculosis during ICI therapy, and IGRA testing is a useful tool to assess the risk of developing active tuberculosis [57].
ICI use may be associated with a risk of worsening chronic viral infections. A meta-analysis of 186 ICI-treated patients with chronic viral infections (HBV (n = 89) or HCV (n = 98)) found an increased risk of hepatic cytolysis in chronic liver infections, but no deaths from fulminant hepatitis.

4. Bruton’s Tyrosine Kinase Inhibitors

The BTK gene was discovered in 1993 and over 800 mutations in the BTK gene have been described. Most result in a deficiency in the production of the BTK protein. Ibrutinib, acalabrutinib and zanubrutinib are oral drugs that irreversibly inhibit Bruton’s tyrosine kinase (BTK) in the pathway or at the B-cell receptor (BCR). Stimulation of the transmembrane BCR protein leads to activation of several tyrosine kinases, including BTK and phosphatidylinositol 3-kinase (PI3K), which in turn activate proliferation and survival signals of B lymphocytes. Occupation of the BTK activation site by ibrutinib does not appear to have a direct effect on the normal B cell. B cells in chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) differ from normal B cells in that they often have higher levels of ongoing BCR or other signaling pathway activity. This suggests that the effect of ibrutinib is likely to be minimal in normal B cells but marked in CLL or MCL cells.
BTK inhibitors are currently approved for the treatment of several lymphoproliferative disorders, including mantle cell lymphoma, chronic lymphocytic leukemia, Walden-Strom macroglobulinemia and marginal zone lymphoma [25,58].
One of the most common adverse effects observed in patients treated with Bruton’s tyrosine kinase inhibitors is infection. In a systematic review of ibrutinib clinical trials that included 48 studies and more than 2000 patients, infections (of any grade) were reported in 56% of patients treated with ibrutinib [59]. A more recent study found a cumulative incidence of 0.55 infections per 1000 person-days during the first year of targeted therapy, with higher rates in the first 3–6 months [60]. In a retrospective study of 378 patients receiving ibrutinib for chronic lymphocytic leukemia (CLL) or non-Hodgkin’s lymphoma, 43 (11.4%) patients developed serious infections. Of those with serious infections, 23 (53.5%) developed serious bacterial infections, 16 (37.2%) developed invasive fungal infections, and 4 (9.3%) developed viral infections [61]. The main infections reported in the literature are bacterial infections, especially those related to Staphylococcus aureus. Invasive fungal infections, although rarely reported in clinical trials, have also been associated with the use of ibrutinib in several observational studies [61,62,63]. The most common causative agents were Aspergillus spp. although non-Aspergillus infections including disseminated cryptococcosis, endemic fungal infections and Pneumocystis jirovecii pneumonia have also been reported [64,65,66]. Other rare infections such as tuberculosis and progressive multifocal leukoencephalopathy (PML) have also been reported [67].
According to the literature, one of the peculiarities of these infections is the non-neutropenic status of the patient at the time of diagnosis and the very early onset, typically during the first six months after initiation of treatment [61,68]. One possible explanation is inhibition of the BTK pathway in macrophages, which is involved in fungal defense [62,69]. The incidence of invasive aspergillosis among patients treated with BTK inhibitors is high. The central nervous system was involved in 25–40% of cases [70]. Furthermore, despite the early introduction of effective antifungal treatment, mortality in this population is high. This highlights the importance of identifying infectious complications, especially fungal ones. Currently, antifungal prophylaxis is not recommended for all patients. However, the introduction of regular screening, particularly using serum markers of fungal infection, or even the implementation of a preventive pharmacologic strategy should be discussed, especially in patients identified as being at highest risk, such as those concomitantly treated with other immunosuppressive drugs or with a history of invasive fungal infection [63]. Finally, there is a CYP3A4 interaction between ibrutinib and voriconazole, the current standard of care for invasive aspergillosis. Studies in patients treated with idelalisib have shown a five-fold increase in the risk of Pneumocystis jirocevii pneumonia, justifying the systematic prescription of Pneumocystis jirocevii prophylaxis in this population. Impaired responses to vaccination have also been reported in ibrutinib-treated patients [71].

5. Phosphatidylinositol 3-Kinase (pi3k) Inhibitors

PI3K inhibitors are orally administered small molecules that inhibit the PI3K signaling pathway, which plays a central role in the development of B lymphocytes and is overexpressed in many lymphoproliferative disorders. Currently, three PI3K inhibitors (idelalisib, duvelisib and umbralisib) are approved for the treatment of chronic lymphocytic leukemia and/or other lymphoid malignancies.
A variety of adverse events have been reported. In particular, inflammatory manifestations such as colitis, hepatitis and pneumonitis often require treatment with high-dose corticosteroids, which increases the risk of infection [14]. In an observational study of 110 patients treated with idelalisib, lower respiratory tract infections were reported in 34.5%, diarrhea in 30.9% and colitis in 9.1% of patients [15].
Neutropenia is also a common AE during the first weeks of idelalisib treatment, occurring in half of patients and in approximately 20% of patients with grade 3–4 neutropenia. Neutropenia is associated with an increased rate of infections, including opportunistic infections (Pneumocytis jirovecii pneumonia and CMV reactivations and infections) [72].
Pneumocystis jirovecii infections have been reported in up to 3.5% of patients not receiving prophylaxis. Therefore, some guidelines recommended that patients treated with PI3K receive prophylaxis against PJP from the start of treatment until 2–6 months after completion of treatment [33]. Cytomegalovirus (CMV) reactivation occurred in 2.4% of patients during the first six months of treatment [25,72,73,74]. Current expert opinions recommend that CMV serology be performed prior to treatment initiation and that CMV viral load be measured monthly [72]. Acyclovir prophylaxis is also recommended because of the potential for serious skin infections and varicella zoster infections.

6. Antiapoptotic Protein BCL-2 Inhibitors

Venetoclax is a potent oral inhibitor of the anti-apoptotic protein BCL-2, which is overexpressed by tumor cells. Venetoclax is currently approved as a single agent or in combination with anti-CD20 monoclonal antibodies for the treatment of chronic lymphocytic leukemia and/or acute myeloid leukemia (AML). The immunosuppressive effect of veneto-clax is associated with cytopenia. Neutropenia occurred in 40–50% of patients treated with venetoclax [20,75]. In a study of 350 patients treated with venetoclax for chronic lymphocytic leukemia, infections of any grade occurred in 72% of patients [20]. The most commonly reported infectious complication was lower respiratory tract infection. In a study of 235 patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukemia, the overall incidence of bacterial infections was 33.6% and the incidence of probable or confirmed invasive fungal infections was 5.1%.
Venetoclax is metabolized by CY3A4 and therefore has drug–drug interactions with many anti-infectives, including azoles.

7. Janus Kinase Inhibitors

Janus kinases (JAKs) are protein tyrosine kinases that bind to transmembrane cytokine receptors and mediate cellular responses to numerous cytokines and growth factors. JAKs phosphorylate sites on the cytoplasmic tail of a variety of hematopoietic and inflammatory cytokine receptors, activating downstream targets via the signal transducer and activator of transcription (STAT) pathway. Through these mechanisms, JAKs play important roles in hematopoiesis and immune cell differentiation.
Ruxolitinib targets JAK1 and JAK2 and induces downregulation of the T helper cell type 1 (Th1) response and cytokines such as interleukin IL-1, IL-6 and tumor necrosis factor α (TNF-α). The most commonly reported adverse events are generally not serious, but an increased risk of serious infectious events has been reported. A systematic review found a high incidence of herpes zoster infections in patients treated with ruxolitinib (OR = 7.39 (95% CI 1.33–41.07)) [76,77]. Whenever possible, patients should be vaccinated against herpes zoster before starting a JAK inhibitor. In addition, patients with complicated herpes zoster or recurrent herpes zoster may be switched to an alternative therapy, or the patient may be treated with daily suppressive antiviral therapy indefinitely if the JAK inhibitor needs to be restarted. In a study of 1144 patients, the most common infectious complications were herpes zoster (8%), bronchitis (6.1%) and urinary tract infections (6%). Rare cases of opportunistic infections (mycobacterial infections, Pneumocystis jirovecii pneumonia, invasive fungal infections, PML, disseminated cryptococcosis, HBV reactivation) have also been reported [25,78,79,80]. We may suggest that patients receiving Janus kinase inhibitor therapy be screened for chronic HBV infection or latent tuberculosis prior to initiation of therapy.

