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Risk of infection associated with new therapies for lymphoproliferative syndromes
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Review
Risk of infection associated with new therapies for the treatment of lymphoproliferative syndromes夽 Ibai Los-Arcos a,b , Juan Aguilar-Company a,c,⁎ , Isabel Ruiz-Camps a,b a b c
Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d’Hebron, Barcelona, Spain Red Espa˜ nola de Investigación en Patologías Infecciosas (REIPI), Instituto de Salud Carlos III, Madrid, Spain Servicio de Oncología Médica, Hospital Universitari Vall d’Hebron, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 4 June 2019 Accepted 25 July 2019 Available online xxx Keywords: Ibrutinib Idelalisib Immune checkpoint inhibitors Vaccination Rituximab Alemtuzumab
a b s t r a c t Over the last decade, there have been important developments in the treatment of lymphoproliferative disorders. Apart from conventional chemotherapy, a wide array of therapies have been developed, with different indications. The aim of this review is to evaluate the risk of infection associated with these therapies, as well as establishing prevention recommendations. In all cases, the patient’s underlying disease as well as concomitant or previous therapies have an impact in the risk of infection. Anti-CD20 antibodies (rituximab, ofatumumab and obinutuzumab) have been associated to a higher risk of bacterial and viral infection, as well as reactivation of latent infections and opportunistic infections. Alemtuzumab is associated to severe, protracted immunosuppression. Ibrutinib and acalabrutinib have been linked to bacterial infections (especially respiratory infections), invasive fungal infections and opportunistic infections. Idelalisib carries a higher risk of Pneumocystis jirovecii and infection and cytomegalovirus reactivation. Venetoclax is associated with respiratory infections and neutropenia. Immune checkpoint inhibitors are not directly associated with a higher risk of infection; nevertheless, the use of corticosteroids and immunosuppressants to control immune-related adverse events results in an increase of the risk of infection. Brentuximab, lenalidomide and HDAC inhibitors do not seem to be associated to a higher risk of infections. Although data are scarce, a higher number of infections have been observed with cellular therapies, mostly in patients with more than 3 previous antineoplastic treatments or those receiving tocilizumab or corticosteroids for managing the cytokine release syndrome. In all patients, we recommend appropriate vaccination, screening for latent infections, and individualized prophylaxis recommendations. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Riesgo de infección asociado a nuevas terapias para el tratamiento de los síndromes linfoproliferativos r e s u m e n Palabras clave: Ibrutinib Idelalisib Inhibidores del checkpoint inmune Vacunación Rituximab Alemtuzumab
En la última década se han experimentado grandes cambios en los tratamientos de los síndromes linfoproliferativos. A la quimioterapia convencional se suman ahora un amplio abanico de terapias dirigidas con diferentes indicaciones. El objetivo de esta revisión es evaluar el riesgo de infección asociado a estas terapias, así como tratar de establecer unas recomendaciones de prevención. En todos los casos, la enfermedad de base del paciente, así como los tratamientos concomitantes o los recibidos previamente impactan en el riesgo de infección. Los anticuerpos anti CD20 (rituximab, ofatumumab y obinutuzumab) se asocian a un mayor riesgo de infección bacteriana, vírica y de reactivación de infecciones latentes, así como a infecciones oportunistas. Alemtuzumab se asocia a inmunosupresión grave y mantenida. Ibrutinib y acalabrutinib se asocian a infecciones bacterianas, especialmente respiratorias, infección fúngica invasora e infecciones oportunistas. Idelalisib se asocia a un aumento de la incidencia de neumonía por
夽 Please cite this article as: Los-Arcos I, Aguilar-Company J, Ruiz-Camps I. Riesgo de infección asociado a nuevas terapias para el tratamiento de los síndromes linfoproliferativos. Med Clin (Barc). 2019. https://doi.org/10.1016/j.medcli.2019.07.026 ∗ Corresponding author. E-mail address: [email protected] (J. Aguilar-Company). ˜ S.L.U. All rights reserved. 2387-0206/© 2019 Elsevier Espana,
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Pneumocystis jirovecii y reactivación de citomegalovirus (CMV). Venetoclax se asocia a infecciones respiratorias y neutropenia. Los inhibidores de checkpoint inmune parecen no incrementar, por sí mismos, el riesgo de infección; sin embargo, el uso de glucocorticoides e inmunosupresores para controlar efectos adversos inmunorelacionados sí conlleva un aumento del número de infecciones, incluyendo infecciones oportunistas. Brentuximab, lenalidomida y los inhibidores de HDAC no parecen asociarse a un mayor riesgo de infección. Aunque existe poca experiencia en el uso de terapias celulares, se ha observado un mayor número de infecciones en pacientes que han recibido más de 3 tratamientos antineoplásicos previamente, o en aquellos que han requerido tocilizumab o glucocorticoides para el manejo del síndrome de liberación de citocinas. En todos los pacientes se recomienda una actualización del calendario vacunal, despistaje de infecciones latentes y profilaxis individualizada. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction Lymphoproliferative diseases (LPD) are a heterogeneous group of disorders of clonal origin that affect lymphoid cells (cytotoxic or helper T lymphocytes, natural killer lymphocytes, B lymphocytes or plasma cells) and that have in common the proliferation of lymphoid cells, with a tendency to invade the bone marrow and peripheral blood in addition to lymphoid organs. In the last decade there has been a considerable change in the treatment of LPD and an increase in overall survival. Biological therapies or targeted therapies have been added to conventional chemotherapy which, selectively, try to stop or, in some cases, prevent the progression of tumour cells. These therapies include a series of monoclonal antibodies, receptor analogues and small molecules designed to bind to different molecular targets.1 These drugs have advantages over chemotherapy in terms of potency and specificity and, theoretically, produce less adverse effects. However, if these drugs are correlated with a greater number of infections it is a difficult fact to establish, since there is a large number of factors that lead to confusion. First, the patient’s own hemopathy is often associated with an increased risk of infections including opportunistic infections (OI). Secondly, some of the previous treatments received cause immune disorders that persist over time, even after their discontinuation, and may increase the risk of infection. Thirdly, the effect of other drugs, either associated with the treatment, or used to control the adverse effects produced by it, and which may also increase the risk (for example, glucocorticoids), must also be added. Finally, to establish the exact correlation, it would take a very high number of patients who have received the therapy in question for a long period of time and who have developed a specific infection. Today, all of this entails difficulties when establishing prevention and prophylaxis recommendations and, on occasion, these are based more on the experience of the prescriber than on the available evidence. In this review, the existing data on infection with the new treatments for LPD will be presented, and attempts will be made to establish prevention recommendations and diagnostic strategies useful for doctors treating these patients. As a summary, risk factors, related infections and recommended preventive measures for each class of drugs are shown in Table 1.
