Risk of infection associated with targeted therapies for solid organ and hematological malignancies

Higher risks of infection are associated with some targeted drugs used to treat solid organ and hematological malignancies, and an individual patient’s risk of infection is strongly influenced by underlying diseases and concomitant or prior treatments. This review focuses on risk levels and specific suggestions for management, analyzing groups of agents associated with a significant effect on the risk of infection. Due to limited clinical experience and ongoing advances in these therapies, recommendations may be revised in the near future. Bruton tyrosine kinase (BTK) inhibitors are associated with a higher rate of infections, including invasive fungal infection, especially in the first months of treatment and in patients with advanced, pretreated disease. Phosphatidylinositol 3-kinase (PI3K) inhibitors are associated with an increased risk of Pneumocystis pneumonia and cytomegalovirus (CMV) reactivation. Venetoclax is associated with cytopenias, respiratory infections, and fever and neutropenia. Janus kinase (JAK) inhibitors may predispose patients to opportunistic and fungal infections; need for prophylaxis should be assessed on an individual basis. Mammalian target of rapamycin (mTOR) inhibitors have been linked to a higher risk of general and opportunistic infections. Breakpoint cluster region-Abelson (BCR-ABL) inhibitors are associated with neutropenia, especially over the first months of treatment. Anti-CD20 agents may cause defects in the adaptative immune response, hypogammaglobulinemia, neutropenia, and hepatitis B reactivation. Alemtuzumab is associated with profound and long-lasting immunosuppression; screening is recommended for latent infections and prevention strategies against CMV, herpesvirus, and Pneumocystis infections. Checkpoint inhibitors (CIs) may cause immune-related adverse events for which prolonged treatment with corticosteroids is needed: prophylaxis against Pneumocystis is recommended.

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1095. Investigation of Risk Factors Associated with Serious Bacterial, Viral and Invasive Fungal Infections in Hematologic Patients on Ibrutinib

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1281 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S576-S577

Author(s):

Thomas Holowka ◽

Harry Cheung ◽

Maricar F Malinis ◽

Sarah Perreault ◽

Iris Isufi ◽

...

Keyword(s):

Risk Factors ◽

Fungal Infections ◽

Antimicrobial Prophylaxis ◽

Hematologic Malignancy ◽

Invasive Fungal Infections ◽

Risk Of Infection ◽

Factors Associated ◽

Serious Infection ◽

Increased Risk ◽

Serious Infections

Abstract Background Ibrutinib is a tyrosine kinase inhibitor used to treat hematologic malignancies that may increase the risk of serious infection including invasive fungal infections (IFI). In a study of 378 patients with hematologic malignancy on ibrutinib, serious infection and IFI occurred in 11% and 4% respectively (Varughese et al. Clin Infect Dis). The primary aims of our study were to determine the incidence of serious infection and associated risk factors in patients on ibrutinib. Methods We performed a retrospective analysis of patients with hematologic malignancy prescribed ibrutinib for ≥ 1 week at Yale New Haven Hospital from 2014 to 2019 to identify serious infections defined as those requiring inpatient management. We collected demographic, clinical and oncologic data. Chi-squared tests were used to determine factors associated with an increased risk of infection. Results A total of 254 patients received ibrutinib including 156 with CLL, 89 with NHL and 9 with other leukemias. Among these, 21 underwent HSCT, 9 complicated by GVHD. There were 51 (20%) patients with serious infections including 45 (17.7%) bacterial, 9 (3.5%) viral and 5 (2%) IFI (1 pulmonary cryptococcosis, 4 pulmonary aspergillosis). Anti-mold prophylaxis was prescribed to 7 (2.8%) patients, none of whom developed IFI. Risk factors associated with serious infection included ECOG score ≥ 2 (OR 4.6, p < 0.001), concurrent steroid use (≥ 10 mg prednisone daily for ≥ 2 weeks; OR 3.0, p < 0.001), neutropenia (OR 3.6, p < 0.01), lymphopenia (OR 2.4, p < 0.05) and maximum ibrutinib dose of 560 mg (OR 2, p < 0.05). There was a dose dependent increase in infections based on number of chemotherapy regimens prior to ibrutinib initiation: 14.3% with 0, 19.7% with 1-2 and 28.7% with ≥ 3 prior treatments. Conclusion The incidence of serious infection in hematologic patients on ibrutinib was higher than previously reported (20% versus 11%) but the rate of IFI was lower (2% versus 4%). High ECOG score, leukopenia, steroids, and higher ibrutinib doses were associated with an increased risk for serious infection. Targeted antimicrobial prophylaxis should be considered for patients on ibrutinib with these risk factors. Improving functional status may also reduce the risk of infection in patients on ibrutinib. Disclosures All Authors: No reported disclosures