8. CAR-T Cell Therapy

Adoptive cellular therapy (ACT) has traditionally referred to three different approaches: tumor-infiltrating lymphocyte (TIL) infusion; genetically modified T cell receptor (TCR) therapy; and chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) [81].
CAR-T cells are lymphocytes that have been genetically modified to produce a CAR that specifically targets tumor cell antigens [82,83]. CAR-T cells therapies have produced impressive initial responses in patients with refractory B-cell acute lymphoblastic leukemia [84,85]. CAR T-cell therapy is currently approved for the treatment of diffuse large B-cell lymphoma, acute lymphoblastic leukemia, mantle cell lymphoma, and multiple myeloma [22,23,24,86,87]. Despite excellent anti-malignant activity, adverse events are common with CAR T-cell therapy and include cytokine release syndrome (CRS) (77–93%), neurotoxicity or neurologic events (40–64%), neutropenia (53–87%), and grade 3 or 4 infections (10–31%) [22,23,24].
Most patients undergoing CAR-T cell therapy are at risk of infection (intensive care unit admission, presence of a central venous catheter, prolonged cytopenias). Risk factors for infection have been identified as the presence of severe cytokine release syndrome, the use of multiple lines of treatment prior to CAR-T cell prescription, and the prescription of high doses of CAR-T cells. According to published studies, most infections occur early after CAR-T cell infusion. Bacterial infections are the most common, while fungal infections appear to be rare. The reported viral infections are mainly related to viral reactivations, especially gastrointestinal viruses such as adenovirus, but few respiratory viruses.

8.1. Bacterial Infections

Infections following CAR-T cell infusion are common, but their microbiological diagnosis is challenging. In fact, only 72% of infections are microbiologically documented [88]. Most patients undergoing CAR-T cell therapy have often received multiple lines of prior antibiotic therapy and are therefore at risk of colonization and infection with multi-drug resistant bacteria, especially during the neutropenic phase. A recent study showed that 40% of infections occur within the first 90 days after CAR-T cell infusion [89]. In addition, there appears to be a high rate of Clostridioides difficile-related infections in the community, with infection rates ranging from 12.5% to 20% [90,91,92].
Several risk factors are associated with the occurrence of severe bacterial infection. These include severe CRS, neurotoxicity, use of tocilizumab and corticosteroids, and bridging therapy [91]. In addition, failure to respond to CAR-T cell therapy appears to be a strong predictor of severe bacterial infection [88].

8.2. Viral Infections

In contrast to bacterial pathogens, viruses are more common later in the course of CAR-T cell therapy. After the first month following CAR-T cell inoculation, lymphopenia (either B- or T-lymphocyte) and hypogammaglobulinemia occur, exposing patients to infectious risks, particularly viral risks. Viral infections typically include respiratory syncytial virus, cytomegalovirus, influenza, and polyomaviruses [91,92,93]. The incidence of viral infections after the first month following CAR-T cell infusion ranged from 9.2 to 28%. In addition, many patients have profound CD4 lymphopenia associated with B-cell aplasia, and reactivation of herpesviruses is frequently observed 6–12 months after CAR-T cell infusion [94]. In addition, cytomegalovirus reactivation has been reported in 1–2% of patients. These data are probably underestimated because most centers do not monitor CMV viral replication in patients undergoing CAR-T cell therapy [67,95]. More recently, it has been shown that patients with hematologic malignancies, especially those treated with CAR-T cell therapy, are at risk for severe forms of SARS-CoV-2 respiratory infection [96,97]. In a study of 57 patients with SARS-CoV-2 infection, 39.3% had a severe form of the infection and the mortality rate was 50%. Lymphopenia was the factor statistically associated with severe infection [98].
In addition, in the population, the viral shedding time of SARS-CoV-2 virus in patients receiving CAR-T cells could be up to two months [99].

8.3. Fungal Infections

Despite the high degree of multifactorial immune suppression, fungal infections have been rarely reported in patients receiving CAR-T cell therapy [100], with an incidence ranging from 1 to 5% [100,101,102]. Most fungal infections occur early in the period of initial neutropenia or CRS and are mainly candidemia [102]. Several species of molds have been observed to cause lung disease (Aspergillus spp., Fusarium spp., Mucorales). The most important risk factors for fungal infections are the duration of neutropenia and the prolonged course of systemic corticosteroids prescribed for severe adverse reactions.

8.4. Prevention Strategies

Recommendations for prophylaxis and management strategies for infections after CAR T-cell therapy are largely based on guidelines used for HSCT recipients [103,104].
Antibacterial prophylaxis: Most bacterial infections are secondary to the onset of neutropenia and are often related to the depth and duration of neutropenia. The use of granulocyte colony-stimulating factors to shorten the duration of neutropenia in combination with antibiotic prophylaxis has been widely debated.
There have been some concerns that G-CSF may interfere with the CAR T cell response or worsen cytokine release syndrome by activating myeloid-related cytokines [105,106]. Currently, most recommendations are to consider the use of G-CSF only in patients with prolonged neutropenia [84,107]. For example, studies on a possible adverse effect of G-CSF by exacerbation of cytokine release syndrome have shown that its prescription two weeks after CAR-T cell infusion is safe [108].
Antiviral Prophylaxis: Acyclovir prophylaxis is recommended from the start of lymphodepleting chemotherapy and is usually prescribed for at least 3–6 months after CAR-T cell therapy [88]. This duration of prophylaxis is controversial, as cases of herpes virus reactivation have been reported some time after CAR-T cell therapy [92]. For patients with hepatitis B virus (positive HbS antigen or positive anti-HbC antibody alone), it is important to ensure the absence of viral replication prior to CAR-T cell therapy, and antiviral prophylaxis should be administered for at least 6 months and associated with close monitoring of liver enzymes and/or HBV replication.
Given the significant risk of severe SARS-CoV-2 pulmonary infection in the CAR-T cell therapy patient population, many prescribe pre-exposure prophylaxis with monoclonal antibodies (tixagevimab/cilgavimab) despite their lower efficacy against the omicron variant [109].
Antifungal prophylaxis: Because fungal infections are uncommon in patients undergoing CAR-T cell therapy, antifungal prophylaxis is not routine. Thus, for low-risk patients with no history of invasive fungal infections, treatment with fluconazole is most commonly prescribed during the neutropenia period. On the other hand, for high-risk patients with a history of previous fungal infections or high-grade CAR-T cell-associated complications, later-generation antifungal azoles may be indicated [101,104,110]. Trimethoprim/sulfamethoxazole is currently recommended as the gold standard for prophylactic treatment of Pneumocystis jirovecii infection and should be initiated approximately one month after CAR-T cell infusion.
Vaccination: Patients undergoing CAR-T cell therapy have significant immune dysregulation, affecting innate immunity in the early phase and both humoral and cellular adaptive immunity in the later phase. A lower rate of seroprotection after vaccination in patients treated with CAR-T cell infusion and its large inter-individual variability argues for the systematic implementation of vaccinations. It is recommended to start vaccination with killed or inactivated vaccines 3 to 6 months after CAR-T cell treatment and to delay the administration of live vaccines until 12 months after CAR-T cell infusion [111].