Review by drug groups Anti-CD20, CD56, CD30 monoclonal antibodies Monoclonal anti-CD20 antibodies constitute a family of agents directed against B-cell proliferation (CD20 positive) haematological diseases and have been used alone or in combination in this context. These antibodies alter the immune response by modulating the interaction between B and T cells rather than by direct action
on humoral immunity. Rituximab is a chimeric antibody, while obinutuzumab and ofatumumab are humanized antibodies and show greater persistence in B cells and greater antibody-dependent cytotoxicity. There are a large number of confounding factors to establish direct causality with certain infectious conditions, since most patients have received previous therapies with an effect on the immune system or receive the antibody in combination with other drugs.2,3 There is a meta-analysis that confirms that there is a higher incidence of bacterial infections with the use of rituximab (although this incidence is not higher than that presented with glucocorticoids).4,5 More important is the reactivation of hepatitis B (5.7 times higher risk),6 infections by herpes or progressive multifocal leukoencephalopathy (PML)-type OI or Pneumocystis jirovecii pneumonia (PJP). Although a first meta-analysis pointed to a risk of PJP 3.57 times higher, other studies show a lower incidence (1.5–3%). The risk of real infection is determined by the combination of cancer-specific treatment that the patient receives,2 the basic pathology and associations with other drugs (mainly glucocorticoids); OIs are rare when rituximab is used alone and as an initial treatment agent.7 The association of rituximab, fludarabine and chlorambucil can cause delayed and prolonged immune-mediated type neutropenia with a not entirely clear relationship with the risk of infection. Ofatumumab and obinutuzumab have a profile of bacterial and viral infections similar to that of rituximab, although currently available data reflect a lower risk of OI. Obinutuzumab is associated with a greater number of episodes of neutropenia, which appear not to increase the risk of infection.5 There seems to be a reduced response to vaccination during treatment with anti-CD20, so it is advisable to delay it up to 6 months after the end of treatment.8 Although there are alternatives to improve the immune response in this population (high load vaccines, use of adjuvant vaccines, intradermally), there are no consistent data on its theoretical benefit.9 Brentuximab vedotin is a conjugated antibody directed against CD30 indicated in the treatment of adult patients with CD30+ Hodgkin lymphoma or relapsed or refractory anaplastic lymphoma and in cutaneous T-cell lymphoma after a first line treatment. Although it produces neutropenia, fever episodes are rare. There does not seem to be a high risk of infectious complications. The incidence of PJP is between 0.1–1% and that of herpes simplex infections or varicella zoster virus between 1–10%. PML cases have been reported, both in pivotal and post-marketing studies, which would require alertness to neurological manifestations.10 Alemtuzumab, an anti-CD52 monoclonal antibody only used nowadays in some patients with chronic lymphatic leukaemia (CLL), produces serious immune defects (with involvement of B, T and NK lymphocytes) that persist up to 9 months after the end of treatment. It has been correlated with a large number of bacterial, viral and fungal infections. The high rate of repli-
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Table 1 Main drugs of recent introduction in the treatment of lymphoproliferative diseases. Group
Drugs
Use
Risk of infection
Recommendations
Anti-CD20
Rituximab
B-cell LPD
Moderate
HBV reactivation screening and prophylaxis Prophylaxis for PJP in patients receiving glucocorticoids
Obinotuzumab
HBV reactivation
Ofatumumab
Increase of herpes group virus infections Increase in PJP in patients with other treatments Low
Anti-CD30
Brentuximab vedotin
Anti-CD52
Alemtuzumab
Hodgkin lymphoma Anaplastic Lymphoma Chronic lymphatic leukaemia
Some cases of PML Moderate-High Increased risk of fungal, bacterial and viral infections
Bruton tyrosine kinase inhibitors
Anti-PI3K
BCL-2 inhibitors
Ibrutinib
Mantle cell lymphoma
Moderate-High
Acalabrutinib
Chronic lymphatic leukaemia Waldeström macroglobulinemia
Increase of bacterial infections
Idelalisib
Venetoclax
Marginal zone lymphoma Chronic lymphatic leukaemia Follicular lymphoma Chronic lymphatic leukaemia
CMV monitoring Acyclovir prophylaxis for herpes group virus PJP prophylaxis Screening and prophylaxis of HBV reactivation Assess antifungal prophylaxis and/or early screening with biomarkers if other risk factors (fludarabine, alemtuzumab . . .) Prophylaxis for PJP in patients receiving glucocorticoids
Increased risk of filamentous fungal infections (especially first 3–6 months and high frequency of disseminated disease) Moderate-High
PJP prophylaxis
Increase of opportunistic infections such as PJP and CMV Low-Moderate
Monthly CMV monitoring
HDAC inhibitors
Panobinostat
Multiple myeloma
Increase the risk of neutropenia, the increased risk of infection is not clear Low
T-cell lymphomas
Possible increased risk of HBV reactivation
Anti-CTLA4
Vorinostat Belinostat Romidepsin Ipilimumab
Hodgkin lymphoma
Low.
Anti PD-1
Pidilizumab
Associated with cell therapies (under study)
Opportunistic infections (PJP, fungal or CMV infections) have been reported in patients receiving prolonged glucocorticoid treatment for the management of immune-related adverse effects.
Anti PDL-1
Prophylaxis for PJP in patients receiving glucocorticoids
Prophylaxis for PJP in patients receiving glucocorticoids.
HBV reactivation screening and prophylaxis
Prophylaxis for PJP in patients receiving glucocorticoids Early IA screening in patients receiving glucocorticoids
Nivolimumab Pembrolizumab Durvalumab Athezolizumab
IA: invasive aspergillosis; CMV: cytomegalovirus; PML: progressive multifocal leukoencephalopathy; PJP: Pneumocystis jirovecii pneumonia; LPD: lymphoproliferative disease; HBV: hepatitis B virus.
cation/cytomegalovirus disease (CMV) stands out, especially in patients who have previously received other treatment lines.5,7,11
Bruton tyrosine kinase inhibitors Ibrutinib and acalabrutinib are oral drugs that irreversibly inhibit the Bruton Tyrosine Kinase (BTK), acting in the signalling pathway of the B cell receptor (BCR). The stimulation of the transmembrane BCR protein leads to the activation of different tyrosines, including BTK and phosphatidylinositol 3-kinase (PI3K), which in turn activate proliferation and survival signals of B lymphocytes. BTK inhibitors bind to it irreversibly, thereby inducing apoptosis in tumour B-cell. The first of the BTK inhibitors marketed was ibrutinib. Currently, ibrutinib is approved for the treatment of mantle cell lymphoma, CLL, Waldeström macroglobulinemia and marginal zone lymphoma.12
Ibrutinib seems to increase the risk of developing infections,13 although this increased risk is difficult to attribute exclusively to ibrutinib. The most common infections are bacterial, and especially respiratory infections, which occur mainly in the first 6 months after the start of drug administration.14 The increase in frequency and severity of these infections is greater in patients with refractory or relapsing lymphoproliferative disease.10 Having received at least 3 antineoplastic treatments prior to the onset of ibrutinib and developing neutropenia during treatment are independent risk factors for the subsequent occurrence of serious infections.15 Although fungal infections were very rare in clinical trials, subsequent observational studies have shown an increase in them.14 These infections, as well as bacterial ones, have been described especially during the first 3 months of treatment, in patients who have received other treatment lines and in association with glucocorticoids, being exceptional when ibrutinib is used as a first-line treatment. In patients with primary central nervous sys-