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Parasitic Infections Associated with Unfavourable Outcomes in Transplant Recipients

Medicina ◽

10.3390/medicina54020027 ◽

2018 ◽

Vol 54 (2) ◽

pp. 27 ◽

Cited By ~ 1

Author(s):

Wojciech Wołyniec ◽

Małgorzata Sulima ◽

Marcin Renke ◽

Alicja Dębska-Ślizień

Keyword(s):

Bone Marrow ◽

Opportunistic Infections ◽

Immunosuppressive Treatment ◽

Parasitic Infection ◽

Parasitic Infections ◽

Solid Organ ◽

Tropical Countries ◽

Real Risk ◽

Increased Risk ◽

Disseminated Disease

Introduction. The immunosuppression used after transplantation (Tx) is associated with an increased risk of opportunistic infections. In Europe, parasitic infections after Tx are much less common than viral, bacterial and fungal ones. However, diseases caused by parasites are very common in tropical countries. In the last years the number of travellers with immunosuppression visiting tropical countries has increased. Methods. We performed a literature review to evaluate a risk of parasitic infections after Tx in Europe. Results. There is a real risk of parasitic infection in patients after Tx travelling to tropical countries. Malaria, leishmaniasis, strongyloidiasis and schistosomiasis are the most dangerous and relatively common. Although the incidence of these tropical infections after Tx has not increased, the course of disease could be fatal. There are also some cosmopolitan parasitic infections dangerous for patients after Tx. The greatest threat in Europe is toxoplasmosis, especially in heart and bone marrow recipients. The most severe manifestations of toxoplasmosis are myocarditis, encephalitis and disseminated disease. Diarrhoea is one of the most common symptoms of parasitic infection. In Europe the most prevalent pathogens causing diarrhoea are Giardia duodenalis and Cryptosporidium. Conclusions. Solid organ and bone marrow transplantations, blood transfusions and immunosuppressive treatment are associated with a small but real risk of parasitic infections in European citizens. In patients with severe parasitic infection, i.e., those with lung or brain involvement or a disseminated disease, the progression is very rapid and the prognosis is bad. Establishing a diagnosis before the patient’s death is challenging.

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ANTIFUNGAL PROPHYLAXIS IN IMMUNOCOMPROMISED PATIENTS

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2016.040 ◽

2016 ◽

Vol 8 ◽

pp. e2016040 ◽

Cited By ~ 9

Author(s):

Lourdes Vazquez

Keyword(s):

Gold Standard ◽

Concomitant Medication ◽

Hematological Malignancies ◽

Fungal Infections ◽

Antifungal Prophylaxis ◽

Antifungal Drugs ◽

Risk Of Infection ◽

Scientific Societies ◽

Hematopoietic Stem ◽

Poor Efficacy

Invasive fungal infections (IFIs) represent significant complications in patients with hematological malignancies. Chemoprevention of IFIs may be important in this setting, but most antifungal drugs have demonstrated poor efﬁcacy, particularly in the prevention of invasive aspergillosis. Antifungal prophylaxis in hematological patients is currently regarded as the gold standard in situations with a high risk of infection, such as acute leukemia, myelodysplastic syndromes, and autologous or allogeneic hematopoietic stem cell transplantation. Over the years, various scientific societies have established a series of recommendations for antifungal prophylaxis based on prospective studies performed with different drugs. However, the prescription of each agent must be personalized, adapting its administration to the characteristics of individual patients and taking into account possible interactions with concomitant medication.