9. Conclusions

New targeted therapies have revolutionized the treatment of hematologic and solid organ malignancies. A high proportion of patients treated with these targeted therapies experience infectious complications, sometimes secondary to the management of side effects. Screening for latent infections and individualized prophylaxis may be advisable.

Author Contributions

Conceptualization, B.P., J.-R.Z. and D.M.; methodology, B.P., J.-R.Z. and D.M.; software, data curation, B.P. and Y.K.; writing—original draft preparation, B.P., Y.K. and P.H.; writing—review and editing, J.-R.Z. and D.M.; supervision, J.-R.Z. and D.M. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Vigneron, C.; Charpentier, J.; Valade, S.; Alexandre, J.; Chelabi, S.; Palmieri, L.-J.; Franck, N.; Laurence, V.; Mira, J.-P.; Jamme, M.; et al. Patterns of ICU Admissions and Outcomes in Patients with Solid Malignancies over the Revolution of Cancer Treatment. Ann. Intensive Care 2021, 11, 182. [Google Scholar] [CrossRef] [PubMed]
  2. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010, 363, 711–723. [Google Scholar] [CrossRef] [PubMed]
  3. O’Day, S.J.; Maio, M.; Chiarion-Sileni, V.; Gajewski, T.F.; Pehamberger, H.; Bondarenko, I.N.; Queirolo, P.; Lundgren, L.; Mikhailov, S.; Roman, L.; et al. Efficacy and Safety of Ipilimumab Monotherapy in Patients with Pretreated Advanced Melanoma: A Multicenter Single-Arm Phase II Study. Ann. Oncol. 2010, 21, 1712–1717. [Google Scholar] [CrossRef] [PubMed]
  4. Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.-J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Nivolumab plus Ipilimumab or Nivolumab Alone versus Ipilimumab Alone in Advanced Melanoma (CheckMate 067): 4-Year Outcomes of a Multicentre, Randomised, Phase 3 Trial. Lancet Oncol 2018, 19, 1480–1492. [Google Scholar] [CrossRef] [PubMed]
  5. Byrd, J.C.; Brown, J.R.; O’Brien, S.; Barrientos, J.C.; Kay, N.E.; Reddy, N.M.; Coutre, S.; Tam, C.S.; Mulligan, S.P.; Jaeger, U.; et al. Ibrutinib versus of atumumab in Previously Treated Chronic Lymphoid Leukemia. N. Engl. J. Med. 2014, 371, 213–223. [Google Scholar] [CrossRef][Green Version]
  6. Coutré, S.E.; Furman, R.R.; Flinn, I.W.; Burger, J.A.; Blum, K.; Sharman, J.; Jones, J.; Wierda, W.; Zhao, W.; Heerema, N.A.; et al. Extended Treatment with Single-Agent Ibrutinib at the 420 Mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Clin. Cancer Res. 2017, 23, 1149–1155. [Google Scholar] [CrossRef][Green Version]
  7. Byrd, J.C.; Furman, R.R.; Coutre, S.E.; Burger, J.A.; Blum, K.A.; Coleman, M.; Wierda, W.G.; Jones, J.A.; Zhao, W.; Heerema, N.A.; et al. Three-Year Follow-up of Treatment-Naïve and Previously Treated Patients with CLL and SLL Receiving Single-Agent Ibrutinib. Blood 2015, 125, 2497–2506. [Google Scholar] [CrossRef]
  8. Rule, S.; Dreyling, M.; Goy, A.; Hess, G.; Auer, R.; Kahl, B.; Hernández-Rivas, J.-Á.; Qi, K.; Deshpande, S.; Parisi, L.; et al. Ibrutinib for the Treatment of Relapsed/Refractory Mantle Cell Lymphoma: Extended 3.5-Year Follow up from a Pooled Analysis. Haematologica 2019, 104, e211–e214. [Google Scholar] [CrossRef][Green Version]
  9. Tam, C.S.; Dimopoulos, M.; Garcia-Sanz, R.; Trotman, J.; Opat, S.; Roberts, A.W.; Owen, R.; Song, Y.; Xu, W.; Zhu, J.; et al. Pooled Safety Analysis of Zanubrutinib Monotherapy in Patients with B-Cell Malignancies. Blood Adv. 2022, 6, 1296–1308. [Google Scholar] [CrossRef]
  10. Korycka-Wołowiec, A.; Wołowiec, D.; Robak, T. The Safety of Available Chemo-Free Treatments for Mantle Cell Lymphoma. Expert Opin. Drug Saf. 2020, 19, 1377–1393. [Google Scholar] [CrossRef]
  11. Jensen, J.L.; Mato, A.R.; Pena, C.; Roeker, L.E.; Coombs, C.C. The Potential of Pirtobrutinib in Multiple B-Cell Malignancies. Adv. Hematol. 2022, 13, 20406207221101696. [Google Scholar] [CrossRef] [PubMed]
  12. Byrd, J.C.; Smith, S.; Wagner-Johnston, N.; Sharman, J.; Chen, A.I.; Advani, R.; Augustson, B.; Marlton, P.; Renee Commerford, S.; Okrah, K.; et al. First-in-Human Phase 1 Study of the BTK Inhibitor GDC-0853 in Relapsed or Refractory B-Cell NHL and CLL. Oncotarget 2018, 9, 13023–13035. [Google Scholar] [CrossRef] [PubMed][Green Version]
  13. Driscoll, N. Idelalisib: Practical Tools for Identifying and Managing Adverse Events in Clinical Practice. J. Adv. Pr. Oncol. 2016, 7, 604–613. [Google Scholar] [CrossRef] [PubMed]
  14. Cuneo, A.; Barosi, G.; Danesi, R.; Fagiuoli, S.; Ghia, P.; Marzano, A.; Montillo, M.; Poletti, V.; Viale, P.; Zinzani, P.L. Management of Adverse Events Associated with Idelalisib Treatment in Chronic Lymphocytic Leukemia and Follicular Lymphoma: A Multidisciplinary Position Paper. Hematol Oncol 2019, 37, 3–14. [Google Scholar] [CrossRef] [PubMed][Green Version]
  15. Eyre, T.A.; Preston, G.; Kagdi, H.; Islam, A.; Nicholson, T.; Smith, H.W.; Cursley, A.P.; Ramroth, H.; Xing, G.; Gu, L.; et al. A Retrospective Observational Study to Evaluate the Clinical Outcomes and Routine Management of Patients with Chronic Lymphocytic Leukaemia Treated with Idelalisib and Rituximab in the UK and Ireland (RETRO-Idel). Br. J. Haematol. 2021, 194, 69–77. [Google Scholar] [CrossRef]
  16. Flinn, I.W.; Cherry, M.A.; Maris, M.B.; Matous, J.V.; Berdeja, J.G.; Patel, M. Combination Trial of Duvelisib (IPI-145) with Rituximab or Bendamustine/Rituximab in Patients with Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia. Am J Hematol 2019, 94, 1325–1334. [Google Scholar] [CrossRef]
  17. Wang, Z.; Zhou, H.; Xu, J.; Wang, J.; Niu, T. Safety and Efficacy of Dual PI3K-δ, γ Inhibitor, Duvelisib in Patients with Relapsed or Refractory Lymphoid Neoplasms: A Systematic Review and Meta-Analysis of Prospective Clinical Trials. Front. Immunol. 2022, 13, 1070660. [Google Scholar] [CrossRef]
  18. Bajaj, S.; Barrett, S.M.; Nakhleh, R.E.; Brahmbhatt, B.; Bi, Y. Umbralisib-Induced Immune-Mediated Colitis: A Concerning Adverse Effect of the Novel PI3Kδ/CK1ε Inhibitor. ACG Case Rep. J. 2021, 8, e00701. [Google Scholar] [CrossRef]