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tem lymphoma, an incidence of 39% of invasive aspergillosis (IA) has been reported in a series of 18 patients.14 The clinical presentation of IA is also different, reporting a high frequency of extrapulmonary infection (25–40% of patients had central nervous system involvement).10,15 The BTK pathway in the macrophage is involved in the defence against Aspergillus spp., so its inhibition could explain the increased risk of fungal infection in these patients.16 At the present time, universal antifungal prophylaxis is not recommended. In patients with some other additional risk factor (fludarabine, alemtuzumab, use of other immunosuppressants or previous invasive fungal infection), pharmacological prophylaxis or periodic infection screening (by galactomannan, PCR, etc.) could be assessed individually.14 It is important to note the interaction of ibrutinib with potent CYP34A inhibitor drugs such as voriconazole, the main treatment of IA. It is recommended, if possible, to avoid this combination, and if not possible, reduce the dose of ibrutinib to 140 mg/day.3,17 A series of 8 patients treated with ibrutinib and isavuconazole, a new triazole with a lower risk of interactions, have been reported, this combination being well tolerated, without adverse effects.18 With regard to the PJP, the data are controversial, and the incidence of this infection is generally less than 1% except in some specific study.10 However, if ibrutinib is administered in combination with glucocorticoids or the patient received purine analogues, prophylaxis against PJP is recommended.13 On the other hand, cases of disseminated cryptococcosis as well as endemic fungal infections, miliary tuberculosis and cases of PML caused by the JC virus have also been reported.10 Acalabrutinib is a second generation BTK inhibitor, with a more selective BTK inhibition.12 In addition, it has a faster oral absorption and a shorter half-life than ibrutinib. It has been approved for the treatment of mantle cell lymphoma, but the clinical experience is limited for now. The results of 2 clinical trials have been published; in the first one, 61 patients with mantle lymphoma were included, of which 14 (23%) had upper respiratory infections and only one patient died from pneumonia.19 In the second study, 124 patients were included, of which 66 (53%) had infections, most of them mild, although 6 patients (5%) had pneumonia, one patient had PJP and another CMV viremia.20 Phosphoinositol 3-kinase inhibitors Idelalisib is a small molecule that acts as a selective inhibitor of the PI3K delta isoform in the B lymphocyte signalling pathway,13 which plays a central role in the development of these cells and is overexpressed in B-LPD. By blocking this molecule, idelalisib promotes apoptosis of B lymphocytes. Idelalisib is an oral drug approved for the treatment of CLL (associated with rituximab) and refractory follicular lymphoma10 (in monotherapy). Adverse effects such as colitis, hepatitis and pneumonitis14 requiring treatment with high-dose glucocorticoids, which in turn may increase the risk of infection21 have been described. A higher incidence of bacterial infections with idelalisib has not been described. An increased risk of presenting an OI, such as PJP and CMV disease, has been described in a characteristic way. Specifically, an increase in the frequency of PJP has been observed in patients treated with idelalisib compared to those treated with rituximab ± Bendamustine (2.5% vs. 0.2%) and also for patients treated with ofatumumab (5% vs. 1%). In addition, this increase occurs independently of the CD4 T-cell count.10 Both the European Medicines Agency and different scientific societies consider it necessary to perform universal prophylaxis against NJP in patients receiving idelalisib from the start of treatment and up to 2–6 months after its completion.13,14 As for the reactivation of CMV, it is up to 5 times more common in these patients.14 52 of 2204 patients (2.4%) showed CMV reactivation during the first 6 months of treatment
in the pivotal studies. This incidence was even higher if idelalisib was combined with bendamustine (13/208 patients; 6.3%). A serology for CMV is recommended before the start of treatment and at least a monthly monitoring of CMV viral load during the treatment and whenever there is any sign or symptom suspected for CMV disease. In addition, blood products from CMV negative or irradiated patients is recommended in CMV seronegative patients.10,13 BCL-2 inhibitors Venetoclax is a potent and selective inhibitor of BCL-2 antiapoptotic protein (B-cell lymphoma), overexpressed by tumour cells. It is used as a single agent or associated with anti-CD20 monoclonal antibodies for CLL patients pre-treated or with unfavourable cytogenetics (CD17 deletion). It is metabolized via CY3A4 and therefore has interactions with many drugs, including azoles. The main toxicity is neutropenia, which occurs in approximately 40–50% of patients in studies. The rates of severe infection, most of them respiratory, range from 6 to 33%, depending on the profile of patients included in each study (CLL in progression, recurrent neutropenia, association with rituximab, etc.).14,22 The impact on latent viral infections, such as hepatitis B, is yet to be clarified although it seems not to be superior to that of the LLC itself in patients with uncontrolled disease and who have received ibrutinib. In a pivotal study, isolated cases of herpes zoster and PJP were described in patients who had previously received fludarabine.23 However, today, prophylaxis should be individualized and based on previous infections, administered treatment lines and concomitant therapies. Histone deacetylase inhibitors Histone deacetylase (HDAC) is one of the main enzymes responsible for controlling histone acetylation and is overexpressed in different tumours. The inhibition of HDAC on the one hand, produces reduction in migration, invasion and angiogenesis and, on the other, favours the apoptosis of tumour cells. Panobinostat is approved by the FDA and the European Medicines Agency for the treatment of multiple myeloma (in combination with bortezomib and dexamethasone). Vorinostat, belinostat and romidepsin are approved by the FDA for the treatment of T-cell lymphomas, specifically; belinostat for peripheral T-cell lymphoma, vorinostat for cutaneous T-lymphomas and romidepsin for both types of lymphomas.24 HDAC inhibitors cause an inhibition of innate immunity with a theoretical increase in the risk of infection and a reduction in the inflammatory response. However, an increased risk of infection with respect to comparator groups has not been observed in clinical trials. Due to the decrease in the inflammatory response caused by these drugs, the latest ECIL guidelines recommend screening and prophylaxis for hepatitis B virus. In addition, they recommend the discontinuation of the HDAC inhibitor in case of active infection and highlight the risk that these patients have to develop interstitial pneumonitis.10 Lenalidomide Lenalidomide is an immunomodulatory agent used alone or in association with glucocorticoids or anti-CD20 monoclonal antibodies. There is no clear evidence that OI increase with their use.3,5 Prophylaxis against PJP would be indicated in associations with fludarabine and rituximab. Immune checkpoint inhibitors This group of drugs comprises monoclonal antibodies whose objective is to restore or enhance the action of the immune sys-
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tem against tumour cells. Its operation is based on the fact that tumour cells have mechanisms of immunological evasion through the usurpation of different signalling pathways or immune checkpoints (IC), such as the C 4 protein pathway of the T lymphocyte (CTLA-4) or that of programmed cell death (PD-1). These pathways are exploited by neoplastic cells, mainly by overexpression of ligands, to induce a decrease in T cell proliferation, cytotoxicity and cytokine production, contributing to generate and maintain an immunological tolerance microenvironment. The pharmacological blockade of these pathways allows to reactivate antitumor activity of the immune system.25 Currently, the main drugs in this class belong to 2 groups: the anti-PD-1/anti PDL-1 and the anti CTLA-4. In both groups there is extensive experience of use and established indications in solid organ cancer; recently, immune checkpoint (IC) inhibitors have also joined the therapeutic arsenal in haematology. Currently there are very favourable data of its use in Hodgkin lymphoma, where they have shown high response rates in patients with standard treatment-resistant disease or who have relapsed, and their use is being investigated in clinical trials against other nonHodgkin’s lymphomas as well as in association with cell therapies or hematopoietic stem cell transplantation.26 IC can trigger immune-related adverse effects in multiple organs, the most important being cutaneous, endocrinological, digestive, hepatic and pulmonary adverse effects. The treatment of these adverse effects involves in most cases the use of systemic glucocorticoids or other immunosuppressants such as infliximab or mycophenolate. Data on the risk of infections associated with the use of IC are mainly derived from studies conducted in patients with solid organ cancer. A study conducted in more than 740 patients with malignant melanoma who received IC showed that 7.3% of patients had a serious infection, from bacterial, viral, fungal infections to PJP; the main factor associated with the development of infections was the use of glucocorticoids and infliximab.27 Cases of CMV enterocolitis have also been reported in relation to immunosuppressive therapy in patients with immuno-mediated enterocolitis28 and tuberculosis,29 probably by an immune reconstitution mechanism. There are also data that seem to indicate that the use of IC is safe in patients with chronic viral infections such as hepatitis B virus or HIV infection.30 As previously mentioned, the potential use of IC is being investigated along with other therapies such as chemotherapy, monoclonal antibodies including bispecific antibodies, chimeric antigen receptor T-cells (CART) or hematopoietic stem cell transplantation.31 The use of these combinations could lead to a greater number of adverse effects, including effects on the immune system and infection susceptibility.
