Leukemia (2019) 33:844–862 https://doi.org/10.1038/s41375-019-0388-x REVIEW ARTICLE Infectious medicine, virology Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL) Georg Maschmeyer 1 Julien De Greef 2,3 Sibylle C. Mellinghoff4,5 Annamaria Nosari6 ● ● ● ● Anne Thiebaut-Bertrand7 Anne Bergeron8 Tomas Franquet9 Nicole M. A. Blijlevens10 ● ● ● ● Johan A. Maertens11,12 on behalf of the European Conference on Infections in Leukemia (ECIL) ● Received: 19 October 2018 / Revised: 31 December 2018 / Accepted: 11 January 2019 / Published online: 30 January 2019 © The Author(s) 2019. This article is published with open access Abstract A multitude of new agents for the treatment of hematologic malignancies has been introduced over the past decade. Hematologists, infectious disease specialists, stem cell transplant experts, pulmonologists and radiologists have met within 1234567890();,: 1234567890();,: the framework of the European Conference on Infections in Leukemia (ECIL) to provide a critical state-of-the-art on infectious complications associated with immunotherapeutic and molecular targeted agents used in clinical routine. For brentuximab vedotin, blinatumomab, CTLA4- and PD-1/PD-L1-inhibitors as well as for ibrutinib, idelalisib, HDAC inhibitors, mTOR inhibitors, ruxolitinib, and venetoclax, a detailed review of data available until August 2018 has been conducted, and specific recommendations for prophylaxis, diagnostic and differential diagnostic procedures as well as for clinical management have been developed. Introduction Immunotherapeutic agents and small molecules for mole- cular targeted treatment have profoundly changed the landscape of antineoplastic therapy in hematology and oncology. Their impact on innate and adaptive immunity is a joint venture of the European Group for Blood and Marrow not yet completely understood. Given to heavily pretreated Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International patients and combined with other anticancer treatment Immunocompromised Host Society (ICHS) and the European modalities, they may be associated with unexpected, Leukemia Net (ELN) * Georg Maschmeyer 6 Department of Hematology, ASST Grande Ospedale georg.maschmeyer@klinikumevb.de Metropolitano Niguarda, Milan, Italy 1 7 Department of Hematology, Oncology and Palliative Care, Department of Hematology, Université Grenoble Alpes, Klinikum Ernst von Bergmann, Charlottenstrasse 72, 14467 Grenoble, France Potsdam, Germany 8 Department of Pneumology, Université Paris Diderot, APHP 2 Department of Internal Medicine and Infectious Diseases, Saint- Saint-Louis Hospital, Paris, France Luc University Hospital, Université Catholique de Louvain, 9 Department of Radiology, Hospital de Sant Pau, Barcelona, Spain Brussels, Belgium 10 3 Department of Hematology, Radboud University Medical Centre, Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Nijmegen, Netherlands Hematology, Henri Mondor Teaching Hospital, Créteil, France 11 4 Department of Hematology, University Hospitals Leuven, Department I of Internal Medicine, University Hospital of Leuven, Belgium Cologne, Cologne, Germany 12 5 Department of Microbiology and Immunology, University of Cologne Excellence Cluster on Cellular Stress Responses in Leuven, Leuven, Belgium Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology.. . . 845 potentially serious infections. However, in heavily pre- mogamulizumab). A systematic literature review including treated patients, particularly those with chronic lymphocytic research papers, case reports, published study results and leukemia and other indolent B-cell lymphomas, it may be meta-analyses or review articles was conducted using difficult to identify a causal relationship between those drug- and class-based search strings: “(agent)” OR infections and drugs administered for lymphoma treatment. “(class)” AND “mode of action” OR “approval” OR As immune-related autoinflammatory reactions are typical “study” OR “infection” OR “infectious” OR “toxicity” adverse events (irAE) occurring in many of these patients, OR “adverse events” OR “viral” OR “bacterial” OR differential diagnostic efforts to distinguish those reactions “Pneumocystis” OR “fungal” OR “pneumonia” OR from infections are crucial. In patients affected by irAE, “pneumonitis” OR “CNS” OR “hepatitis” OR “cytome- immunosuppressive treatment will often be required, galovirus” OR “immune-related” OR “prophylaxis”. The resulting in secondary infections. This complex scenario group compiled an extensive slide set including mode of calls for a high alertness to formerly unexpected clinical action, state of approval, impact on innate and adaptive complications among hematologists and oncologists using immunity, reported infectious complications and recom- these newer antineoplastic agents. At the same time, mendations for clinical practice. After mail-based and unjustified attribution of infections to these agents and face-to-face group discussions, the revised and consented recommendations for routine antimicrobial prophylaxis slides were presented to the plenary of the seventh ECIL should be avoided. This position paper updates our current conference in Sophia Antipolis, France, on 22 and 23 knowledge of infections associated with these agents and September 2017. The plenary decided to abandon grading provides recommendations for a rational clinical manage- and strength of recommendations, because the data com- ment of prevention and treatment of infections in patients prised represent a “moving target” with a rapidly growing treated with immunotherapeutic and molecular targeted body of reports. In order to provide a critical and detailed antineoplastic agents. summary of the current knowledge in the field, the result Immunotherapeutic and molecular targeted anti- should be published as an ECIL position paper. neoplastic agents including checkpoint inhibitors, idelalisib, All co-authors have been actively involved in the pre- mTOR inhibitors, and, to a lesser extent, ibrutinib have paration and discussion of this manuscript. been associated with drug-related pneumonitis. This pneu- The agents included are addressed in the following monitis is clinically indistinguishable from infectious sequence: (1) immunotherapeutic drugs and (2) molecular pneumonias, and the diagnosis relies on the exclusion of targeted drugs/drug classes, both in alphabetical order. differential diagnoses. The specific management of drug- A summary of available data as well as ECIL recom- related pneumonitis includes drug withdrawal and con- mendations is listed in Table 1. sideration for corticosteroids according to the severity. Immunotherapeutic agents (blinatumomab, Methods brentuximab vedotin, immune checkpoint inhibitors): characterization, impact on A group of experts in hematology and oncology, infectious immunity, reported infectious complications diseases (including virology), pulmonology, diagnostic and recommendations for clinical practice radiology and hematopoietic stem cell transplantation from six European countries was nominated by the ECIL Blinatumomab organization committee in 2016. Immunotherapeutic and molecular targeted agents, which have become available Blinatumomab is a bispecific T-cell engaging (BiTE) anti- for clinical use within the past decade, including bren- body, approved for the treatment of Philadelphia- tuximab vedotin, blinatumomab and immune checkpoint chromosome negative relapsed or refractory B-precursor inhibitors as well as HDAC inhibitors, ibrutinib, idelalisib, acute lymphoblastic leukemia (R/R ALL) [1]. It is made of mTOR inhibitors, ruxolitinib and venetoclax, were a single-chain anti-CD19 antibody attached by a flexible addressed. Other agents approved during the last 10 years