  19. Sawas, A.; Farber, C.M.; Schreeder, M.T.; Khalil, M.Y.; Mahadevan, D.; Deng, C.; Amengual, J.E.; Nikolinakos, P.G.; Kolesar, J.M.; Kuhn, J.G.; et al. A Phase 1/2 Trial of Ublituximab, a Novel Anti-CD20 Monoclonal Antibody, in Patients with B-Cell Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukaemia Previously Exposed to Rituximab. Br. J. Haematol. 2017, 177, 243–253. [Google Scholar] [CrossRef][Green Version]
  20. Davids, M.S.; Hallek, M.; Wierda, W.; Roberts, A.W.; Stilgenbauer, S.; Jones, J.A.; Gerecitano, J.F.; Kim, S.Y.; Potluri, J.; Busman, T.; et al. Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Clin. Cancer Res. 2018, 24, 4371–4379. [Google Scholar] [CrossRef][Green Version]
  21. Hoisnard, L.; Lebrun-Vignes, B.; Maury, S.; Mahevas, M.; El Karoui, K.; Roy, L.; Zarour, A.; Michel, M.; Cohen, J.L.; Amiot, A.; et al. Adverse Events Associated with JAK Inhibitors in 126,815 Reports from the WHO Pharmacovigilance Database. Sci. Rep. 2022, 12, 7140. [Google Scholar] [CrossRef] [PubMed]
  22. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef] [PubMed]
  23. Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef]
  24. Wang, M.; Munoz, J.; Goy, A.; Locke, F.L.; Jacobson, C.A.; Hill, B.T.; Timmerman, J.M.; Holmes, H.; Jaglowski, S.; Flinn, I.W.; et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N. Engl. J. Med. 2020, 382, 1331–1342. [Google Scholar] [CrossRef]
  25. Reinwald, M.; Silva, J.T.; Mueller, N.J.; Fortún, J.; Garzoni, C.; de Fijter, J.W.; Fernández-Ruiz, M.; Grossi, P.; Aguado, J.M. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the Safety of Targeted and Biological Therapies: An Infectious Diseases Perspective (Intracellular Signaling Pathways: Tyrosine Kinase and MTOR Inhibitors). Clin. Microbiol. Infect. 2018, 24 (Suppl. 2), S53–S70. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Dummer, R.; Smylie, M.; Rutkowski, P.; et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N. Engl. J. Med. 2015, 373, 23–34. [Google Scholar] [CrossRef][Green Version]
  27. Robert, C.; Thomas, L.; Bondarenko, I.; O’Day, S.; Weber, J.; Garbe, C.; Lebbe, C.; Baurain, J.-F.; Testori, A.; Grob, J.-J.; et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N. Engl. J. Med. 2011, 364, 2517–2526. [Google Scholar] [CrossRef][Green Version]
  28. Naimi, A.; Mohammed, R.N.; Raji, A.; Chupradit, S.; Yumashev, A.V.; Suksatan, W.; Shalaby, M.N.; Thangavelu, L.; Kamrava, S.; Shomali, N.; et al. Tumor Immunotherapies by Immune Checkpoint Inhibitors (ICIs); the Pros and Cons. Cell Commun. Signal 2022, 20, 44. [Google Scholar] [CrossRef]
  29. Robert, C.; Schachter, J.; Long, G.V.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.; Lotem, M.; et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2015, 372, 2521–2532. [Google Scholar] [CrossRef]
  30. Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H.; Lao, C.D.; et al. Nivolumab versus Chemotherapy in Patients with Advanced Melanoma Who Progressed after Anti-CTLA-4 Treatment (CheckMate 037): A Randomised, Controlled, Open-Label, Phase 3 Trial. Lancet Oncol. 2015, 16, 375–384. [Google Scholar] [CrossRef]
  31. Reck, M.; Rodríguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2016, 375, 1823–1833. [Google Scholar] [CrossRef][Green Version]
  32. Ribas, A.; Shin, D.S.; Zaretsky, J.; Frederiksen, J.; Cornish, A.; Avramis, E.; Seja, E.; Kivork, C.; Siebert, J.; Kaplan-Lefko, P.; et al. PD-1 Blockade Expands Intratumoral Memory T Cells. Cancer Immunol. Res. 2016, 4, 194–203. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Horn, D.L.; Neofytos, D.; Anaissie, E.J.; Fishman, J.A.; Steinbach, W.J.; Olyaei, A.J.; Marr, K.A.; Pfaller, M.A.; Chang, C.-H.; Webster, K.M. Epidemiology and Outcomes of Candidemia in 2019 Patients: Data from the Prospective Antifungal Therapy Alliance Registry. Clin. Infect. Dis. 2009, 48, 1695–1703. [Google Scholar] [CrossRef] [PubMed]
  34. Schadendorf, D.; Hodi, F.S.; Robert, C.; Weber, J.S.; Margolin, K.; Hamid, O.; Patt, D.; Chen, T.-T.; Berman, D.M.; Wolchok, J.D. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J. Clin. Oncol. 2015, 33, 1889–1894. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Lemiale, V.; Meert, A.-P.; Vincent, F.; Darmon, M.; Bauer, P.R.; Van de Louw, A.; Azoulay, E. Groupe de Recherche en Reanimation Respiratoire du patient d’Onco-Hématologie (Grrr-OH) Severe Toxicity from Checkpoint Protein Inhibitors: What Intensive Care Physicians Need to Know? Ann. Intensive Care 2019, 9, 25. [Google Scholar] [CrossRef][Green Version]
  36. Ross, J.A.; Komoda, K.; Pal, S.; Dickter, J.; Salgia, R.; Dadwal, S. Infectious Complications of Immune Checkpoint Inhibitors in Solid Organ Malignancies. Cancer Med. 2022, 11, 21–27. [Google Scholar] [CrossRef]
  37. Postow, M.A.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.; McDermott, D.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N. Engl. J. Med. 2015, 372, 2006–2017. [Google Scholar] [CrossRef][Green Version]
  38. Martins, F.; Sofiya, L.; Sykiotis, G.P.; Lamine, F.; Maillard, M.; Fraga, M.; Shabafrouz, K.; Ribi, C.; Cairoli, A.; Guex-Crosier, Y.; et al. Adverse Effects of Immune-Checkpoint Inhibitors: Epidemiology, Management and Surveillance. Nat. Rev. Clin. Oncol. 2019, 16, 563–580. [Google Scholar] [CrossRef]
  39. Del Castillo, M.; Romero, F.A.; Argüello, E.; Kyi, C.; Postow, M.A.; Redelman-Sidi, G. The Spectrum of Serious Infections Among Patients Receiving Immune Checkpoint Blockade for the Treatment of Melanoma. Clin. Infect Dis. 2016, 63, 1490–1493. [Google Scholar] [CrossRef][Green Version]
  40. Oltolini, C.; Ripa, M.; Andolina, A.; Brioschi, E.; Cilla, M.; Petrella, G.; Gregorc, V.; Castiglioni, B.; Tassan Din, C.; Scarpellini, P. Invasive Pulmonary Aspergillosis Complicated by Carbapenem-Resistant Pseudomonas Aeruginosa Infection During Pembrolizumab Immunotherapy for Metastatic Lung Adenocarcinoma: Case Report and Review of the Literature. Mycopathologia 2019, 184, 181–185. [Google Scholar] [CrossRef]