Chimeric antigen receptor T-cells There are still few publications that clearly address the incidence of infections in patients with new Chimeric Antigen Receptor T-cells therapies (CART cells).32,33 The risk factors for infection would be the largest number of previous treatment lines (>3–4), the infusion of high doses of CART cells (2 × 107 cells/kg) and the presence of cytokine release syndrome or severe neurotoxicity. The use of glucocorticoids at high-doses and tocilizumab would be associated with a greater infection correlation. It should be noted that between 5–9.5% of patients may present with an invasive fungal infection, and this seems to be related to treatments for the management of cytokine release syndrome. There are no clear rules regarding prevention measures. Most patients received prophylaxis with acyclovir, cotrimoxazole and micafungin in the study by Park et al.33 in patients with acute lymphoblastic leukaemia.
5
General prevention measures Although there are no universal prevention standards, there are some general measures that should ideally be carried out in all patients before the start of any cancer-specific treatment and these would be: Vaccine schedule update An excellent review on vaccination in patients receiving this type of treatment has been recently published.9 No vaccine with attenuated microorganisms should be administered. A diphtheria-tetanus-pertussis, pneumococcus, hepatitis A and B (if not immunized) and annual flu vaccination update would be recommended. Although the vaccine against Haemophilus influenzae does not appear as recommended, it could be considered individually. A recent study has shown that serological response to influenza34 and pneumococcal35 vaccination is reduced in patients treated with ibrutinib, hence the need to vaccinate before the start of any treatment. Latent infection screening Tuberculosis To rule out latent tuberculosis, either through PPD if the patient is not previously immunocompromised or with an interferon gamma release test in the immunocompromised is important. To the question of whether every patient with a positive test should receive prophylaxis there is no universal answer; the indication should be individualized based on comorbidities, patient’s age, prognosis of the underlying disease and expected treatment. Viral infections Viral serologies should be available for herpes group viruses (herpes simplex virus 1 and 2, varicella zoster virus, CMV, EpsteinBarr) prior to the start of treatment to establish the need for prophylaxis or to monitor the replication of these viruses by PCR. HIV infection should also be ruled out, which would help to start treatment as early as possible. Hepatitis virus The hepatitis A, B and C viruses deserve special mention. The baseline serological status of patients is important to proceed with vaccination before the start of treatment in seronegative cases or antiviral prophylaxis in cases where virus B replication is common (for example, rituximab). Imported infections In a study conducted at our center,36 50% of patients from non-EU areas had a latent infection. Many of them are likely to be reactivated in periods of immunosuppression leading to severe conditions, which can be avoided with adequate preventive treatment. Table 2 shows the infections that should be ruled out according to area of origin. Pneumocystis jirovecii pneumonia prevention PJP in HIV seronegative patients behaves more aggressively and is associated with higher mortality in part due to a diagnosis and the delayed introduction of treatment. On the other hand, there is no clear correlation with the number of CD4 lymphocytes, as occurs in patients with HIV infection. The risk-benefit of prophylaxis with cotrimoxazole should be assessed, which could also prevent other infections related to cellular immunity (Listeria spp., Legionella spp., Salmonella spp., Nocardia spp., Toxoplasma gondii, Haemophilus spp. etc.).37 We recommend starting prophylaxis in
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Table 2 Screening of imported infectious diseases prior to the start of a haematology-oncology treatment.
TST/IGRA, HIV, HBV, HCV, syphilis, Toxoplasma Stool culture Serology for Strongyloides stercolaris Plasmodium spp. PCR Serology for Trypanosoma cruzi Serology for Schistosoma mansoni
South America
Caribbean Islands
North Africa and the Middle East
Sub-Saharan Africa
Asia
Yes Yes Yes Amazon area Yes Brazil
Yes Yes Yes Yes No Yes
Yes Yes Yes No No No
Yes Yes Yes Yes No Yes
Yes Yes Yes Yes No No
PCR: polymerase chain reaction; TST/IGRA: tuberculin skin test/interferon gamma release analysis; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus. Adapted from Sánchez-Montalvá et al.36
patients with sustained lymphopenia (below 1000/mm3 ) or whenever glucocorticoids or other immunosuppressants are associated with biological treatments. Bacterial infections It has not been universally proven that antibiotic prophylaxis prevents bacterial infections and improves survival. It should be borne in mind that the long-term use of antibiotics and at a sub-therapeutic dose is correlated with infections by multidrugresistant microorganisms, against which our therapeutic arsenal is, today, limited. Screening for latent infections such as syphilis would be indicated in patients at risk. In summary, in the absence of existing evidence in our days and in the absence of action guidelines in patients receiving biological therapies, prevention as far as possible and early diagnosis of infections are the key to the management of our patients. Conflict of interests The authors declare no conflict of interest. References 1. Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016;91:330–40. 2. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003;101:6–14. 3. Facchinelli D, Marchesini G, Nadali G, Pagano L. Invasive fungal infections in patients with chronic lymphoproliferative disorders in the era of target drugs. Mediterr J Hematol Infect Dis. 2018;10:1–11. 4. Lanini S, Molloy AC, Fine PE, Prentice AG, Ippolito G, Kibbler CC. Risk of infection in patients with lymphoma receiving rituximab: systematic review and metaanalysis. BMC Med. 2011;9:36. 5. Ippolito G, Drgona L, Mikulska M, Lanini S, Fernández-Ruiz M, Salzberger B, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect. 2018;24:S71–82. 6. Evens AM, Jovanovic BD, Su Y-C, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22:1170–80. 7. Hilal T, Gea-Banacloche JC, Leis JF. Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections. Blood Rev. 2018;32:387–99. 8. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. Executive summary: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:309–18. 9. Peremiquel-Trillas P, Leguízamo LM, Asensio Ostos C, Martínez-Gómez X. Vacunas para pacientes en tratamiento con fármacos inmunodepresores, inmunomoduladores o biológicos. Med Clin (Barc). 2018;151:498–502. 10. Maschmeyer G, De Greef J, Mellinghoff SC, Nosari A, Thiebaut-Bertrand A, Bergeron A, et al. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL). Leukemia. 2019;33:844–62.
11. Martin SI, Gribben JG, Fiumara K, Marty FM, Baden LR, Treon SP. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis. 2006;43:16–24. 12. da Cunha-Bang C, Niemann CU. Targeting Bruton’s Tyrosine kinase across B-cell malignancies. Drugs. 2018;78:1653–63. 13. Reinwald M, Silva JT, Mueller NJ, Fortún J, Garzoni C, de Fijter JW, et al. 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:S53–70. 14. Teh BW, Tam CS, Handunnetti S, Worth LJ, Slavin MA. Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies. Blood Rev. 2018;32:499–507. 15. Varughese T, Taur Y, Cohen N, Palomba ML, Seo SK, Hohl TM, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67:687–92. 16. Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018;132:1985–8. 17. Ibrutinib: summary of product characteristics s. f. 18. Cummins KC, Cheng MP, Kubiak DW, Davids MS, Marty FM, Issa NC. Isavuconazole for the treatment of invasive fungal disease in patients receiving ibrutinib. Leuk Lymphoma. 2018:1–4. 19. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–32. 20. Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391:659–67. 21. Cuneo A, Barosi G, Danesi R, Fagiuoli S, Ghia P, Marzano A, et al. 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. 22. Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131:1704–11. 23. Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: Results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36:1973–80. 24. Shah RR. Safety and tolerability of histone deacetylase (HDAC) inhibitors in oncology. Drug Saf. 2019;42:235–45. 25. Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 2015;125:3393–400. 26. Matsuki E, Younes A. Checkpoint inhibitors and other immune therapies for hodgkin and non-hodgkin lymphoma. Curr Treat Options Oncol. 2016:17. 27. Del Castillo M, Romero FA, Argüello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis. 2016;63:1490–3. 28. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. Autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab. J Immunother. 2015;38:212–5. 29. Fujita K, Terashima T, Mio T. Anti-PD1 antibody treatment and the development of acute pulmonary tuberculosis. J Thorac Oncol. 2016;11:2238–40. 30. Ostios-Garcia L, Faig J, Leonardi GC, Adeni AE, Subegdjo SJ, Lydon CA, et al. Safety and efficacy of PD-1 inhibitors among HIV-positive patients with non–small cell lung cancer. J Thorac Oncol. 2018;13:1037–42. 31. Alatrash G, Daver N, Mittendorf EA. Targeting immune checkpoints in hematologic malignancies. Pharmacol Rev. 2016;68:1014–25. 32. Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T cell immunotherapy. Blood. 2018;131:121–30. 33. Park JH, Romero FA, Taur Y, Sadelain M, Brentjens RJ, Hohl TM, et al. 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;67:533–40.