linker peptide to a single-chain anti-CD3 antibody. It (such as obinutuzumab, newer proteasome inhibitors, induces a close contact between effector T-cells and CD19- pomalidomide, daratumumab, elotuzumab or inotuzumab positive cells, with subsequent T-cell activation and targeted ozogamicin) were excluded, because thorough literature lysis of CD19-positive cells [2]. CD19 is expressed in all searches did not identify relevant infection risks attribu- B-cell lineage leukemia, and a majority of B-cell lineage table to these agents, or no new signals as compared to lymphomas. In normal cells, it is expressed all along B-cell older drugs from the same class of agents were found, or differentiation, with the exception of pluripotent stem cells because their approval was extremely limited (such as and plasma cells [3]. Table 1 Summary of drug characteristics, reported infectious complications and ECIL recommendations for clinical practice 846 Class of agents Agent Impact on immune system Infectious events ECIL recommendations CD19-directed CD3 Blinatumomab B-cell aplasia; hypogammaglobulinemia; No clear evidence of increased infection •Consideration of IgG substitution in bispecific T-cell engager neutropenia rate case of serious infection Anti-CD30 antibody Brentuximab vedotin Poorly defined; impairment of memory cell Pneumocystis pneumonia; CMV and •CMV monitoring; generation and survival; transient neutropenia HBV reactivation; JC virus-associated •No routine systemic antimicrobial PML prophylaxis; •High alertness to PML Immune checkpoint Ipilimumab (anti-CTLA4); No direct immunosuppression Frequent immune-related auto- •High alertness to infections if anti- inhibitors Nivolumab, pembrolizumab, inflammatory complications; infections inflammatory/immunosuppressive atezolizumab and others (anti- due to anti-inflammatory/ agents are required; PD-1/anti-PD-L1) immunosuppressive agents •Pneumocystis prophylaxis if glucocorticosteroid medication exceeds 3−4 weeks Bruton Tyrosine Kinase Ibrutinib Toll-like receptor-mediated recognition of Slight increase in bacterial, fungal and •Update protective vaccinations Inhibitor infectious agents; viral infections, particularly in heavily before ibrutinib treatment; Maturation, recruitment and function of innate pretreated patients; •Increased alertness to infections; immune cells, including neutrophils, Cerebral aspergillosis in patients treated •At signs of infection, diagnostics monocytes and macrophages; Regulation of for lymphoma with brain involvement including bacterial, viral and fungal NLRP3 inflammasome activation pathogens; •No routine systemic antimicrobial prophylaxis Phosphatidylinositol- 3- Idelalisib Decrease in number and function of regulatory Slight increase in Pneumocystis •Anti-Pneumocystis prophylaxis (see kinase inhibitor T cells; pneumonia label); Inhibition of NK cell and neutrophil •Check CMV serostatus and consider inflammatory response; CMV monitoring; Neutropenia •At signs of infection, consider immune-related adverse reaction Histone deacetylase Vorinostat, panobinostat, Inhibition of toll-like receptor-mediated No clear evidence of increased infection •HBV screening, consideration of inhibitors romidepsin dendritic cell and macrophage function rate antiviral prophylaxis in HBsAg- or (sensing, phagocytosis, cytokine production, anti-HBc-positive patients adhesion) mTOR inhibitors Sirolimus, temsirolimus, Inhibition of T-cell proliferation, antigen- No clear evidence of increased infection •High alertness of infections; everolimus presenting cells, B cells, neutrophil rate •No routine antimicrobial granulocytes prophylaxis; •At signs of pulmonary infection, consider immune-related adverse reaction Janus kinase inhibitor Ruxolitinib Inhibition of dendritic cell and CD4+ T-cell Marginally increased risk of •Careful monitoring for infections; function; opportunistic infections; •HBV screening, prophylactic Reduction of regulatory T cells; Occasional HBV reactivation entecavir in HBsAg- or anti-HBc- NK cell inhibition positive patients; •MTB screening in patients-at-risk G. Maschmeyer et al. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology.. . . 847 Even at very low doses, blinatumomab has been shown NLRP3, NLR (nucleotide-binding domain, leucine-rich repeat) family, pyrin domain containing 3, G-CSF granulocyte-colony stimulating factor, HBV hepatitis B virus, CMV cytomegalovirus, JC •At combination with posaconazole, venetoclax dose reduction by ≥75% to induce a rapid and sustained decrease of measurable peripheral B cells [4, 5]. All B cells are depleted, •Management according to including CD19-negative plasma cells as a consequence ECIL recommendations of precursors and CD19-positive plasmablast clearance. A decrease of immunoglobulin (IgG, IgA, IgM) levels •Consider G-CSF; has been reported with slow recovery at long-term follow- neutropenia; up [6]. The exact impact on preexisting immunity is unknown, and, although anticipated, a correlation with increased risk of infection has not been proven. Interest- ingly, CTL019, another anti-CD19 antibody-based immunotherapy, also induces B-cell aplasia and hypo- gammaglobulinemia, but stable titers of several vaccine- and pathogen-specific serum immunoglobulin G and A John Cunningham polyomavirus, PML progressive multifocal leucoencephalopathy, IgG immunoglobulin G, MTB Mycobacterium tuberculosis 15−20% grade ≥ 3 infections were noted [7]. The second known immunosuppressive effect of blina- tumomab is neutropenia, with grade 3 neutropenia reported in 18−32% of patients [1]. This rate is variable according to Infectious events the context, and in advanced ALL, grade 3 or higher neu- tropenia has been shown to be 20% less frequent with bli- natumomab than with chemotherapy (37.8% vs. 57.8%) [8]. In a follow-up of blood counts in patients treated with bli- natumomab for R/R ALL, median neutrophil count decreased in responders from 1.8 × 103/μL to 0.6 × 103/μL on day 7, but did not decrease anymore during subsequent cycles. Febrile neutropenia was not reported in clinical studies in the context of MRD-positive ALL or NHL, but grade 3 events occurred in up to 24% of patients in R/R Impact on immune system ALL [5, 9]. Overall, infections of all grades were reported in 45% of treated patients, with grade 3 or higher in 27% [1]. This infection rate must be interpreted cautiously in Neutropenia the context of advanced hematologic malignancies and heavily pretreated patients. Results of the phase-3 TOWER trial were confirmatory, showing lower grade 3 or higher infection rates in the blinatumomab group compared to chemotherapy (34.1% vs. 52.3%) [8]. Inva- sive fungal infections have been reported rarely, and a recent review has identified ten reported cases associated with blinatumomab use in ALL, again probably linked to the context [10]. Venous catheter-related infections constitute an important concern, blinatumo- Venetoclax mab being administered by continuous infusion for 2 −4 weeks [11]. Agent In conclusion, blinatumomab has not been associated with a high infectious risk, but some practical recom- mendations can be made. A particular attention should be put on central venous lines management, and Table 1 (continued) clinicians should be alert for the risk of catheter-related BCL2 inhibitor Class of agents infections. Immunoglobulin level monitoring and sup- plementation in case of low IgG concentration is recom- mended, particularly in patients with a history of serious infections [12]. 