  41. Liu, Z.; Liu, T.; Zhang, X.; Si, X.; Wang, H.; Zhang, J.; Huang, H.; Sun, X.; Wang, J.; Wang, M.; et al. Opportunistic Infections Complicating Immunotherapy for Non-Small Cell Lung Cancer. Thorac. Cancer 2020, 11, 1689–1694. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Taima, K.; Tanaka, H.; Itoga, M.; Ishioka, Y.; Kurose, A.; Tasaka, S. Destroyed Lung Due to Sustained Inflammation after Chemoradiotherapy Followed by Durvalumab. Respirol. Case Rep. 2020, 8, e00580. [Google Scholar] [CrossRef]
  43. Kyi, C.; Hellmann, M.D.; Wolchok, J.D.; Chapman, P.B.; Postow, M.A. Opportunistic Infections in Patients Treated with Immunotherapy for Cancer. J. Immunother. Cancer 2014, 2, 19. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Gupta, A.; Tun, A.; Ticona, K.; Baqui, A.; Guevara, E. Invasive Aspergillosis in a Patient with Stage III (or 3a or 3b) Non-Small-Cell Lung Cancer Treated with Durvalumab. Case Rep. Oncol. Med. 2019, 2019, 2178925. [Google Scholar] [CrossRef] [PubMed]
  45. Malek, A.E.; Taremi, M.; Spallone, A.; Alvarez-Cardona, J.J.; Kontoyiannis, D.P. Necrotizing Soft Tissue Invasive Aspergillosis in a Cancer Patient Treated with Immunosupressants Due to Checkpoint Inhibitor-Induced Hepatitis. J. Infect. 2020, 80, 232–254. [Google Scholar] [CrossRef] [PubMed]
  46. Arriola, E.; Wheater, M.; Krishnan, R.; Smart, J.; Foria, V.; Ottensmeier, C. Immunosuppression for Ipilimumab-Related Toxicity Can Cause Pneumocystis Pneumonia but Spare Antitumor Immune Control. Oncoimmunology 2015, 4, e1040218. [Google Scholar] [CrossRef][Green Version]
  47. Schwarz, M.; Kocher, F.; Niedersuess-Beke, D.; Rudzki, J.; Hochmair, M.; Widmann, G.; Hilbe, W.; Pircher, A. Immunosuppression for Immune Checkpoint-Related Toxicity Can Cause Pneumocystis Jirovecii Pneumonia (PJP) in Non-Small-Cell Lung Cancer (NSCLC): A Report of 2 Cases. Clin. Lung Cancer 2019, 20, e247–e250. [Google Scholar] [CrossRef]
  48. Si, S.; Erickson, K.; Evageliou, N.; Silverman, M.; Kersun, L. An Usual Presentation of Pneumocystis Jirovecii Pneumonia in a Woman Treated With Immune Checkpoint Inhibitor. J. Pediatr. Hematol. Oncol. 2021, 43, e163–e164. [Google Scholar] [CrossRef]
  49. Diamantopoulos, P.T.; Kalopisis, K.; Tsatsou, A.; Efthymiou, A.; Giannakopoulou, N.; Hatzidavid, S.; Viniou, N.-A. Progressive Multifocal Leukoencephalopathy in the Context of Newer Therapies in Hematology and Review of New Treatment Strategies. Eur. J. Haematol. 2022, 108, 359–368. [Google Scholar] [CrossRef]
  50. Lambert, N.; El Moussaoui, M.; Maquet, P. Immune Checkpoint Inhibitors for Progressive Multifocal Leukoencephalopathy: Identifying Relevant Outcome Factors. Eur. J. Neurol. 2021, 28, 3814–3819. [Google Scholar] [CrossRef]
  51. Martinot, M.; Ahle, G.; Petrosyan, I.; Martinez, C.; Gorun, D.M.; Mohseni-Zadeh, M.; Fafi-Kremer, S.; Tebacher-Alt, M. Progressive Multifocal Leukoencephalopathy after Treatment with Nivolumab. Emerg. Infect Dis. 2018, 24, 1594–1596. [Google Scholar] [CrossRef] [PubMed]
  52. Furuta, Y.; Miyamoto, H.; Naoe, H.; Shimoda, M.; Hinokuma, Y.; Miyamura, T.; Miyashita, A.; Fukushima, S.; Tanaka, M.; Sasaki, Y. Cytomegalovirus Enterocolitis in a Patient with Refractory Immune-Related Colitis. Case Rep. Gastroenterol. 2020, 14, 103–109. [Google Scholar] [CrossRef] [PubMed]
  53. Gueguen, J.; Bailly, E.; Machet, L.; Miquelestorena-Standley, E.; Stefic, K.; Gatault, P.; Büchler, M. CMV Disease and Colitis in a Kidney Transplanted Patient under Pembrolizumab. Eur. J. Cancer 2019, 109, 172–174. [Google Scholar] [CrossRef] [PubMed]
  54. Lee, K.A.; Shaw, H.; Bataille, V.; Nathan, P. Campylobacteriosis Following Immunosuppression for Immune Checkpoint Inhibitor-Related Toxicity. J. Immunother. Cancer 2020, 8, e000577. [Google Scholar] [CrossRef]
  55. Spain, L.; Diem, S.; Larkin, J. Management of Toxicities of Immune Checkpoint Inhibitors. Cancer Treat Rev. 2016, 44, 51–60. [Google Scholar] [CrossRef]
  56. Baden, L.R.; Bensinger, W.; Angarone, M.; Casper, C.; Dubberke, E.R.; Freifeld, A.G.; Garzon, R.; Greene, J.N.; Greer, J.P.; Ito, J.I.; et al. Prevention and Treatment of Cancer-Related Infections. J. Natl. Compr. Canc. Netw. 2012, 10, 1412–1445. [Google Scholar] [CrossRef][Green Version]
  57. Fujita, K.; Yamamoto, Y.; Kanai, O.; Okamura, M.; Hashimoto, M.; Nakatani, K.; Sawai, S.; Mio, T. Incidence of Active Tuberculosis in Lung Cancer Patients Receiving Immune Checkpoint Inhibitors. Open Forum Infect Dis. 2020, 7, ofaa126. [Google Scholar] [CrossRef][Green Version]
  58. da Cunha-Bang, C.; Niemann, C.U. Targeting Bruton’s Tyrosine Kinase Across B-Cell Malignancies. Drugs 2018, 78, 1653–1663. [Google Scholar] [CrossRef]
  59. Tillman, B.F.; Pauff, J.M.; Satyanarayana, G.; Talbott, M.; Warner, J.L. Systematic Review of Infectious Events with the Bruton Tyrosine Kinase Inhibitor Ibrutinib in the Treatment of Hematologic Malignancies. Eur. J. Haematol. 2018, 100, 325–334. [Google Scholar] [CrossRef]
  60. Stefania Infante, M.; Fernández-Cruz, A.; Núñez, L.; Carpio, C.; Jiménez-Ubieto, A.; López-Jiménez, J.; Vásquez, L.; Del Campo, R.; Romero, S.; Alonso, C.; et al. Severe Infections in Patients with Lymphoproliferative Diseases Treated with New Targeted Drugs: A Multicentric Real-world Study. Cancer Med. 2021, 10, 7629–7640. [Google Scholar] [CrossRef]
  61. Varughese, T.; Taur, Y.; Cohen, N.; Palomba, M.L.; Seo, S.K.; Hohl, T.M.; Redelman-Sidi, G. Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer. Clin. Infect Dis. 2018, 67, 687–692. [Google Scholar] [CrossRef] [PubMed][Green Version]
  62. Zarakas, M.A.; Desai, J.V.; Chamilos, G.; Lionakis, M.S. Fungal Infections with Ibrutinib and Other Small-Molecule Kinase Inhibitors. Curr. Fungal. Infect Rep. 2019, 13, 86–98. [Google Scholar] [CrossRef] [PubMed]
  63. Teh, B.W.; Chui, W.; Handunnetti, S.; Tam, C.; Worth, L.J.; Thursky, K.A.; Slavin, M.A. High Rates of Proven Invasive Fungal Disease with the Use of Ibrutinib Monotherapy for Relapsed or Refractory Chronic Lymphocytic Leukemia. Leuk Lymphoma 2019, 60, 1572–1575. [Google Scholar] [CrossRef]
  64. Anastasopoulou, A.; DiPippo, A.J.; Kontoyiannis, D.P. Non-Aspergillus Invasive Mould Infections in Patients Treated with Ibrutinib. Mycoses 2020, 63, 787–793. [Google Scholar] [CrossRef]