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34. Douglas AP, Trubiano JA, Barr I, Leung V, Slavin MA, Tam CS. Ibrutinib may impair serological responses to influenza vaccination. Haematologica. 2017;102:e397–9. 35. Andrick B, Alwhaibi A, DeRemer DL, Quershi S, Khan R, Bryan LJ, et al. Lack of adequate pneumococcal vaccination response in chronic lymphocytic leukaemia patients receiving ibrutinib. Br J Haematol. 2018;182:712–4.
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36. Sanchez-Montalva A, Salvador F, Ruiz-Camps I, Barba P, Valcarcel D, Sulleiro E, et al. Imported disease screening prior to chemotherapy and bone marrow transplantation for oncohematological malignancies. Am J Trop Med Hyg. 2016;95:1463–8. 37. Bodro M, Paterson DL. Has the time come for routine trimethoprimsulfamethoxazole prophylaxis in patients taking biologic therapies? Clin Infect Dis. 2013;56:1621–8.
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www.elsevier.es/medicinaclinica
Review
Risk of infection associated with new therapies for the treatment of lymphoproliferative syndromes夽 Ibai Los-Arcos a,b , Juan Aguilar-Company a,c,⁎ , Isabel Ruiz-Camps a,b a b c
Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d’Hebron, Barcelona, Spain Red Espa˜ nola de Investigación en Patologías Infecciosas (REIPI), Instituto de Salud Carlos III, Madrid, Spain Servicio de Oncología Médica, Hospital Universitari Vall d’Hebron, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 4 June 2019 Accepted 25 July 2019 Available online xxx Keywords: Ibrutinib Idelalisib Immune checkpoint inhibitors Vaccination Rituximab Alemtuzumab
a b s t r a c t Over the last decade, there have been important developments in the treatment of lymphoproliferative disorders. Apart from conventional chemotherapy, a wide array of therapies have been developed, with different indications. The aim of this review is to evaluate the risk of infection associated with these therapies, as well as establishing prevention recommendations. In all cases, the patient’s underlying disease as well as concomitant or previous therapies have an impact in the risk of infection. Anti-CD20 antibodies (rituximab, ofatumumab and obinutuzumab) have been associated to a higher risk of bacterial and viral infection, as well as reactivation of latent infections and opportunistic infections. Alemtuzumab is associated to severe, protracted immunosuppression. Ibrutinib and acalabrutinib have been linked to bacterial infections (especially respiratory infections), invasive fungal infections and opportunistic infections. Idelalisib carries a higher risk of Pneumocystis jirovecii and infection and cytomegalovirus reactivation. Venetoclax is associated with respiratory infections and neutropenia. Immune checkpoint inhibitors are not directly associated with a higher risk of infection; nevertheless, the use of corticosteroids and immunosuppressants to control immune-related adverse events results in an increase of the risk of infection. Brentuximab, lenalidomide and HDAC inhibitors do not seem to be associated to a higher risk of infections. Although data are scarce, a higher number of infections have been observed with cellular therapies, mostly in patients with more than 3 previous antineoplastic treatments or those receiving tocilizumab or corticosteroids for managing the cytokine release syndrome. In all patients, we recommend appropriate vaccination, screening for latent infections, and individualized prophylaxis recommendations. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Riesgo de infección asociado a nuevas terapias para el tratamiento de los síndromes linfoproliferativos r e s u m e n Palabras clave: Ibrutinib Idelalisib Inhibidores del checkpoint inmune Vacunación Rituximab Alemtuzumab
En la última década se han experimentado grandes cambios en los tratamientos de los síndromes linfoproliferativos. A la quimioterapia convencional se suman ahora un amplio abanico de terapias dirigidas con diferentes indicaciones. El objetivo de esta revisión es evaluar el riesgo de infección asociado a estas terapias, así como tratar de establecer unas recomendaciones de prevención. En todos los casos, la enfermedad de base del paciente, así como los tratamientos concomitantes o los recibidos previamente impactan en el riesgo de infección. Los anticuerpos anti CD20 (rituximab, ofatumumab y obinutuzumab) se asocian a un mayor riesgo de infección bacteriana, vírica y de reactivación de infecciones latentes, así como a infecciones oportunistas. Alemtuzumab se asocia a inmunosupresión grave y mantenida. Ibrutinib y acalabrutinib se asocian a infecciones bacterianas, especialmente respiratorias, infección fúngica invasora e infecciones oportunistas. Idelalisib se asocia a un aumento de la incidencia de neumonía por
夽 Please cite this article as: Los-Arcos I, Aguilar-Company J, Ruiz-Camps I. Riesgo de infección asociado a nuevas terapias para el tratamiento de los síndromes linfoproliferativos. Med Clin (Barc). 2019. https://doi.org/10.1016/j.medcli.2019.07.026 ∗ Corresponding author. E-mail address: [email protected] (J. Aguilar-Company). ˜ S.L.U. All rights reserved. 2387-0206/© 2019 Elsevier Espana,
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Pneumocystis jirovecii y reactivación de citomegalovirus (CMV). Venetoclax se asocia a infecciones respiratorias y neutropenia. Los inhibidores de checkpoint inmune parecen no incrementar, por sí mismos, el riesgo de infección; sin embargo, el uso de glucocorticoides e inmunosupresores para controlar efectos adversos inmunorelacionados sí conlleva un aumento del número de infecciones, incluyendo infecciones oportunistas. Brentuximab, lenalidomida y los inhibidores de HDAC no parecen asociarse a un mayor riesgo de infección. Aunque existe poca experiencia en el uso de terapias celulares, se ha observado un mayor número de infecciones en pacientes que han recibido más de 3 tratamientos antineoplásicos previamente, o en aquellos que han requerido tocilizumab o glucocorticoides para el manejo del síndrome de liberación de citocinas. En todos los pacientes se recomienda una actualización del calendario vacunal, despistaje de infecciones latentes y profilaxis individualizada. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction Lymphoproliferative diseases (LPD) are a heterogeneous group of disorders of clonal origin that affect lymphoid cells (cytotoxic or helper T lymphocytes, natural killer lymphocytes, B lymphocytes or plasma cells) and that have in common the proliferation of lymphoid cells, with a tendency to invade the bone marrow and peripheral blood in addition to lymphoid organs. In the last decade there has been a considerable change in the treatment of LPD and an increase in overall survival. Biological therapies or targeted therapies have been added to conventional chemotherapy which, selectively, try to stop or, in some cases, prevent the progression of tumour cells. These therapies include a series of monoclonal antibodies, receptor analogues and small molecules designed to bind to different molecular targets.1 These drugs have advantages over chemotherapy in terms of potency and specificity and, theoretically, produce less adverse effects. However, if these drugs are correlated with a greater number of infections it is a difficult fact to establish, since there is a large number of factors that lead to confusion. First, the patient’s own hemopathy is often associated with an increased risk of infections including opportunistic infections (OI). Secondly, some of the previous treatments received cause immune disorders that persist over time, even after their discontinuation, and may increase the risk of infection. Thirdly, the effect of other drugs, either associated with the treatment, or used to control the adverse effects produced by it, and which may also increase the risk (for example, glucocorticoids), must also be added. Finally, to establish the exact correlation, it would take a very high number of patients who have received the therapy in question for a long period of time and who have developed a specific infection. Today, all of this entails difficulties when establishing prevention and prophylaxis recommendations and, on occasion, these are based more on the experience of the prescriber than on the available evidence. In this review, the existing data on infection with the new treatments for LPD will be presented, and attempts will be made to establish prevention recommendations and diagnostic strategies useful for doctors treating these patients. As a summary, risk factors, related infections and recommended preventive measures for each class of drugs are shown in Table 1.