848 G. Maschmeyer et al. Brentuximab vedotin was described in the BV + AVD group than in the ABVD group, but was mitigated by G-CSF administration [22]. Brentuximab vedotin (BV) is an antibody-drug conjugate However, some specific concerns have been raised about (ADC) of a chimeric anti-CD30 antibody and the synthetic particular pathogens or situations. anti-tubulin monomethyl auristatin E (MMAE). The ADC Pneumonia has been reported in up to 10% of BV-treated binds to the membrane glycoprotein CD30, inducing sub- patients [14], with even higher rates when combined with sequent intracytosolic release of MMAE after internaliza- chemotherapy [24]. Pneumocystis pneumonia (PcP) was tion and proteolytic cleavage of the dipeptidic ADC linker rare (0.1−1%) [14]. Noninfectious pulmonary toxicity has [13]. The drug is approved for the treatment of relapsed or been reported [25], but is more likely to be attributable to refractory CD30-positive classical Hodgkin’s lymphoma the coadministration of bleomycin, so that this combination (HL), as consolidation therapy after autologous hemato- has become contra-indicated [9]. Large phase 3 studies did poietic stem cell transplantation in HL, and for relapsed or not show pulmonary toxicity when BV was not combined refractory anaplastic large T-cell lymphoma (ALCL) [14]. with bleomycin [21, 23]. CD30 is a member of the Tumor Necrosis Factor Varicella Zoster Virus (VZV) and Herpes Simplex Virus receptor superfamily, which is highly expressed by Reed- (HSV) infections are described as common side effect of Sternberg cells in HL and by malignant cells in ALCL. It BV, with an incidence of 1−10% [149]. Extensive or dis- shows a variable level of expression on the surface of seminated diseases have been reported [26, 27]; however, a malignant cells in other NHL. CD30 has a low level of clear causal relationship is doubtful because of the impact of expression in normal cells, mainly restricted to a small many other risk factors in affected patients. subset of activated B-, T- (CD4- and CD8-positive) and Although not described in pivotal studies, two case series natural killer (NK) cells [15]. CD30 has been shown to play of cytomegalovirus (CMV) reactivation under BV have a complex role in immune response, which has not been been published, questioning the true incidence of this event fully elucidated yet. Among other, it is thought to help to and a possible causal relationship. In allogeneic stem cell maintain CD8-positive effector cell activity during antigenic recipients, 5 CMV viremias among 25 patients treated with challenge [16]. It is involved in the transition from effector BV for HL recurring after allogeneic HSCT were reported. cells to central memory cells and the survival of memory Three patients required treatment and one died in the cells. This role in the control of memory cells could help to setting of CMV reactivation [28]. Another report described control pathogens such as listeria and mycobacteria [17]. three cases of CMV reactivation with retinitis among Other mechanisms have also been suggested implying 32 lymphoma patients treated with BV. Patients responded CD30-positive cells in antimycobacterial immune response, to therapy, but two out of three relapsed after BV rechal- and those cells have been found in positive tuberculin skin lenge [29]. tests and TB-infected tissues [18]. By killing CD30-positive Concerns about a risk of JC virus (John Cunningham cells, BV may induce an immune dysbalance facilitating polyoma virus) infection in patients treated with BV have those infections, but it should be noted that no clinical been raised early after the approval of BV. A boxed association has been demonstrated as yet. warning was inserted in the drug label in 2012. At that time, Transient dose-dependent neutropenia is a commonly two proven and one probable case of progressive multifocal observed side effect of BV. When given as a single agent in leukoencephalopathy (PML) had been reported among 2000 relapsed or refractory HL or ALCL or for consolidation patients treated worldwide [30]. Additional cases have been therapy after autologous HSCT, BV was shown to induce described since then [31], with a total of 15 cases reported grade ≥3 neutropenia in 20−29% of patients. However, until July 2015 to the FDA’s Adverse Event Reporting febrile neutropenia was extremely rare [19–21]. In contrast, System. The case fatality rate was 33.3% [32]. It must be myelosuppression appears to be an important concern when kept in mind that those reported cases do not prove a causal BV is used in combination with chemotherapy. In a phase relationship, as lymphoid malignancy, multiagent che- 3 study evaluating BV + AVD vs. ABVD in stage III or IV motherapy or hematopoietic cell transplantation are PML HL, the use of BV was associated with a higher risk of risk factors [33]. While there is no estimated PML incidence grade ≥3 neutropenia (58% vs. 45% respectively) and with known for patients with HL, the rate for those with NHL is higher rates of febrile neutropenia, mainly during the first estimated to be 8.3 (95% CI 1.71–24.24) per 100,000 cycle (9% vs. 4% respectively). The risk was reduced by person-years [34]. primary G-CSF prophylaxis [22]. For clinical practice, no specific recommendation can be Overall, BV does not appear to be associated with a high made with regards to antimicrobial prophylaxis. G-CSF risk of infectious complications. Phase 3 studies did not prophylaxis should be considered when BV is used in show a higher infection rate in the BV group compared to combination with chemotherapeutic agents. PcP prophy- controls [21, 23]. A slightly higher overall infectious risk laxis is not required, if BV is given without concomitant Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology.. . . 849 treatment [35]. The same rule applies to HSV and VZV CTLA-4 is a second immune-checkpoint expressed prophylaxis [36]. CMV should be taken into consideration during priming of T cells [41]. in case of symptoms compatible with infection, but no Inhibition of the PD-1/PD-L1 as well as the CTLA-4 prophylaxis, routine monitoring or preemptive therapy can pathway non-specifically activates the immune system be recommended for patients undergoing treatment with resulting in imbalance. A broad spectrum of immune-related BV. For JC virus, no prophylaxis is available, but clinicians adverse events (irAE) may occur, involving the gut, skin, should be alert and prompt a complete work-up in case of endocrine glands, liver, lungs [59], and possibly other new-onset neurological symptoms suggestive of PML. BV organs [60, 61]. One rare irAE is neutropenia caused by should be withheld until PML has been excluded. In case of autoantibodies against neutrophils. Two cases have been confirmation, BV should be discontinued with the aim to reported, one of them associated with a Staphylococcus restore immunity against JC virus. In some cases this may aureus infection [62, 63]. IrAE often require immunosup- be complicated by an immune reconstitution inflammatory pressive medication, which in turn increases the suscept- syndrome [37]. However, in the case of BV-associated ibility to severe infections [47, 64, 65], resulting in up to PML, due to underlying disease and previous or concurrent 7.3% opportunistic infections in patients affected [66]. Few treatments, immune recovery is uncertain and the clinical data (mostly preclinical) report on higher risk for tubercu- course is unpredictable. PML cases should be notified to losis [67], histoplasmosis [68], and listeriosis [69, 70] due to local competent authorities, in order to document this rare ICI. At present, the incidence of infection is undetermined possible association. and the role of prophylactic antiviral and antifungal therapy in this setting is undefined. Immune checkpoint inhibitors Prophylaxis of PcP should be considered if secondary immunosuppression is given for at least 3 weeks [35, 71, 72] Immune checkpoint inhibition (ICI) has introduced a new As patients receiving ICI are at increased risk of infection due era of cancer therapy [38]. It represents a novel therapeutic to their underlying malignancy, it is recommended that they concept, as the primary target is the crosstalk between receive all appropriate vaccines at the earliest possible immune cells and cancer cells in the tumor microenviron- moment [73]. Future identification of biomarkers predicting ment. Two immune checkpoints are currently targeted by AE, e.g. microbiota in the gut, may help to facilitate pre- approved drugs: the programmed death 1 (PD-1)/PD-ligand emptive treatment [74, 75]. 