  65. Messina, J.A.; Maziarz, E.K.; Spec, A.; Kontoyiannis, D.P.; Perfect, J.R. Disseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib. Open Forum. Infect Dis. 2017, 4, ofw261. [Google Scholar] [CrossRef][Green Version]
  66. Stankowicz, M.; Banaszynski, M.; Crawford, R. Cryptococcal Infections in Two Patients Receiving Ibrutinib Therapy for Chronic Lymphocytic Leukemia. J. Oncol. Pharm. Pr. 2019, 25, 710–714. [Google Scholar] [CrossRef]
  67. Wang, D.; Mao, X.; Que, Y.; Xu, M.; Cheng, Y.; Huang, L.; Wang, J.; Xiao, Y.; Wang, W.; Hu, G.; et al. Viral Infection/Reactivation during Long-Term Follow-up in Multiple Myeloma Patients with Anti-BCMA CAR Therapy. Blood Cancer J. 2021, 11, 168. [Google Scholar] [CrossRef]
  68. Baron, M.; Zini, J.M.; Challan Belval, T.; Vignon, M.; Denis, B.; Alanio, A.; Malphettes, M. Fungal Infections in Patients Treated with Ibrutinib: Two Unusual Cases of Invasive Aspergillosis and Cryptococcal Meningoencephalitis. Leuk Lymphoma 2017, 58, 2981–2982. [Google Scholar] [CrossRef]
  69. Bercusson, A.; Colley, T.; Shah, A.; Warris, A.; Armstrong-James, D. Ibrutinib Blocks Btk-Dependent NF-ĸB and NFAT Responses in Human Macrophages during Aspergillus Fumigatus Phagocytosis. Blood 2018, 132, 1985–1988. [Google Scholar] [CrossRef][Green Version]
  70. Chamilos, G.; Lionakis, M.S.; Kontoyiannis, D.P. Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin. Infect Dis. 2018, 66, 140–148. [Google Scholar] [CrossRef][Green Version]
  71. Douglas, A.P.; Trubiano, J.A.; Barr, I.; Leung, V.; Slavin, M.A.; Tam, C.S. Ibrutinib May Impair Serological Responses to Influenza Vaccination. Haematologica 2017, 102, e397–e399. [Google Scholar] [CrossRef][Green Version]
  72. Coutré, S.E.; Barrientos, J.C.; Brown, J.R.; de Vos, S.; Furman, R.R.; Keating, M.J.; Li, D.; O’Brien, S.M.; Pagel, J.M.; Poleski, M.H.; et al. Management of Adverse Events Associated with Idelalisib Treatment: Expert Panel Opinion. Leuk Lymphoma 2015, 56, 2779–2786. [Google Scholar] [CrossRef][Green Version]
  73. Cheah, C.Y.; Fowler, N.H. Idelalisib in the Management of Lymphoma. Blood 2016, 128, 331–336. [Google Scholar] [CrossRef][Green Version]
  74. Ward, L.M.; Peluso, M.J.; Budak, J.Z.; Elicker, B.M.; Chin-Hong, P.V.; Lampiris, H.; Mulliken, J.S. Opportunistic Coinfection with Pneumocystis Jirovecii and Coccidioides Immitis Associated with Idelalisib Treatment in a Patient with Chronic Lymphocytic Leukaemia. BMJ Case Rep. 2020, 13, e234113. [Google Scholar] [CrossRef]
  75. DiNardo, C.D.; Pratz, K.W.; Letai, A.; Jonas, B.A.; Wei, A.H.; Thirman, M.; Arellano, M.; Frattini, M.G.; Kantarjian, H.; Popovic, R.; et al. Safety and Preliminary Efficacy of Venetoclax with Decitabine or Azacitidine in Elderly Patients with Previously Untreated Acute Myeloid Leukaemia: A Non-Randomised, Open-Label, Phase 1b Study. Lancet Oncol. 2018, 19, 216–228. [Google Scholar] [CrossRef]
  76. Vannucchi, A.M.; Kiladjian, J.J.; Griesshammer, M.; Masszi, T.; Durrant, S.; Passamonti, F.; Harrison, C.N.; Pane, F.; Zachee, P.; Mesa, R.; et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. N. Engl. J. Med. 2015, 372, 426–435. [Google Scholar] [CrossRef][Green Version]
  77. Passamonti, F.; Griesshammer, M.; Palandri, F.; Egyed, M.; Benevolo, G.; Devos, T.; Callum, J.; Vannucchi, A.M.; Sivgin, S.; Bensasson, C.; et al. Ruxolitinib for the Treatment of Inadequately Controlled Polycythaemia Vera without Splenomegaly (RESPONSE-2): A Randomised, Open-Label, Phase 3b Study. Lancet Oncol. 2017, 18, 88–99. [Google Scholar] [CrossRef]
  78. Cohen, S.; Radominski, S.C.; Gomez-Reino, J.J.; Wang, L.; Krishnaswami, S.; Wood, S.P.; Soma, K.; Nduaka, C.I.; Kwok, K.; Valdez, H.; et al. Analysis of Infections and All-Cause Mortality in Phase II, Phase III, and Long-Term Extension Studies of Tofacitinib in Patients with Rheumatoid Arthritis. Arthritis. Rheumatol. 2014, 66, 2924–2937. [Google Scholar] [CrossRef]
  79. Bechman, K.; Subesinghe, S.; Norton, S.; Atzeni, F.; Galli, M.; Cope, A.P.; Winthrop, K.L.; Galloway, J.B. A Systematic Review and Meta-Analysis of Infection Risk with Small Molecule JAK Inhibitors in Rheumatoid Arthritis. Rheumatology 2019, 58, 1755–1766. [Google Scholar] [CrossRef]
  80. Wollenhaupt, J.; Lee, E.-B.; Curtis, J.R.; Silverfield, J.; Terry, K.; Soma, K.; Mojcik, C.; DeMasi, R.; Strengholt, S.; Kwok, K.; et al. Safety and Efficacy of Tofacitinib for up to 9.5 Years in the Treatment of Rheumatoid Arthritis: Final Results of a Global, Open-Label, Long-Term Extension Study. Arthritis Res. 2019, 21, 89. [Google Scholar] [CrossRef][Green Version]
  81. Rosenberg, S.A.; Restifo, N.P.; Yang, J.C.; Morgan, R.A.; Dudley, M.E. Adoptive Cell Transfer: A Clinical Path to Effective Cancer Immunotherapy. Nat. Rev. Cancer 2008, 8, 299–308. [Google Scholar] [CrossRef]
  82. Johnson, L.A.; June, C.H. Driving Gene-Engineered T Cell Immunotherapy of Cancer. Cell Res. 2017, 27, 38–58. [Google Scholar] [CrossRef][Green Version]
  83. Kochenderfer, J.N.; Rosenberg, S.A. Treating B-Cell Cancer with T Cells Expressing Anti-CD19 Chimeric Antigen Receptors. Nat. Rev. Clin. Oncol. 2013, 10, 267–276. [Google Scholar] [CrossRef]
  84. Kansagra, A.J.; Frey, N.V.; Bar, M.; Laetsch, T.W.; Carpenter, P.A.; Savani, B.N.; Heslop, H.E.; Bollard, C.M.; Komanduri, K.V.; Gastineau, D.A.; et al. Clinical Utilization of Chimeric Antigen Receptor T-Cells (CAR-T) in B-Cell Acute Lymphoblastic Leukemia (ALL)-an Expert Opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT). Bone Marrow Transpl. 2019, 54, 1868–1880. [Google Scholar] [CrossRef]
  85. Jain, T.; Bar, M.; Kansagra, A.J.; Chong, E.A.; Hashmi, S.K.; Neelapu, S.S.; Byrne, M.; Jacoby, E.; Lazaryan, A.; Jacobson, C.A.; et al. Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Biol. Blood Marrow Transpl. 2019, 25, 2305–2321. [Google Scholar] [CrossRef]
  86. Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A.; et al. Anti-BCMA CAR T-Cell Therapy Bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef]