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Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting

The Journal of Rheumatology ◽

10.3899/jrheum.161270 ◽

2017 ◽

Vol 45 (2) ◽

pp. 170-176 ◽

Cited By ~ 10

Author(s):

Arthur N. Lau ◽

Matthew Wong-Pack ◽

Rod Rodjanapiches ◽

George Ioannidis ◽

Sally Wade ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Opportunistic Infection ◽

Opportunistic Infections ◽

Biologic Agent ◽

Risk Of Infection ◽

Group 4 ◽

Concurrent Use ◽

Serious Infection ◽

Increased Risk ◽

Group 3

Objective.Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone.Methods.A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded.Results.A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period.Conclusion.This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.

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Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios

Cancers ◽

10.3390/cancers13194750 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4750

Author(s):

Francesca Palandri ◽

Massimo Breccia ◽

Valerio De Stefano ◽

Francesco Passamonti

Keyword(s):

Hematological Malignancies ◽

Myeloproliferative Neoplasms ◽

Published Data ◽

Future Scenarios ◽

Risk Of Infection ◽

Immunosuppressive Activity ◽

Chronic Myeloproliferative Neoplasms ◽

Increased Risk ◽

Abrupt Discontinuation ◽

Case Basis

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.

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Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies

Journal of Fungi ◽

10.3390/jof7121058 ◽

2021 ◽

Vol 7 (12) ◽

pp. 1058

Author(s):

Jessica S. Little ◽

Zoe F. Weiss ◽

Sarah P. Hammond

Keyword(s):

Targeted Therapies ◽

Hematological Malignancies ◽

Fungal Infections ◽

High Risk Patient ◽

Underlying Disease ◽

Infectious Complications ◽

Invasive Fungal Infections ◽

Individual Risk ◽

Increased Risk ◽

The Impact

The use of targeted biologic therapies for hematological malignancies has greatly expanded in recent years. These agents act upon specific molecular pathways in order to target malignant cells but frequently have broader effects involving both innate and adaptive immunity. Patients with hematological malignancies have unique risk factors for infection, including immune dysregulation related to their underlying disease and sequelae of prior treatment regimens. Determining the individual risk of infection related to any novel agent is challenging in this setting. Invasive fungal infections (IFIs) represent one of the most morbid infectious complications observed in hematological malignancy. In recent years, growing evidence suggests that certain small molecule inhibitors, such as BTK inhibitors and PI3K inhibitors, may cause an increased risk of IFI in certain patients. It is imperative to better understand the impact that novel targeted therapies might have on the development of IFIs in this high-risk patient population.

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Checkpoint inhibition in immunosuppressed or immunocompromised patients with advanced cutaneous squamous cell carcinoma (CSCC): Data from prospective CemiplimAb-rwlc Survivorship and Epidemiology (C.A.S.E.) study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9547 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9547-9547

Author(s):

Guilherme Rabinowits ◽

Soo J Park ◽

David M. Ellison ◽

Francis P. Worden ◽

Rhonda W. Gentry ◽

...