1 (PD-L1) axis as well as cytotoxic T-lymphocyte antigen-4 (CTLA-4). Blockade of the PD-1 or PD-L1 pathway has been shown to exert therapeutic activity in patients with Molecular targeted agents (ibrutinib, Hodgkin lymphoma [39], head and neck squamous cell idelalisib, HDAC inhibitors, mTOR inhibitors, carcinoma [40], advanced melanoma [41, 42], non-small ruxolitinib, venetoclax): characterization, cell lung carcinoma [43, 44], and renal cell carcinoma impact on immunity, reported infectious [45, 46]. Further indications may follow soon [47, 48]. The complications and recommendations for anti-CTLA-4 antibody ipilimumab was the first immune- clinical practice checkpoint antibody approved for the treatment of patients with advanced melanoma due to its survival benefit com- Ibrutinib pared to standard chemotherapy [41, 49, 50]. PD-1 is a cell surface coinhibitory receptor expressed The inhibition of Bruton’s tyrosine kinase (BTK) is a cru- on T- and B-lymphocytes, monocytes and NK-cells after cial strategy for treating B-cell malignancies. Ibrutinib, an activation [51]. To date, PD-L1 (B7-H1) and PD-L2 (B7- irreversible inhibitor of BTK, is now approved for the DC) have been identified as ligands of PD-1. Both ligands treatment of chronic lymphocytic leukemia (B-CLL) are expressed on antigen-presenting cells, and PD-L1 is [76, 77], mantle cell lymphoma [78], marginal zone lym- additionally detected on the surface of various non- phoma [79], small lymphocytic lymphoma [80] and hematopoietic cells including tumor cells. The binding of Waldenström’s macroglobulinemia [81]. Ibrutinib is also PD-1 to its ligands results in an inhibition of T-cell the first approved therapy for the treatment of chronic graft- receptor signaling on activated T-lymphocytes. In addi- versus-host disease after failure of one or more lines of tion, the PD-1/PD-L1 pathway is a key component in the systemic therapy [82]. BTK has been widely characterized development and maintenance of self-tolerance [52]. as a critical mediator of B-cell receptor signaling that reg- Furthermore, there is increasing evidence that the PD-1/ ulates B-cell survival, activation, differentiation, and inter- PD-L1 pathway is important in the pathogenesis of dif- action with the environment [83]. Germline mutations in ferent tumors by inhibiting, and thus limiting antitumor the gene encoding for BTK result in an almost complete immune response [53–58]. absence of mature B cells and hypogammaglobulinemia, the 850 G. Maschmeyer et al. hallmark of X-linked (Bruton’s) agammaglobulinemia [84]. per microliter), (e) and no patient required intravenous Hence, BTK is essential in the development and functioning therapy, adjunctive steroid treatment or mechanical venti- of adaptive immunity. However, BTK also plays a major lation. Of note, only one of these five cases was confirmed role in innate immunity: (a) in Toll-like receptor-mediated by immunofluorescence, still considered the gold diagnostic recognition of infectious agents, (b) in maturation, recruit- standard for PcP. The FDA Division of Pharmacovigilance ment and function of innate immune cells, including neu- recently reviewed 13 additional cases of confirmed and trophils, monocytes and macrophages, and (c) in regulating presumed PcP submitted to the FDA Adverse Event NLRP3 inflammasome activation [85]. Thus, targeting BTK Reporting System [101]. Contrary to the previous case with ibrutinib in a population already characterized by an series, ten of these cases had refractory underlying disease immune dysregulation (e.g. CLL) will most likely result in with prior exposure to other immunosuppressive agents an increased risk of infection. and six cases reported concomitant use of such agents. Collectively, the randomized pivotal trials demonstrate Thus, although the inhibitory effect of ibrutinib on that upper respiratory tract infections are the most common interleukin-2-inducible kinase makes an increased risk for infectious complications in ibrutinib-treated patients, albeit PcP biologically plausible, PcP prophylaxis is not routinely mostly self-resolving [76–81]. Pneumonia is the most recommended; its risk-benefit should be outweighed in the common serious infectious event. The frequency and pat- context of diminished T-cell immunity due to previous tern of infections appears to reflect what is typically seen in (e.g. fludarabine-cyclophosphamide-rituximab therapy) or this B-cell malignancy population, rather than a drug- concomitant therapy [35]. specific adverse event profile. Infectious complications are Among thousands of patients with a variety of B-cell considerably fewer and less severe in treatment-naïve (TN) malignancies treated with ibrutinib, invasive mold infec- compared with relapsed/refractory (R/R) patients, i.e., 13% tions have been reported only sporadically. The frequency vs. 51% ≥ grade 3 infections: pneumonia (6% vs. 25%), of invasive yeast and mold infections in the clinical studies sepsis (0% vs. 7%), cellulitis (0% vs. 5%) sinusitis (0% vs. was low, ranging from 0 to 3.2% [1–6]. More recently, a 5%) and bacteremia (0% vs. 4%) [86]. The infectious retrospective French survey reported 27 cases of invasive morbidity appears to decrease over time; grade ≥ 3 infec- aspergillosis from 16 centers [102]. Most cases occurred tions are observed more frequently during the first 6 months early-on within a median of 3 months after starting ibrutinib of therapy, often during the first 2−3 months. This trend is for relapsed/refractory disease. Cerebral involvement was related to the extended time from last chemotherapy in R/R frequent (40%). Unfortunately, the survey did not report a cases, early response and disease control, and the immu- denominator, and the majority of patients had at least one nomodulating potential of ibrutinib. In addition, prolonged additional factor, aside from hypogammaglobulinemia, that ibrutinib treatment results in a partial reconstitution of increased their risk for fungal infections [102]. During a the humoral immunity with stabilization or improvement 5-year period (2012−2016), invasive fungal infection of immunoglobulin levels and of the normal B-cell popu- (including pulmonary and disseminated aspergillosis, pul- lations [87]. monary cryptococcosis, and PcP) developed in 4.2% of Not unexpectedly in these often heavily pretreated ibrutinib-treated patients at the Memorial Sloan Kettering patients, opportunistic infections have been sporadically Cancer Center [103]. Experimental use of single-agent reported, including cases of cryptococcal disease (menin- ibrutinib in patients with primary central nervous system goencephalitis/disseminated disease) [88–91], (miliary) lymphoma was associated with a 5−27% frequency of tuberculosis [92, 93], endemic mycosis, PML (in rituximab invasive aspergillosis, including cerebral disease [104, 105]. pretreated patients) caused by JC virus [94–96], Epstein Clearly BTK plays a role in innate fungal immune sur- −Barr Virus (EBV)-driven hemophagocytic syndrome [97], veillance (as demonstrated in Btk−/− mice studies [104]) via and reactivations of Hepatitis B