  87. Schuster, S.J.; Bishop, M.R.; Tam, C.S.; Waller, E.K.; Borchmann, P.; McGuirk, J.P.; Jäger, U.; Jaglowski, S.; Andreadis, C.; Westin, J.R.; et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl. J. Med. 2019, 380, 45–56. [Google Scholar] [CrossRef]
  88. Wudhikarn, K.; Palomba, M.L.; Pennisi, M.; Garcia-Recio, M.; Flynn, J.R.; Devlin, S.M.; Afuye, A.; Silverberg, M.L.; Maloy, M.A.; Shah, G.L.; et al. Infection during the First Year in Patients Treated with CD19 CAR T Cells for Diffuse Large B Cell Lymphoma. Blood Cancer J. 2020, 10, 79. [Google Scholar] [CrossRef]
  89. Wittmann Dayagi, T.; Sherman, G.; Bielorai, B.; Adam, E.; Besser, M.J.; Shimoni, A.; Nagler, A.; Toren, A.; Jacoby, E.; Avigdor, A. Characteristics and Risk Factors of Infections Following CD28-Based CD19 CAR-T Cells. Leuk Lymphoma 2021, 62, 1692–1701. [Google Scholar] [CrossRef]
  90. Abbasi, A.; Peeke, S.; Shah, N.; Mustafa, J.; Khatun, F.; Lombardo, A.; Abreu, M.; Elkind, R.; Fehn, K.; de Castro, A.; et al. Axicabtagene Ciloleucel CD19 CAR-T Cell Therapy Results in High Rates of Systemic and Neurologic Remissions in Ten Patients with Refractory Large B Cell Lymphoma Including Two with HIV and Viral Hepatitis. J. Hematol. Oncol. 2020, 13, 1. [Google Scholar] [CrossRef][Green Version]
  91. Logue, J.M.; Zucchetti, E.; Bachmeier, C.A.; Krivenko, G.S.; Larson, V.; Ninh, D.; Grillo, G.; Cao, B.; Kim, J.; Chavez, J.C.; et al. Immune Reconstitution and Associated Infections Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma. Haematologica 2021, 106, 978–986. [Google Scholar] [CrossRef] [PubMed][Green Version]
  92. Baird, J.H.; Epstein, D.J.; Tamaresis, J.S.; Ehlinger, Z.; Spiegel, J.Y.; Craig, J.; Claire, G.K.; Frank, M.J.; Muffly, L.; Shiraz, P.; et al. Immune Reconstitution and Infectious Complications Following Axicabtagene Ciloleucel Therapy for Large B-Cell Lymphoma. Blood Adv. 2021, 5, 143–155. [Google Scholar] [CrossRef] [PubMed]
  93. Park, J.H.; Romero, F.A.; Taur, Y.; Sadelain, M.; Brentjens, R.J.; Hohl, T.M.; Seo, S.K. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated With Chimeric Antigen Receptor T Cells. Clin. Infect Dis. 2018, 67, 533–540. [Google Scholar] [CrossRef] [PubMed]
  94. Liu, H.; Li, P.; Zhao, A.; Lei, W.; Liang, A.; Qian, W. Incidence and Prophylaxis of Herpes Zoster in Relapsed or Refractory B-Cell Lymphoma Patients after CD19-Specific CAR-T Cell Therapy. Leuk. Lymphoma 2022, 63, 1001–1004. [Google Scholar] [CrossRef]
  95. Heldman, M.R.; Ma, J.; Gauthier, J.; O’Hara, R.A.; Cowan, A.J.; Yoke, L.M.; So, L.; Gulleen, E.; Duke, E.R.; Liu, C.; et al. CMV and HSV Pneumonia After Immunosuppressive Agents for Treatment of Cytokine Release Syndrome Due to Chimeric Antigen Receptor-Modified T (CAR-T)-Cell Immunotherapy. J. Immunother 2021, 44, 351–354. [Google Scholar] [CrossRef]
  96. Hensley, M.K.; Bain, W.G.; Jacobs, J.; Nambulli, S.; Parikh, U.; Cillo, A.; Staines, B.; Heaps, A.; Sobolewski, M.D.; Rennick, L.J.; et al. Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study. Clin. Infect Dis. 2021, 73, e815–e821. [Google Scholar] [CrossRef]
  97. Abid, M.B.; Mughal, M.; Abid, M.A. Coronavirus Disease 2019 (COVID-19) and Immune-Engaging Cancer Treatment. JAMA Oncol. 2020, 6, 1529–1530. [Google Scholar] [CrossRef]
  98. Spanjaart, A.M.; Ljungman, P.; de La Camara, R.; Tridello, G.; Ortiz-Maldonado, V.; Urbano-Ispizua, A.; Barba, P.; Kwon, M.; Caballero, D.; Sesques, P.; et al. Poor Outcome of Patients with COVID-19 after CAR T-Cell Therapy for B-Cell Malignancies: Results of a Multicenter Study on Behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group. Leukemia 2021, 35, 3585–3588. [Google Scholar] [CrossRef]
  99. Busca, A.; Salmanton-García, J.; Corradini, P.; Marchesi, F.; Cabirta, A.; Di Blasi, R.; Dulery, R.; Lamure, S.; Farina, F.; Weinbergerová, B.; et al. COVID-19 and CAR T Cells: A Report on Current Challenges and Future Directions from the EPICOVIDEHA Survey by EHA-IDWP. Blood Adv. 2022, 6, 2427–2433. [Google Scholar] [CrossRef]
  100. Rejeski, K.; Kunz, W.G.; Rudelius, M.; Bücklein, V.; Blumenberg, V.; Schmidt, C.; Karschnia, P.; Schöberl, F.; Dimitriadis, K.; von Baumgarten, L.; et al. Severe Candida Glabrata Pancolitis and Fatal Aspergillus Fumigatus Pulmonary Infection in the Setting of Bone Marrow Aplasia after CD19-Directed CAR T-Cell Therapy—A Case Report. BMC Infect Dis. 2021, 21, 121. [Google Scholar] [CrossRef]
  101. Hill, J.A.; Li, D.; Hay, K.A.; Green, M.L.; Cherian, S.; Chen, X.; Riddell, S.R.; Maloney, D.G.; Boeckh, M.; Turtle, C.J. Infectious Complications of CD19-Targeted Chimeric Antigen Receptor-Modified T-Cell Immunotherapy. Blood 2018, 131, 121–130. [Google Scholar] [CrossRef] [PubMed]
  102. Haidar, G.; Garner, W.; Hill, J.A. Infections after Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Hematologic Malignancies: Timeline, Prevention, and Uncertainties. Curr. Opin. Infect Dis. 2020, 33, 449–457. [Google Scholar] [CrossRef] [PubMed]
  103. Yakoub-Agha, I.; Chabannon, C.; Bader, P.; Basak, G.W.; Bonig, H.; Ciceri, F.; Corbacioglu, S.; Duarte, R.F.; Einsele, H.; Hudecek, M.; et al. Management of Adults and Children Undergoing Chimeric Antigen Receptor T-Cell Therapy: Best Practice Recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica 2020, 105, 297–316. [Google Scholar] [CrossRef] [PubMed]
  104. Los-Arcos, I.; Iacoboni, G.; Aguilar-Guisado, M.; Alsina-Manrique, L.; Díaz de Heredia, C.; Fortuny-Guasch, C.; García-Cadenas, I.; García-Vidal, C.; González-Vicent, M.; Hernani, R.; et al. Recommendations for Screening, Monitoring, Prevention, and Prophylaxis of Infections in Adult and Pediatric Patients Receiving CAR T-Cell Therapy: A Position Paper. Infection 2021, 49, 215–231. [Google Scholar] [CrossRef] [PubMed]
  105. Norelli, M.; Camisa, B.; Barbiera, G.; Falcone, L.; Purevdorj, A.; Genua, M.; Sanvito, F.; Ponzoni, M.; Doglioni, C.; Cristofori, P.; et al. Monocyte-Derived IL-1 and IL-6 Are Differentially Required for Cytokine-Release Syndrome and Neurotoxicity Due to CAR T Cells. Nat. Med. 2018, 24, 739–748. [Google Scholar] [CrossRef] [PubMed]