Keyword(s):

Clinical Trials ◽

Checkpoint Inhibitors ◽

Hematologic Malignancy ◽

Objective Response ◽

Organ Transplant ◽

Immunosuppressed Patient ◽

Solid Organ ◽

Immunocompromised Patients ◽

Increased Risk ◽

Initial Cohort

9547 Background: Immunosuppressed and/or immunocompromised patients are at increased risk for solid tumors and cutaneous malignancies. Limited data exist on the safety and effectiveness of immune checkpoint inhibitors (ICIs) in these patients because they are frequently excluded from clinical trials. Here, we describe the safety and effectiveness results from the initial cohort of immunosuppressed and/or immunocompromised patients with advanced CSCC enrolled in the C.A.S.E. study (NCT03836105). Methods: C.A.S.E. is a prospective, real-world, multi-center, longitudinal study evaluating the effectiveness, safety, quality of life, and survivorship in patients with advanced CSCC treated with cemiplimab. Patients received cemiplimab 350 mg intravenously every 3 weeks per routine standard of care. Patient demographics, disease characteristics, immunosuppression, and relevant medical history were collected. Immunosuppressive regimens varied amongst patients. Investigator assessment of objective response rate (ORR), safety, and tolerability was conducted. Data from 26 immunosuppressed and/or immunocompromised patients with advanced CSCC treated with cemiplimab are presented. Recruitment is ongoing. Results: As of November 17, 2020, 121 patients were enrolled in the C.A.S.E. study, of which 26 patients (median age: 74 years [IQR: 71-84]; 85% male; 89% Caucasian) were designated as immunocompromised or immunosuppressed due to a history of solid organ transplant (n = 6), autoimmune disorder (n = 11), or hematologic malignancy (n = 9). Median duration of cemiplimab exposure was 14 months (IQR: 9.1–42, range: 0, 67). Among 19 immunocompromised or immunosuppressed patients who enrolled in C.A.S.E. prior to their third dose of cemiplimab, ORR per investigator assessment was 47% (95% CI: 24–71); 1 (5%) patient had complete response; 8 (42%) had partial response. One patient had a treatment-related serious adverse reaction of organ transplant rejection. One (3.8%) patient discontinued treatment due to increased alanine aminotransferase (not treatment-related). Immune-related AEs (irAEs) occurred in 23% of patients. No treatment-related AEs led to death. Conclusions: The safety, tolerability, and effectiveness of cemiplimab in this initial cohort of immunosuppressed and/or immunocompromised patients with advanced CSCC appear to be consistent with those observed in clinical trials that excluded these patients. Further follow-up and additional data would add to our general understanding of safety and effectiveness of anti-PD1 therapy in immunocompromised and/or immunosuppressed patient populations overall. Clinical trial information: NCT03836105.

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Indirect Effects of Cytomegalovirus Infection

European Oncology & Haematology ◽

10.17925/eoh.2009.03.1.41 ◽

2009 ◽

Vol 03 (01) ◽

pp. 41 ◽

Cited By ~ 1

Author(s):

Götz Ulrich Grigoleit ◽

Markus Kapp ◽

Hermann Einsele ◽

◽

...

Keyword(s):

Indirect Effects ◽

Opportunistic Infections ◽

Organ Transplant ◽

Clinical Manifestations ◽

Treatment Strategies ◽

Haematopoietic Stem Cell ◽

Solid Organ ◽

Direct Effects ◽

Cmv Infection ◽

Increased Risk

Primary cytomegalovirus (CMV) infection often presents as an asymptomatic self-limiting disease in immunocompetent individuals and is followed by latent persistence in different host tissues. However, solid organ transplant (SOT) recipients and patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of life-threatening complications caused by CMV infection. Direct effects (or CMV disease) are marked by viral proliferation in a variety of tissues and organs. Clinical manifestations that are observed after SOT and alloHSCT are gastroenteritis, pneumonitis, hepatitis, uveitis, retinitis, encephalitis and graft rejection. In contrast to the direct effects, indirect effects are a consequence of the maintenance of persistent low-level viral replication and have been associated with an increased risk of rejection and graft dysfunction, graft-versus-host disease, accelerated atherosclerosis, opportunistic infections, malignancies, posttransplant diabetes and Guillain-Barré syndrome. This article aims to summarise these indirect effects of CMV, their possible causes and possible treatment strategies.