virus (HBV) [98, 99]. a series of mechanisms mentioned before [85]. Obviously Following a report of five cases of PcP in a cohort of 96 ibrutinib impairs that fungal immune surveillance, thereby patients [100], concern has risen that ibrutinib therapy could contributing to the complex “net state of immunosuppres- increase the risk of PcP, although no other study has sion”, although the increased susceptibility to fungal disease reported a frequency above 1%. These PcP cases occurred in ibrutinib-treated patients remains primarily dictated by in previously untreated CLL patients receiving ibrutinib the status of the underlying lymphoid malignancy, the monotherapy and presented in a “nontypical” way [100]: (a) combined action with other immunosuppressive therapies patients were asymptomatic or had only mild, often chronic and the environmental exposure to fungal pathogens respiratory symptoms; (b) there was no long-term use of [103, 106]. However, these reports underscore the need for steroids or other immunosuppressive drugs; (c) chest com- heightened awareness and vigilance to identify any puted tomography scan revealed nontypical multifocal change in fungal epidemiology in view of the rapidly nodular infiltrates; (d) CD4+ T-cell counts were high (>500 growing availability of novel therapeutic agents with Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology.. . . 851 immunosuppressive characteristics. Pending further epide- AKT (protein kinase B) signaling and promotes apoptosis miological data, routine mold-active prophylaxis is cur- of B-lymphocytes. rently not recommended (outside the setting of severe Few reports describe a higher risk of opportunistic graft-versus-host disease post-allogeneic stem cell trans- infections in patients treated with idelalisib, particularly PcP plantation, where ibrutinib may become a treatment option). and CMV infections, even in the setting of normal neu- It must be kept in mind that mold-active azoles interfere trophil counts and absence of profound lymphocytopenia. It with ibrutinib elimination by inhibiting the CYP3A4 was hypothesized that PI3K inhibitors cause an increased enzyme system, potentially increasing the risk of adverse susceptibility to infections through impairment of granulo- events [107]. However, as the indications for ibrutinib use cyte activation [119]. Four trials have been published on continue to expand, better identification of risk factors for monotherapy [120–123], three in combination with invasive fungal disease may define populations in which anti CD20 [124–126] and four with other combinations monitoring and antifungal prophylaxis can be studied as [127–130]; three of them were stopped early because of potential preventive strategies [103]. excess adverse event rates (hepatotoxicity and pneumonitis) Guidelines recommend vaccination against influenza and [128–130]. pneumococcal disease in patients with B-cell malignancies Regarding bacterial infections, no increased risk was [73, 108]. However, recent prospective data demonstrate found to be associated with idelalisib. For clinical practice, that ibrutinib may dramatically impair adequate serological no specific recommendations for antibacterial prophylaxis responses to vaccination [109, 110]; hence, clinicians may can be given. Sehn et al. published a retrospective analysis consider vaccinating patients before the initiation of anti- of 2198 patients receiving idelalisib alone or in combination neoplastic therapy. with co-therapy (anti-CD20 antibody or bendamustine + Finally, there have been sporadic reports of pneumonitis rituximab) and patients receiving only co-therapy (anti- in patients receiving ibrutinib [111]. These cases present CD20 ± bendamustine) [131]. The overall incidence of PcP early (1−4 months) after initiation of therapy and are was 2.5% in patients on idelalisib ± co-therapy vs. 0.2% in clinically indistinguishable from infectious complications patients receiving anti-CD20 antibody alone or in combi- (e.g. PcP or viral pneumonitis). Diagnosis is established by nation with bendamustine (relative risk, 12.5). A correlation ruling out other differential diagnoses; treatment includes between CD4 counts (e.g., <200 cells/µL) and an increased ibrutinib withdrawal and corticosteroids. risk of PcP was not observed. Only 1.2% of patients receiving anti-Pneumocystis prophylaxis developed this Idelalisib complication, as compared to 3.5% of those without pro- phylaxis, and among the 20% of patients in whom Idelalisib is a selective inhibitor of adenosine-5’-triphosphate PcP prophylaxis was administered, no deaths occurred. in the phosphatidylinositol-3-kinase delta (PI3Kδ). It is Thus, there is a small, but increased risk of PcP during approved since 2014 in combination with rituximab for the treatment with idelalisib. Prophylaxis with trimethoprim- treatment of relapsed chronic lymphocytic leukemia (B-CLL) sulfamethoxazole is included in the label now, and the and for first-line therapy of B-CLL with del17p or TP53 European Society of Clinical Microbiology and Infectious mutation and as a monotherapy for refractory follicular Diseases study group for infections in compromised hosts lymphoma. (ESGICH) suggests PcP prophylaxis during idelalisib Phosphatidylinositol 3-kinase (PI3K) comprises a group therapy and for 2−6 months after its discontinuation [132]. of related lipid enzymes regulating pleiotropic downstream From our perspective, PcP prophylaxis is recommended, effector functions. Class I PI3Ks are heterodimers of reg- but based on weak evidence [133, 134]. ulatory and catalytic subunits with four different isoforms, Cytomegalovirus reactivations are notified in randomized α, β, γ and δ, involved in cell proliferation, survival, and trials for 52 of 2204 patients (2.4%) treated with idelalisib motility [112, 113]. The α and β isoforms are widely (https://www.ema.europa.eu/documents/variation-report/ expressed in many tissues, whereas γ and δ isoforms are zydelig-h-c-003843-a20-1439-0023-epar-assessment- restricted to hematopoietic cells. In B lymphocytes, the δ report-article-20_en.pdf) [123, 126, 127, 135]. The inci- isoform (PI3Kδ) plays a central role in normal B-cell dence rate is higher when idelalisib is combined with development and function, transducing signals from B-cell bendamustine (13/207 patients; 6.3%) (https://www.ema. receptor as well as from receptors for various cytokines, europa.eu/documents/variation-report/zydelig-h-c-003843-a chemokines and integrins [114, 115]. PI3Kδ signaling 20-1439-0023-epar-assessment-report-article-20_en.pdf) pathways are frequently hyperactive in many B-cell [127, 135]. CMV serostatus must be defined for all patients malignancies [116–118], so that the inhibition of δ before treatment initiation. For CMV-negative patients, isoform-specific PI3K signaling is a promising approach for CMV-negative or filtered blood products are recommended the therapy of B-cell lymphoma. Idelalisib blocks PI3Kδ- and CMV antigen or PCR should be checked at least every 852 G. Maschmeyer et al. 4 weeks. In case of positive PCR/antigen with increasing mTOR inhibitors (sirolimus, temsirolimus, viral load or symptoms consistent with CMV disease, everolimus) ganciclovir or valganciclovir treatment is recommended and idelalisib should be discontinued [134]. Inhibitors of the mammalian target of rapamycin (mTOR) are approved for immunosuppression post solid organ Histone deacetylase (HDAC) inhibitors transplantation and the treatment of mantle cell lymphoma, (panobinostat, vorinostat, romidepsin) breast cancer, neuroendocrine tumors and renal cell cancer. Sirolimus, temsirolimus and everolimus are available for HDAC inhibitors are used for epigenetic treatment affecting clinical application. the