  106. Giavridis, T.; van der Stegen, S.J.C.; Eyquem, J.; Hamieh, M.; Piersigilli, A.; Sadelain, M. CAR T Cell-Induced Cytokine Release Syndrome Is Mediated by Macrophages and Abated by IL-1 Blockade. Nat. Med. 2018, 24, 731–738. [Google Scholar] [CrossRef]
  107. Schubert, M.-L.; Schmitt, M.; Wang, L.; Ramos, C.A.; Jordan, K.; Müller-Tidow, C.; Dreger, P. Side-Effect Management of Chimeric Antigen Receptor (CAR) T-Cell Therapy. Ann. Oncol. 2021, 32, 34–48. [Google Scholar] [CrossRef]
  108. Galli, E.; Allain, V.; Di Blasi, R.; Bernard, S.; Vercellino, L.; Morin, F.; Moatti, H.; Caillat-Zucman, S.; Chevret, S.; Thieblemont, C. G-CSF Does Not Worsen Toxicities and Efficacy of CAR-T Cells in Refractory/Relapsed B-Cell Lymphoma. Bone Marrow Transpl. 2020, 55, 2347–2349. [Google Scholar] [CrossRef]
  109. Stuver, R.; Shah, G.L.; Korde, N.S.; Roeker, L.E.; Mato, A.R.; Batlevi, C.L.; Chung, D.J.; Doddi, S.; Falchi, L.; Gyurkocza, B.; et al. Activity of AZD7442 (Tixagevimab-Cilgavimab) against Omicron SARS-CoV-2 in Patients with Hematologic Malignancies. Cancer Cell 2022, 40, 590–591. [Google Scholar] [CrossRef]
  110. Meir, J.; Abid, M.A.; Abid, M.B. State of the CAR-T: Risk of Infections with Chimeric Antigen Receptor T-Cell Therapy and Determinants of SARS-CoV-2 Vaccine Responses. Transplant. Cell. Ther. 2021, 27, 973–987. [Google Scholar] [CrossRef]
  111. Mikulska, M.; Cesaro, S.; de Lavallade, H.; Di Blasi, R.; Einarsdottir, S.; Gallo, G.; Rieger, C.; Engelhard, D.; Lehrnbecher, T.; Ljungman, P.; et al. Vaccination of Patients with Haematological Malignancies Who Did Not Have Transplantations: Guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019, 19, e188–e199. [Google Scholar] [CrossRef] [PubMed]
Table 1. Adverse effects and frequencies of new targeted therapies.
Table 1. Adverse effects and frequencies of new targeted therapies.
TreatmentAdverse Effects
Infection (Grade ≥ 3)NeutropeniaDiarrheaHypertensionHemorrhage/BleedingReferences
Immune checkpoint inhibitor2–7%-1–25%--[2,3,4]
BTK inhibitors
PI3K inhibitors
Anti-apoptotic protein BCL-2 inhibitors70–75%40–50%41%--[20]
Janus Kinase inhibitors30–35%----[21]
CAR-T cell therapy10–31%53–87%---[22,23,24]
BTK: Bruton’s Tyrosine Kinase, PI3K: Phosphatidylinositol 3-kinase, JAK: Janus Kinase.
Table 2. Risk infections with new targeted therapies (Adapted from [25]).
Table 2. Risk infections with new targeted therapies (Adapted from [25]).
TreatmentDrugsApproved IndicationsInfectious ComplicationsProphylaxis Suggestions
Immune checkpoint inhibitor
 CTLA-4 targeted agentsIpilimumab
MelanomaDoes not appear independently associated with the occurrence of infection but combination with treatment (corticosteroids and/or TNF-α) for irAEs increased infectious riskAnti-Pneumocystis prophylaxis for patients who are expected to receive 20 mg of prednisone daily for at least 4 weeks
Hepatitis B and C: prophylaxis or therapy if needed.
 (PD)-1 and (PD-L1) targeted agentsNivolumab
Non-small cell lung cancer
Head and neck carcinoma
Hodgkin lymphoma
Metastatic renal cell carcinoma (nivolumab)
Urothelial carcinoma and lung cancer (atezolizumab)
BTK inhibitorIbrutinib
Mantle cell lymphoma
Chronic lymphocytic leukemia
Waldenström macroglobulinemia
Marginal zone lymphoma
Fungal infections: Aspergillus, Pneumocystis jiroveciiAssess antifungal prophylaxis or screening for fungal infections
Anti-Pneumocystis prophylaxis in patients treated with corticosteroids
Bacterial infections: Staphylococcus aureus Mycobacterium tuberculosis
PI3K inhibitorsIdelalisib
Chronic lymphocytic leukemia
Lymphoid malignancies
Fungal infections: Pneumocystis jiroveciiCMV serology be performed prior to treatment initiation and that CMV viral load be measured monthly.
Acyclovir prophylaxis is also recommended
Viral infections: CMV, HSV and VZV reactivation
Antiapoptotic protein BCL-2 inhibitorsVenetoclaxChronic lymphocytic leukemia
Acute myeloid leukemia
Bacterial infections
Fungal infections
JAK inhibitors Myeloproliferative neoplasmsBacterial infections: mycobacterial infectionsChronic HBV infection and latent tuberculosis screening
Fungal infections: Pneumocystis jirovecii, Cryptococcus spp.
Viral infections: HSV, VZV, JC virus, HBV reactivation
CAR-T cells Large B-cell lymphoma
Acute lymphoblastic leukemia
Mantle cell lymphoma
Multiple myeloma
Fungal infections: Aspergillus spp., Fusarium spp., Mucorales, Pneumocystis jiroveciiAnti-Pneumocystis prophylaxis (trimethoprim/sulfamethoxazole)
Assess antifungal prophylaxis or screening for fungal infections
Bacterial infections including Clostridioides difficile infectionsG-CSF in case of prolonged neutropenia
Viral infections: respiratory syncytial virus, cytomegalovirus, influenza, polyomaviruses, SARS-CoV-2Acyclovir for at least 3–6 months after CAR-T cell therapy
Antiviral therapy for hepatitis B virus in case of positive HbS Ag or AntiHbC Ac alone
BTK: Bruton’s Tyrosin Kinase, CMV: Cytomegalovirus, CTLA-4: Cytotoxic-T-lymphocyte-Antigen 4, G-CSF: Granulocyte Colony Stimulating Factor, HBV: Hepatitis B virus, HSV: Herpes Simplex Virus, irAEs: immune related adverse events, JAK: Janus Kinase, JC: John Cunningham, PD-1: Programmed cell death protein 1, PD-L1: Programmed cell death protein ligand-1 PI3K: Phosphatidylinositol 3-kinase, VZV: Varicella Zona Virus.
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Pilmis, B.; Kherabi, Y.; Huriez, P.; Zahar, J.-R.; Mokart, D. Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas. Cancers 2023, 15, 1989.

AMA Style

Pilmis B, Kherabi Y, Huriez P, Zahar J-R, Mokart D. Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas. Cancers. 2023; 15(7):1989.

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Pilmis, Benoît, Yousra Kherabi, Pauline Huriez, Jean-Ralph Zahar, and Djamel Mokart. 2023. "Infectious Complications of Targeted Therapies for Solid Cancers or Leukemias/Lymphomas" Cancers 15, no. 7: 1989.

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