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1729. Profiling Human Neutrophil Functional Responses From Solid-Organ and Stem Cell Transplant Recipients to Candida albicans

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1592 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S634-S634

Author(s):

Nicolas Barros ◽

Natalie Alexander ◽

Adam Viens ◽

Alex Hopke ◽

Sally Knooihuizen ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Human Neutrophil ◽

Stem Cell Transplant ◽

Fungal Infections ◽

Human Neutrophils ◽

Solid Organ ◽

Cell Transplant ◽

Functional Responses ◽

Increased Risk

Abstract Background Solid-organ (SOT) and stem cell transplant (SCT) recipients are at increased risk of invasive fungal disease despite normal neutrophil counts in peripheral blood. However, the neutrophils function against fungi has not been completely defined. In this study, we measure human neutrophil anti-candida activity in SOT and SCT recipients. Methods SOT and SCT patients were identified and consented from September 2018 until April 2019. Healthy control patients (HC) were identified at primary care clinics. EDTA-anticoagulated peripheral blood was obtained from healthy and transplant patients 2–4 months post-transplant. Neutrophils were isolated by negative selection. C. albicans was incubated for 2 hours with and without human neutrophils at multiplicity of infection (MOI) of 10, 5 and 1. Following neutrophil cell lysis, percent remaining live Candida was measured using a viability dye. In addition, growth inhibition of C. albicans by neutrophil swarming to C. albicans spotted onto glass slide arrays was also assessed by live cell imaging. Results 22 SOT (15 kidneys, 7 livers), 20 SCT (allograft) and 22 HC were enrolled. Neutrophils from SCT and SOT had lower C. albicans killing percentages compared with HC at MOI 10 (HC: 47%, SOT: 29%, SCT 24% P = 0.0041); MOI 5 (HC: 72%, SOT: 35%, SCT 38% P < 0.0001) and MOI 1 (HC: 91%, SOT: 48%, SCT: 45% P < 0.0001). Neutrophil swarming and fungal control of C. albicans spots was significantly inhibited by neutrophils from SCT when compared with SOT and controls (P <0.0001). Analysis of medications, including tyrosine kinase inhibitor (TKI) use, did not demonstrate significant differences of a specific drug class when patient groups are compared (SCT vs. SOT). Conclusion Our study indicates that despite normal circulating numbers, neutrophils from SOT and SCT recipients are dysfunctional and show profoundly impaired anti-Candida activity. There were no medications or laboratory values that predicted functional neutrophil outcome. These data strongly support the use of functional neutrophil profiling to risk stratify those individuals at higher risk for invasive fungal infections. Disclosures All authors: No reported disclosures.

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Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update

Diagnostics ◽

10.3390/diagnostics11050875 ◽

2021 ◽

Vol 11 (5) ◽

pp. 875

Author(s):

Katya Prakash ◽

Aditya Chandorkar ◽

Kapil K. Saharia

Keyword(s):

Opportunistic Infections ◽

Organ Transplant ◽

Solid Organ Transplant ◽

High Risk Population ◽

Cell Mediated Immunity ◽

Specific Cell ◽

Solid Organ ◽

Cmv Infection ◽

Current Standard ◽

Increased Risk

Cytomegalovirus (CMV) is one of the most important opportunistic infections in solid organ transplant (SOT) recipients. However, current techniques used to predict risk for CMV infection fall short. CMV-specific cell mediated immunity (CMI) plays an important role in protecting against CMV infection. There is evidence that assays measuring CMV-CMI might better identify SOT recipients at risk of complications from CMV compared to anti-CMV IgG, which is our current standard of care. Here, we review recently published studies that utilize CMV-CMI, at various points before and after transplantation, to help predict risk and guide the management of CMV infection following organ transplantation. The evidence supports the use of these novel assays to help identify SOT recipients at increased risk and highlights the need for larger prospective trials evaluating these modalities in this high-risk population.

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