coiling and uncoiling of DNA around histones, invol- mTOR is acting as a serine/threonine protein kinase in ving histone acetyl transferases and histone deactetylases the PI3k/AKT signaling pathway of growth factor receptors [136]. For use in clinical hematology, panobinostat (in such as epidermal growth factor (including HER-2), vas- combination with bortezomib and dexamethasone for cular endothelial growth factor and insulin-like growth recurrent multiple myeloma), vorinostat (T-cell lymphoma factor-1 receptor. Immunosuppression and impaired wound progressive, persistent or recurrent on or following two healing may result from inhibition of T-cell proliferation, systemic therapies) and romidepsin (treatment of relapsed antigen-presenting cells, B cells, neutrophil granulocytes, cutaneous T-cell lymphoma and peripheral T-cell lym- mast cells and stromal cells [156, 157]. A meta-analysis of phoma) are approved. published reports on 5436 patients treated with mTOR HDAC inhibitors exert a plethora of inhibitory inhibitors showed a nonsignificantly increased risk of all- effects on innate immunity, in particular on toll-like grade leukopenia and neutropenia [158], while another receptor-mediated dendritic cell (DC) and macrophage meta-analysis of 3180 mTOR inhibitor-treated patients function such as sensing, phagocytosis, cytokine pro- [159] demonstrated a relative risk of all-grade and high- duction or adhesion [137], resulting in increased micro- grade infections of 2.00 (95% CI, 1.76−2.28, p < 0.001) bial susceptibility and reduced inflammatory response and 2.60 (95% CI, 1.54−4.41, p < 0.001), respectively, as [138]. However, in controlled clinical trials on HDAC compared with patients in the control arms of the studies. inhibitor use in patients with multiple myeloma, malig- Infections mainly affect the respiratory tract (61.7%), nant lymphoma (T cell, B cell or Hodgkin’s), acute genitourinary tract (29.4%) and skin/soft tissue (4.2%). myeloid or lymphoblastic leukemia or myelodysplastic A difference in incidences or risks between everolimus and syndrome, no significant increase in infection rates or temsirolimus or between different tumor types (renal cell fever have been observed in comparison with control carcinoma vs. others) was not observed. Among respiratory groups [139–150]. A notable rate of asymptomatic inter- tract infections, no increase in the risk of specific types of stitial pneumonitis has been reported from a clinical trial pneumonia such as PcP, invasive mold or CMV infection on panobinostat used for treatment of Waldenström’s was found to be associated with mTOR inhibition [160]. Macroglobulinemia [151]. From observations outside Urinary tract infections caused by polyomavirus or clinical hematology, a potential use of HDAC inhibitors CMV were even less frequently observed in 4930 renal for improved clearance of Human Immunodeficiency transplant recipients receiving mTOR inhibitors as com- Virus has been postulated [152–155]. pared with those treated with mycophenolate for preventing For clinical practice, no clear evidence of HDAC graft rejection [161]. A meta-analysis of 14 clinical trials on inhibitor-attributable increase in the risk of infection or post-transplant mTOR inhibitor treatment confirmed a infection-related mortality has been reported. Hence, there lower rate of CMV reactivation among heart transplant is no rationale for specific prophylaxis and for specific recipients [162]. diagnostic procedures in case of fever in hematologic Studies conducted in patients with metastatic cancers patients under treatment with HDAC inhibitors. Consider- (renal, breast or lung) reported mTOR inhibitor-related ing their negative impact on inflammatory response, pneumonitis with a large variation in incidence [163–165]. screening for HBV and consideration of prophylactic drug For clinical practice, no specific recommendations for treatment in case of reactivation risk may be recommended. antimicrobial prophylaxis or for the diagnostic approach to In patients with active infection, HDAC inhibitor treatment individual patients with fever emerging under treatment should be withheld. In case of cough and/or dyspnea, drug- with mTOR inhibitors can be given. In light of their overall related interstitial lung disease should be taken into con- increased risk of infectious complications, a high level of sideration. HDAC inhibitor use in HIV-positive patients alertness is required. In patients who develop cough and/or with hematologic malignancies does not seem to increase dyspnea, drug-related interstitial lung disease should be the risk of HIV activation. taken into consideration. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology.. . . 853 Ruxolitinib The randomized COMFORT-I study [175] comprised 309 patients with splenomegaly and intermediate-2 or high- Ruxolitinib is an inhibitor of Janus kinases (JAKs), risk IPSS who are probably more sensitive to infections which are non-receptor tyrosine kinases mediating signal due to more advanced disease. Bacterial infections and in transduction induced by cytokines. JAK2V617F mutation particular urinary tract infections (9%) and VZV (1.9%) results in constitutive activation of the JAK/STAT (signal were the main infections that occurred in patients receiving transducer and activator of transcription) signaling ruxolitinib during randomized treatment. At 5-years follow- pathway. Ruxolitinib alleviates constitutional symptoms up [176], the most severe infections were pneumonia and of myelofibrosis (MF) by downregulating interleukin sepsis at similar rates in patients treated with ruxolitinib or (IL)-1b, IL-6 and TNF-α. Ruxolitinib was approved for placebo. Over time, VZV infections occurred at higher rate treatment of advanced MF and Polycythaemia Vera (PV). in patients treated with ruxolitinib compared to placebo, but Until now, three possible mechanisms of ruxolitinib the majority of cases were single episodes grade 1 or 2. immunomodulatory effects and immunosuppressive action After 36 months, no other opportunistic infections occurred. have been identified, mainly based on dendritic, T- and Similar results were obtained in the COMFORT-II trial natural killer (NK) cells. The first mechanism is the [177], in which ruxolitinib was compared with the best ruxolitinib-induced effect on DCs differentiation and func- available therapy in 219 patients. Pneumonia was the only tion in vitro and in vivo blocking DC development [166]. In serious infectious adverse event reported (1% in the rux- the presence of ruxolitinib, the cells morphologically and olitinib group vs. 5% in the “best available therapy” group). phenotypically resemble monocytes rather than DCs, and IL The other infections were of grade 1−2. In the 5-year final −12 cytokine production, which is critical for naive analysis [178], with a median duration of exposure to rux- CD8-positive T-cell activation to acquire cytotoxic activity olitinib of 2.6 years, VZV infections (11.5%), pneumonia and to destroy infected or transformed cells, is markedly (13%), sepsis (7.9%) and urinary tract infections (24.6%) reduced. Finally, proper DC migration to secondary lym- were found; however, grade 3 or 4 urinary tract infection phoid organs, in order to induce T-cell responses, is also was reported only in 1.0% of patients, VZV in 4.3%, and no severely reduced [167]. trends towards an increase in the rate of sepsis were seen The second mechanism involves T-cells. JAK/STAT- over time. Two cases (1%) of tuberculosis (TB) were also signaling is involved in the regulation of CD4-positive documented. T cells, which mediate inflammatory responses and protect Other studies confirmed the predominance of bacterial against a wide range of pathogens