Review by drug groups Anti-CD20, CD56, CD30 monoclonal antibodies Monoclonal anti-CD20 antibodies constitute a family of agents directed against B-cell proliferation (CD20 positive) haematological diseases and have been used alone or in combination in this context. These antibodies alter the immune response by modulating the interaction between B and T cells rather than by direct action
on humoral immunity. Rituximab is a chimeric antibody, while obinutuzumab and ofatumumab are humanized antibodies and show greater persistence in B cells and greater antibody-dependent cytotoxicity. There are a large number of confounding factors to establish direct causality with certain infectious conditions, since most patients have received previous therapies with an effect on the immune system or receive the antibody in combination with other drugs.2,3 There is a meta-analysis that confirms that there is a higher incidence of bacterial infections with the use of rituximab (although this incidence is not higher than that presented with glucocorticoids).4,5 More important is the reactivation of hepatitis B (5.7 times higher risk),6 infections by herpes or progressive multifocal leukoencephalopathy (PML)-type OI or Pneumocystis jirovecii pneumonia (PJP). Although a first meta-analysis pointed to a risk of PJP 3.57 times higher, other studies show a lower incidence (1.5–3%). The risk of real infection is determined by the combination of cancer-specific treatment that the patient receives,2 the basic pathology and associations with other drugs (mainly glucocorticoids); OIs are rare when rituximab is used alone and as an initial treatment agent.7 The association of rituximab, fludarabine and chlorambucil can cause delayed and prolonged immune-mediated type neutropenia with a not entirely clear relationship with the risk of infection. Ofatumumab and obinutuzumab have a profile of bacterial and viral infections similar to that of rituximab, although currently available data reflect a lower risk of OI. Obinutuzumab is associated with a greater number of episodes of neutropenia, which appear not to increase the risk of infection.5 There seems to be a reduced response to vaccination during treatment with anti-CD20, so it is advisable to delay it up to 6 months after the end of treatment.8 Although there are alternatives to improve the immune response in this population (high load vaccines, use of adjuvant vaccines, intradermally), there are no consistent data on its theoretical benefit.9 Brentuximab vedotin is a conjugated antibody directed against CD30 indicated in the treatment of adult patients with CD30+ Hodgkin lymphoma or relapsed or refractory anaplastic lymphoma and in cutaneous T-cell lymphoma after a first line treatment. Although it produces neutropenia, fever episodes are rare. There does not seem to be a high risk of infectious complications. The incidence of PJP is between 0.1–1% and that of herpes simplex infections or varicella zoster virus between 1–10%. PML cases have been reported, both in pivotal and post-marketing studies, which would require alertness to neurological manifestations.10 Alemtuzumab, an anti-CD52 monoclonal antibody only used nowadays in some patients with chronic lymphatic leukaemia (CLL), produces serious immune defects (with involvement of B, T and NK lymphocytes) that persist up to 9 months after the end of treatment. It has been correlated with a large number of bacterial, viral and fungal infections. The high rate of repli-
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3
Table 1 Main drugs of recent introduction in the treatment of lymphoproliferative diseases. Group
Drugs
Use
Risk of infection
Recommendations
Anti-CD20
Rituximab
B-cell LPD
Moderate
HBV reactivation screening and prophylaxis Prophylaxis for PJP in patients receiving glucocorticoids
Obinotuzumab
HBV reactivation
Ofatumumab
Increase of herpes group virus infections Increase in PJP in patients with other treatments Low
Anti-CD30
Brentuximab vedotin
Anti-CD52
Alemtuzumab
Hodgkin lymphoma Anaplastic Lymphoma Chronic lymphatic leukaemia
Some cases of PML Moderate-High Increased risk of fungal, bacterial and viral infections
Bruton tyrosine kinase inhibitors
Anti-PI3K
BCL-2 inhibitors
Ibrutinib
Mantle cell lymphoma
Moderate-High
Acalabrutinib
Chronic lymphatic leukaemia Waldeström macroglobulinemia
Increase of bacterial infections
Idelalisib
Venetoclax
Marginal zone lymphoma Chronic lymphatic leukaemia Follicular lymphoma Chronic lymphatic leukaemia
CMV monitoring Acyclovir prophylaxis for herpes group virus PJP prophylaxis Screening and prophylaxis of HBV reactivation Assess antifungal prophylaxis and/or early screening with biomarkers if other risk factors (fludarabine, alemtuzumab . . .) Prophylaxis for PJP in patients receiving glucocorticoids
Increased risk of filamentous fungal infections (especially first 3–6 months and high frequency of disseminated disease) Moderate-High
PJP prophylaxis
Increase of opportunistic infections such as PJP and CMV Low-Moderate
Monthly CMV monitoring
HDAC inhibitors
Panobinostat
Multiple myeloma
Increase the risk of neutropenia, the increased risk of infection is not clear Low
T-cell lymphomas
Possible increased risk of HBV reactivation
Anti-CTLA4
Vorinostat Belinostat Romidepsin Ipilimumab
Hodgkin lymphoma
Low.
Anti PD-1
Pidilizumab
Associated with cell therapies (under study)
Opportunistic infections (PJP, fungal or CMV infections) have been reported in patients receiving prolonged glucocorticoid treatment for the management of immune-related adverse effects.
Anti PDL-1
Prophylaxis for PJP in patients receiving glucocorticoids
Prophylaxis for PJP in patients receiving glucocorticoids.
HBV reactivation screening and prophylaxis
Prophylaxis for PJP in patients receiving glucocorticoids Early IA screening in patients receiving glucocorticoids
Nivolimumab Pembrolizumab Durvalumab Athezolizumab
IA: invasive aspergillosis; CMV: cytomegalovirus; PML: progressive multifocal leukoencephalopathy; PJP: Pneumocystis jirovecii pneumonia; LPD: lymphoproliferative disease; HBV: hepatitis B virus.