by adopting a series of and viral infections besides sporadic opportunistic infec- distinct differentiated states, i.e., T helper cell type 1 (Th1), tions. The ROBUST trial [179], including 48 patients with Th2, Th17, regulatory T cells (Tregs), etc. Ruxolitinib intermediate-1 and -2 and high risk, showed only bacterial treatment significantly inhibits CD4+ T-cell activation and infections (urinary tract infections 16.7%, respiratory tract differentiation [168, 169] reducing the number of proin- infections 25%) or unexplained fever (12.5%), except one flammatory Th1, Th17 and Tregs, that have also a protective case of PML. There were no reports of VZV, HBV or TB. role against specific viral pathogens (e.g., HSV 2, lym- In the JUMP expanded-access trial [180], 1144 intermediate phocytic choriomeningitis virus, West Nile virus), some and high-risk MF patients without access to ruxolitinib parasites (Plasmodium spp., Toxoplasma gondii) and fungal outside of a clinical study were included. All-grade infec- pathogens (Candida albicans) [170]. tions were mainly bacterial and viral and similar to those The third immunosuppressive mechanism involves present in the registry studies. TB was seen in three patients NK cells probably because cytokine signals mediated (0.3%) and Legionella pneumonia in one patient (0.1%); via the JAK/STAT pathway are determinant for NK no HBV reactivation was reported. Among patients cell activation and maturation. In ruxolitinib-treated with resistant PV and JAK2 mutation included in the patients, NK cell numbers are drastically reduced, in RESPONSE-1 trial [181], the rate of grade 3 or 4 infections part due to defective NK cell terminal maturation [171, at week 32 was 3.6% and 2.7%, respectively, similar in both 172], explaining the time-dependent decrease of NK cell ruxolitinib-treated patients and the control group treated numbers during ruxolitinib intake. Ruxolitinib therapy is with the best available therapy; VZV infections, all of grade associated with the reactivation of HSV and VZV infec- 1 or 2, occurred in seven patients in the ruxolitinib group tions, similar to patients with an inherited functional NK (6.4%) as compared with no patients receiving standard cell deficiency [172]. therapy. Similar results were obtained from the randomized Infections are among the main causes of morbidity and study RESPONSE-2 [182] assessing 149 phlebotomy- mortality in MF, representing the cause of death in around dependent patients resistant or intolerant to hydroxyurea, 10% of the cases [173, 174], mainly in advanced stages of 74 in the ruxolitinib group versus 75 in the “best available disease. therapy” group. Among all patients, grade 3 infections were 854 G. Maschmeyer et al. rare (two cases in the ruxolitinib group; influenza and unknown, because most clinical trials excluded the enroll- bronchitis) and one case (influenza) in the control group. No ment of patients with active HBV. Until now, five case pneumonia or TB reactivation was diagnosed in the rux- reports are described in the literature [197–200], high- olitinib group. Thus, ruxolitinib was not an independent risk lighting the importance of close monitoring of liver function factor for infections in this study. tests and plasma HBV-DNA level in HBV carriers receiving A recent retrospective analysis of 507 MF patients, ruxolitinib therapy. Recently published guidelines [201] diagnosed between 1980 and 2014 in five Italian hematol- recommend HBV-screening for hematologic patients ogy centers [183], described the epidemiology of infections scheduled for chemotherapy and/or immunotherapy for and the impact of ruxolitinib treatment in MF. One hundred both HBV reactivation and HBV risk factors as the first step and twelve patients (22%) experienced 160 infectious in preventing reactivation. Screening should include events (grade 3–4, 45%), more frequent in IPSS HBsAg, anti-HBc and anti-HBs, and HBV-DNA if anti- intermediate-2 and high-risk patients and in those carrying HBc is positive. HBV-seropositive individuals should be an unfavorable karyotype. The infections were mainly started on antivirals in a timely manner. Recent guidelines bacterial (78%), viral (11%, more frequent in IPSS inter- [36, 202, 203] recommend the use of antiviral drugs with a mediate-2/high-risk patients) and fungal (2%); also three higher barrier to resistance rather than lamivudine for first- cases of TB infection (0.5%) were diagnosed. The fre- line treatment. Entecavir and tenofovir are now preferred quency of infections was significantly higher among the 128 because of their lower viral resistance rates. The Centers for patients treated with ruxolitinib (cumulative incidence rate Disease Control and Prevention (CDC) have recommended of 6.1% vs. 3.9 per patient-year). The type and site of routine postvaccination tests for anti-HBs and annual infections were similar to those observed in the general booster doses for sustained immunity among high-risk population, but in ruxolitinib-treated patients, the rate of groups and immunocompromised individuals. Careful infections (44% vs. 20%, p < 0.001) was higher compared assessment of HBV infection is required before starting to ruxolitinib-untreated patients, probably also because ruxolitinib, and monitoring of HBV markers and prophy- these patients were at IPSS intermediate-2/high-risk and laxis might be required for any patients that demonstrate an most (61.7%) carried a large splenomegaly, the two leading HBV infection during the treatment course [204]. risk factors identified for infections by multivariate analysis The notification of TB cases in registry data [177, 178] in this study. Overall, infections were fatal in 9% of the and other studies [180, 183, 184] as well as case reports cases. Finally, in 70 patients with MF at lower risk (inter- [205–213] have suggested a causative role of ruxolitinib in mediate-1) treated with ruxolitinib [184], after a median the emergence of tuberculosis. Before ruxolitinib treatment, time of 8 months from the start of ruxolitinib, infectious an accurate TB history should be always taken, and the complications >grade 2 were 15.9%, and were mainly screening for latent TB must be considered if epidemiolo- bacterial (with one bone TB infection) and viral infections. gical risk factors are significant (history, endemic areas, Overall, these data confirm the predominance of bacterial trips in endemic areas) with Tuberculin Skin Test (TST) infections, in particular in the first months of treatment or (preferably) IFN-γ Release Assay, IGRA (i.e. Quanti- (decreasing along treatment exposition) as well as in FERON test) [204, 208]. After commencing ruxolitinib, patients who did not respond to ruxolitinib, while the VZV regular follow-up of patients is advised, especially for the infection rate increased over time up to 10−11%; infections first 6 months, to assess for the development of opportu- were mostly of grade 1−2. Some authors propose that nistic infections and TB reactivation. In the TB case reports, prophylaxis with antiviral drugs could be considered in case anti-infectious treatment was effective in most patients and, of previous history of Herpes virus disease. Moreover, the if clinically indicated, ruxolitinib was successfully resumed immunosuppressive effects of ruxolitinib may have played a [207, 208] after infection eradication, resulting in MF role in isolated cases of serious opportunistic infections improvement with no TB relapse. [185–196], such as PML [77], toxoplasmosis [186], CMV In conclusion, ruxolitinib-treated patients should be [187], cryptococcosis [188–190], PcP and other fungal carefully evaluated for serious infections at the onset of infections [191–193], EBV [194, 195], VZV meningoen- fever. Age and comorbidities, treatment modalities (such as cephalitis [196] and, more frequently, reactivation of HBV glucocorticosteroids), IPSS score [214] and environmental and TB. exposure may further influence the risk of infections. Main The widespread use of molecularly targeted drugs with reported infections are bacterial, in particular urinary tract immunosuppressive or immunomodulating action has infections, pneumonia, sepsis, and viral, in particular VZV increased the risk of HBV reactivation, which may clini- infection and influenza, but ruxolitinib was also associated cally vary from an asymptomatic replication to severe with a potentially increased risk of opportunistic infections. hepatitis and even fatal hepatic failure. The actual incidence As reported in a recent meta-analysis regarding ruxolitinib- of HBV reactivation following ruxolitinib therapy is associated infections [215], severe infections may delay the Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology.. . . 