cation/cytomegalovirus disease (CMV) stands out, especially in patients who have previously received other treatment lines.5,7,11
Bruton tyrosine kinase inhibitors Ibrutinib and acalabrutinib are oral drugs that irreversibly inhibit the Bruton Tyrosine Kinase (BTK), acting in the signalling pathway of the B cell receptor (BCR). The stimulation of the transmembrane BCR protein leads to the activation of different tyrosines, including BTK and phosphatidylinositol 3-kinase (PI3K), which in turn activate proliferation and survival signals of B lymphocytes. BTK inhibitors bind to it irreversibly, thereby inducing apoptosis in tumour B-cell. The first of the BTK inhibitors marketed was ibrutinib. Currently, ibrutinib is approved for the treatment of mantle cell lymphoma, CLL, Waldeström macroglobulinemia and marginal zone lymphoma.12
Ibrutinib seems to increase the risk of developing infections,13 although this increased risk is difficult to attribute exclusively to ibrutinib. The most common infections are bacterial, and especially respiratory infections, which occur mainly in the first 6 months after the start of drug administration.14 The increase in frequency and severity of these infections is greater in patients with refractory or relapsing lymphoproliferative disease.10 Having received at least 3 antineoplastic treatments prior to the onset of ibrutinib and developing neutropenia during treatment are independent risk factors for the subsequent occurrence of serious infections.15 Although fungal infections were very rare in clinical trials, subsequent observational studies have shown an increase in them.14 These infections, as well as bacterial ones, have been described especially during the first 3 months of treatment, in patients who have received other treatment lines and in association with glucocorticoids, being exceptional when ibrutinib is used as a first-line treatment. In patients with primary central nervous sys-
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tem lymphoma, an incidence of 39% of invasive aspergillosis (IA) has been reported in a series of 18 patients.14 The clinical presentation of IA is also different, reporting a high frequency of extrapulmonary infection (25–40% of patients had central nervous system involvement).10,15 The BTK pathway in the macrophage is involved in the defence against Aspergillus spp., so its inhibition could explain the increased risk of fungal infection in these patients.16 At the present time, universal antifungal prophylaxis is not recommended. In patients with some other additional risk factor (fludarabine, alemtuzumab, use of other immunosuppressants or previous invasive fungal infection), pharmacological prophylaxis or periodic infection screening (by galactomannan, PCR, etc.) could be assessed individually.14 It is important to note the interaction of ibrutinib with potent CYP34A inhibitor drugs such as voriconazole, the main treatment of IA. It is recommended, if possible, to avoid this combination, and if not possible, reduce the dose of ibrutinib to 140 mg/day.3,17 A series of 8 patients treated with ibrutinib and isavuconazole, a new triazole with a lower risk of interactions, have been reported, this combination being well tolerated, without adverse effects.18 With regard to the PJP, the data are controversial, and the incidence of this infection is generally less than 1% except in some specific study.10 However, if ibrutinib is administered in combination with glucocorticoids or the patient received purine analogues, prophylaxis against PJP is recommended.13 On the other hand, cases of disseminated cryptococcosis as well as endemic fungal infections, miliary tuberculosis and cases of PML caused by the JC virus have also been reported.10 Acalabrutinib is a second generation BTK inhibitor, with a more selective BTK inhibition.12 In addition, it has a faster oral absorption and a shorter half-life than ibrutinib. It has been approved for the treatment of mantle cell lymphoma, but the clinical experience is limited for now. The results of 2 clinical trials have been published; in the first one, 61 patients with mantle lymphoma were included, of which 14 (23%) had upper respiratory infections and only one patient died from pneumonia.19 In the second study, 124 patients were included, of which 66 (53%) had infections, most of them mild, although 6 patients (5%) had pneumonia, one patient had PJP and another CMV viremia.20 Phosphoinositol 3-kinase inhibitors Idelalisib is a small molecule that acts as a selective inhibitor of the PI3K delta isoform in the B lymphocyte signalling pathway,13 which plays a central role in the development of these cells and is overexpressed in B-LPD. By blocking this molecule, idelalisib promotes apoptosis of B lymphocytes. Idelalisib is an oral drug approved for the treatment of CLL (associated with rituximab) and refractory follicular lymphoma10 (in monotherapy). Adverse effects such as colitis, hepatitis and pneumonitis14 requiring treatment with high-dose glucocorticoids, which in turn may increase the risk of infection21 have been described. A higher incidence of bacterial infections with idelalisib has not been described. An increased risk of presenting an OI, such as PJP and CMV disease, has been described in a characteristic way. Specifically, an increase in the frequency of PJP has been observed in patients treated with idelalisib compared to those treated with rituximab ± Bendamustine (2.5% vs. 0.2%) and also for patients treated with ofatumumab (5% vs. 1%). In addition, this increase occurs independently of the CD4 T-cell count.10 Both the European Medicines Agency and different scientific societies consider it necessary to perform universal prophylaxis against NJP in patients receiving idelalisib from the start of treatment and up to 2–6 months after its completion.13,14 As for the reactivation of CMV, it is up to 5 times more common in these patients.14 52 of 2204 patients (2.4%) showed CMV reactivation during the first 6 months of treatment
in the pivotal studies. This incidence was even higher if idelalisib was combined with bendamustine (13/208 patients; 6.3%). A serology for CMV is recommended before the start of treatment and at least a monthly monitoring of CMV viral load during the treatment and whenever there is any sign or symptom suspected for CMV disease. In addition, blood products from CMV negative or irradiated patients is recommended in CMV seronegative patients.10,13 BCL-2 inhibitors Venetoclax is a potent and selective inhibitor of BCL-2 antiapoptotic protein (B-cell lymphoma), overexpressed by tumour cells. It is used as a single agent or associated with anti-CD20 monoclonal antibodies for CLL patients pre-treated or with unfavourable cytogenetics (CD17 deletion). It is metabolized via CY3A4 and therefore has interactions with many drugs, including azoles. The main toxicity is neutropenia, which occurs in approximately 40–50% of patients in studies. The rates of severe infection, most of them respiratory, range from 6 to 33%, depending on the profile of patients included in each study (CLL in progression, recurrent neutropenia, association with rituximab, etc.).14,22 The impact on latent viral infections, such as hepatitis B, is yet to be clarified although it seems not to be superior to that of the LLC itself in patients with uncontrolled disease and who have received ibrutinib. In a pivotal study, isolated cases of herpes zoster and PJP were described in patients who had previously received fludarabine.23 However, today, prophylaxis should be individualized and based on previous infections, administered treatment lines and concomitant therapies. Histone deacetylase inhibitors Histone deacetylase (HDAC) is one of the main enzymes responsible for controlling histone acetylation and is overexpressed in different tumours. The inhibition of HDAC on the one hand, produces reduction in migration, invasion and angiogenesis and, on the other, favours the apoptosis of tumour cells. Panobinostat is approved by the FDA and the European Medicines Agency for the treatment of multiple myeloma (in combination with bortezomib and dexamethasone). Vorinostat, belinostat and romidepsin are approved by the FDA for the treatment of T-cell lymphomas, specifically; belinostat for peripheral T-cell lymphoma, vorinostat for cutaneous T-lymphomas and romidepsin for both types of lymphomas.24 HDAC inhibitors cause an inhibition of innate immunity with a theoretical increase in the risk of infection and a reduction in the inflammatory response. However, an increased risk of infection with respect to comparator groups has not been observed in clinical trials. Due to the decrease in the inflammatory response caused by these drugs, the latest ECIL guidelines recommend screening and prophylaxis for hepatitis B virus. In addition, they recommend the discontinuation of the HDAC inhibitor in case of active infection and highlight the risk that these patients have to develop interstitial pneumonitis.10 Lenalidomide Lenalidomide is an immunomodulatory agent used alone or in association with glucocorticoids or anti-CD20 monoclonal antibodies. There is no clear evidence that OI increase with their use.3,5 Prophylaxis against PJP would be indicated in associations with fludarabine and rituximab. Immune checkpoint inhibitors This group of drugs comprises monoclonal antibodies whose objective is to restore or enhance the action of the immune sys-
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tem against tumour cells. Its operation is based on the fact that tumour cells have mechanisms of immunological evasion through the usurpation of different signalling pathways or immune checkpoints (IC), such as the C 4 protein pathway of the T lymphocyte (CTLA-4) or that of programmed cell death (PD-1). These pathways are exploited by neoplastic cells, mainly by overexpression of ligands, to induce a decrease in T cell proliferation, cytotoxicity and cytokine production, contributing to generate and maintain an immunological tolerance microenvironment. The pharmacological blockade of these pathways allows to reactivate antitumor activity of the immune system.25 Currently, the main drugs in this class belong to 2 groups: the anti-PD-1/anti PDL-1 and the anti CTLA-4. In both groups there is extensive experience of use and established indications in solid organ cancer; recently, immune checkpoint (IC) inhibitors have also joined the therapeutic arsenal in haematology. Currently there are very favourable data of its use in Hodgkin lymphoma, where they have shown high response rates in patients with standard treatment-resistant disease or who have relapsed, and their use is being investigated in clinical trials against other nonHodgkin’s lymphomas as well as in association with cell therapies or hematopoietic stem cell transplantation.26 IC can trigger immune-related adverse effects in multiple organs, the most important being cutaneous, endocrinological, digestive, hepatic and pulmonary adverse effects. The treatment of these adverse effects involves in most cases the use of systemic glucocorticoids or other immunosuppressants such as infliximab or mycophenolate. Data on the risk of infections associated with the use of IC are mainly derived from studies conducted in patients with solid organ cancer. A study conducted in more than 740 patients with malignant melanoma who received IC showed that 7.3% of patients had a serious infection, from bacterial, viral, fungal infections to PJP; the main factor associated with the development of infections was the use of glucocorticoids and infliximab.27 Cases of CMV enterocolitis have also been reported in relation to immunosuppressive therapy in patients with immuno-mediated enterocolitis28 and tuberculosis,29 probably by an immune reconstitution mechanism. There are also data that seem to indicate that the use of IC is safe in patients with chronic viral infections such as hepatitis B virus or HIV infection.30 As previously mentioned, the potential use of IC is being investigated along with other therapies such as chemotherapy, monoclonal antibodies including bispecific antibodies, chimeric antigen receptor T-cells (CART) or hematopoietic stem cell transplantation.31 The use of these combinations could lead to a greater number of adverse effects, including effects on the immune system and infection susceptibility.