855 eligibility of MF patients to allogeneic transplantation, so a grade 3 or 4 febrile neutropenia (3.6% vs. 9.6%) and grade careful evaluation of the risk of infections is recommended 3 or 4 infections (17.5% vs. 21.8%) was reported with before ruxolitinib treatment. rituximab−venetoclax in comparison to rituximab−bend- HBV reactivation was occasionally seen in patients with amustin [223]. previous history of hepatitis and/or with occult infection. Neutropenia has usually been managed with dose Before ruxolitinib treatment, HBV screening in all patients reduction or transient interruption, and G-CSF has been and prophylaxis preferably with entecavir in patients used with good response [220, 226]. According to the HBsAg-positive and/or anti-HBc-positive is recommended. manufacturer, treatment should be withheld in case of Screening for latent TB should be considered if epidemio- grade 4 hematologic toxicity or in case of grade 3 or 4 logical risk factors and medical history are significant. neutropenia with infection or fever [227]. Infection In case of fever after ruxolitinib discontinuation, the without neutropenia has seldom led to venetoclax inter- possibility of a rare “ruxolitinib withdrawal syndrome”, a ruption or dose reduction [220]. syndrome presenting respiratory distress, progression of Venetoclax is a substrate of CYP3A, raising concerns splenomegaly, fever or pruritus, mimicking an infection, about the impact of CYP3A inducers or inhibitors, such as should be considered [216, 217]. azole antifungal agents. The impact of posaconazole coad- ministration has been well studied, and venetoclax dose Venetoclax should be reduced by at least 75% [228]. Venetoclax is a potent and specific inhibitor of the anti- Acknowledgements The authors would like to thank the meeting par- ticipants of ECIL 7, Sophia Antipolis, France, 22 and 23 September apoptotic BCL-2 protein. It has been approved for the 2017: Murat Akova, Ankara, Turkey; Mahmoud Aljurf, Riyadh, Saudi treatment of B-CLL (as third-line therapy or as second-line Arabia; Diana Averbuch, Jerusalem, Israel; Anne Bergeron, Paris, therapy in case of 17p deletion or TP53 mutation), where it France; Nicole Blijlevens, Nijmegen, Netherlands; Aida Botelho de has been shown to induce a rapid apoptosis of CLL cells, Sousa, Lisbon, Portugal; Alessandro Busca, Turin, Italy; Thierry Calandra, Lausanne, Switzerland; Simone Cesaro, Verona, Italy; known to be BCL-2 dependent [218]. Catherine Cordonnier, Créteil, France; Roberto Crocchiolo, Milan, Italy; The only immunosuppressive effect associated with Julien De Greef, Brussels, Belgium; Rafael de la Camara, Madrid, Spain; venetoclax is related to cytopenias. High-grade neutropenia Hugues de Lavallade, London, UK; Roberta Di Blasi, Rome, Italy and in particular has been shown to be a common adverse effect Creteil, France; Peter Donnelly, Nijmegen, Netherlands; Lubos Drgona, Bratislava, Slovakia; Rafael Duarte, Madrid, Spain; Sigrun Einarsdottir, in phase I and II studies in CLL [219, 220]. Gothenburg, Sweden; Hermann Einsele, Würzburg, Germany; Giuseppe The relative role of venetoclax in this setting has been Gallo, Verona, Italy; Hildegard Greinix, Graz, Austria; Raoul Herbrecht, questioned, as pretreatments and marrow infiltration by Strasbourg, France; Joshua Hill, Seattle, US; Petr Hubacek, Prague, CLL may have a substantial impact. Neutropenia occurs Czech Republic; Csaba Kassa, Budapest, Hungary; Galina Klyasova, Moscow, Russia; Sylwia Koltan, Bydgoszcz, Poland; Thomas mainly during the first 3 months of treatment, and an Lehrnbecher, Frankfurt, Germany; Per Ljungman, Stockholm, Sweden; inverse correlation has been shown between blood veneto- Olivier Lortholary, Paris, France; Jens Lundgren, Copenhagen, Den- clax concentration and risk of neutropenia and infection mark; Johan Maertens, Leuven, Belgium; Rodrigo Martino, Barcelona, [221]. Improvement may therefore be related to bone mar- Spain; Georg Maschmeyer, Potsdam, Germany; Sibylle Mellinghoff, Cologne, Germany; Malgorzata Mikulska, Genoa, Italy; David Navarro, row clearance from B-CLL. However, the causal role of Valencia, Spain; Anna Maria Nosari, Milan, Italy; Livio Pagano, Rome, venetoclax is highly probable. Venetoclax has been shown Italy; Karlis Paukssen, Uppsala, Sweden; Olaf Penack, Berlin, Germany; to suppress granulopoiesis in vitro and in animal models Zdenek Racil, Brno, Czech Republic; Christine Robin, Créteil, France; [222]. Moreover, comparative data from a phase 3 trial Emmanuel Roilides, Thessaloniki, Greece; Montserrat Rovira, Barcelona, Spain; Monica Slavin, Melbourne, Australia; Jan Styczynski, comparing rituximab-venetoclax to rituximab-bendamustin Bydgoszcz, Poland; Anne Thiebaut, Grenoble, France; Claudio Viscoli, in relapsed or refractory CLL have shown a higher rate of Genoa, Italy; Katherine Ward, London, UK; Christine Wenneras, grade 3 or 4 neutropenia in the venetoclax group (57.7% vs. Gothenburg, Sweden. Representatives of pharmaceutical companies 38.8%) [223]. Interestingly, cyclic administration of vene- supporting ECIL 7: Laurence Dubel, Astellas; Liz Mills, Clinigen; Markus Rupp, MSD; Sonia Sanchez, Gilead; Stefan Zeitler, Basilea. toclax (1 week on therapy, 3 weeks off) was not associated with neutropenia in a study on venetoclax use in systemic lupus erythematosus [224]. Compliance with ethical standards The real risk of infections associated with venetoclax in Conflict of interest GM accepted honoraria for lectures from Gilead, patients with B-CLL is unknown. In an aggregated safety Pfizer, Boehringer Ingelheim, Celgene, Bristol-Myers Squibb, Merck- analysis including one phase 1 and two phase 2 studies of Serono, Novartis, honorarium for advice from Gilead and a travel grant venetoclax monotherapy in relapsed or refractory B-CLL, from Bristol-Myers Squibb. JAM accepted grants, personal fees and nonfinancial support from MSD, Astellas, Pfizer and Gilead, personal the drug has shown a manageable safety profile. Grade 3 or fees and nonfinancial support from Basilea and F2G and personal fees higher overall infection rate was 19% [225]. Reassuringly, from Scynexis. The other authors declare that they have no conflict of although neutropenia was more frequent, a lower rate of interest. 856 G. Maschmeyer et al. Publisher’s note: Springer Nature remains neutral with regard to 13. Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin jurisdictional claims in published maps and institutional affiliations. DR, Sievers EL, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res. Open Access This article is licensed under a Creative Commons 2010;16:888–97. Attribution 4.0 International License, which permits use, sharing, 14. 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