Chimeric antigen receptor T-cells There are still few publications that clearly address the incidence of infections in patients with new Chimeric Antigen Receptor T-cells therapies (CART cells).32,33 The risk factors for infection would be the largest number of previous treatment lines (>3–4), the infusion of high doses of CART cells (2 × 107 cells/kg) and the presence of cytokine release syndrome or severe neurotoxicity. The use of glucocorticoids at high-doses and tocilizumab would be associated with a greater infection correlation. It should be noted that between 5–9.5% of patients may present with an invasive fungal infection, and this seems to be related to treatments for the management of cytokine release syndrome. There are no clear rules regarding prevention measures. Most patients received prophylaxis with acyclovir, cotrimoxazole and micafungin in the study by Park et al.33 in patients with acute lymphoblastic leukaemia.
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General prevention measures Although there are no universal prevention standards, there are some general measures that should ideally be carried out in all patients before the start of any cancer-specific treatment and these would be: Vaccine schedule update An excellent review on vaccination in patients receiving this type of treatment has been recently published.9 No vaccine with attenuated microorganisms should be administered. A diphtheria-tetanus-pertussis, pneumococcus, hepatitis A and B (if not immunized) and annual flu vaccination update would be recommended. Although the vaccine against Haemophilus influenzae does not appear as recommended, it could be considered individually. A recent study has shown that serological response to influenza34 and pneumococcal35 vaccination is reduced in patients treated with ibrutinib, hence the need to vaccinate before the start of any treatment. Latent infection screening Tuberculosis To rule out latent tuberculosis, either through PPD if the patient is not previously immunocompromised or with an interferon gamma release test in the immunocompromised is important. To the question of whether every patient with a positive test should receive prophylaxis there is no universal answer; the indication should be individualized based on comorbidities, patient’s age, prognosis of the underlying disease and expected treatment. Viral infections Viral serologies should be available for herpes group viruses (herpes simplex virus 1 and 2, varicella zoster virus, CMV, EpsteinBarr) prior to the start of treatment to establish the need for prophylaxis or to monitor the replication of these viruses by PCR. HIV infection should also be ruled out, which would help to start treatment as early as possible. Hepatitis virus The hepatitis A, B and C viruses deserve special mention. The baseline serological status of patients is important to proceed with vaccination before the start of treatment in seronegative cases or antiviral prophylaxis in cases where virus B replication is common (for example, rituximab). Imported infections In a study conducted at our center,36 50% of patients from non-EU areas had a latent infection. Many of them are likely to be reactivated in periods of immunosuppression leading to severe conditions, which can be avoided with adequate preventive treatment. Table 2 shows the infections that should be ruled out according to area of origin. Pneumocystis jirovecii pneumonia prevention PJP in HIV seronegative patients behaves more aggressively and is associated with higher mortality in part due to a diagnosis and the delayed introduction of treatment. On the other hand, there is no clear correlation with the number of CD4 lymphocytes, as occurs in patients with HIV infection. The risk-benefit of prophylaxis with cotrimoxazole should be assessed, which could also prevent other infections related to cellular immunity (Listeria spp., Legionella spp., Salmonella spp., Nocardia spp., Toxoplasma gondii, Haemophilus spp. etc.).37 We recommend starting prophylaxis in
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Table 2 Screening of imported infectious diseases prior to the start of a haematology-oncology treatment.
TST/IGRA, HIV, HBV, HCV, syphilis, Toxoplasma Stool culture Serology for Strongyloides stercolaris Plasmodium spp. PCR Serology for Trypanosoma cruzi Serology for Schistosoma mansoni
South America
Caribbean Islands
North Africa and the Middle East
Sub-Saharan Africa
Asia
Yes Yes Yes Amazon area Yes Brazil
Yes Yes Yes Yes No Yes
Yes Yes Yes No No No
Yes Yes Yes Yes No Yes
Yes Yes Yes Yes No No
PCR: polymerase chain reaction; TST/IGRA: tuberculin skin test/interferon gamma release analysis; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus. Adapted from Sánchez-Montalvá et al.36
patients with sustained lymphopenia (below 1000/mm3 ) or whenever glucocorticoids or other immunosuppressants are associated with biological treatments. Bacterial infections It has not been universally proven that antibiotic prophylaxis prevents bacterial infections and improves survival. It should be borne in mind that the long-term use of antibiotics and at a sub-therapeutic dose is correlated with infections by multidrugresistant microorganisms, against which our therapeutic arsenal is, today, limited. Screening for latent infections such as syphilis would be indicated in patients at risk. In summary, in the absence of existing evidence in our days and in the absence of action guidelines in patients receiving biological therapies, prevention as far as possible and early diagnosis of infections are the key to the management of our patients. Conflict of interests The authors declare no conflict of interest. References 1. Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016;91:330–40. 2. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003;101:6–14. 3. Facchinelli D, Marchesini G, Nadali G, Pagano L. Invasive fungal infections in patients with chronic lymphoproliferative disorders in the era of target drugs. Mediterr J Hematol Infect Dis. 2018;10:1–11. 4. Lanini S, Molloy AC, Fine PE, Prentice AG, Ippolito G, Kibbler CC. Risk of infection in patients with lymphoma receiving rituximab: systematic review and metaanalysis. BMC Med. 2011;9:36. 5. Ippolito G, Drgona L, Mikulska M, Lanini S, Fernández-Ruiz M, Salzberger B, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect. 2018;24:S71–82. 6. Evens AM, Jovanovic BD, Su Y-C, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22:1170–80. 7. Hilal T, Gea-Banacloche JC, Leis JF. Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections. Blood Rev. 2018;32:387–99. 8. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. Executive summary: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58:309–18. 9. Peremiquel-Trillas P, Leguízamo LM, Asensio Ostos C, Martínez-Gómez X. Vacunas para pacientes en tratamiento con fármacos inmunodepresores, inmunomoduladores o biológicos. Med Clin (Barc). 2018;151:498–502. 10. Maschmeyer G, De Greef J, Mellinghoff SC, Nosari A, Thiebaut-Bertrand A, Bergeron A, et al. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL). Leukemia. 2019;33:844–62.
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