scholarly journals Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies

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.

The Impact of NOD2/CARD15, TLR and IL23R Polymorphisms on the Incidence of Infectious Complications in Allo-HSCT Recipients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2201-2201
Author(s):  
Alexandra Maria Holowiecka-Goral ◽  
Sebastian Giebel ◽  
Jerzy Wojnar ◽  
Elzbieta Pietruszka ◽  
Agnieszka Karolczyk ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Infectious Complications ◽  
Individual Risk ◽  
Unrelated Donor ◽  
X Rays ◽  
Increased Risk ◽  
Card15 Gene ◽  
The Impact

Abstract BACKGROUND: Infections and graft-vs.-host disease (GvHD) remain the major obstacles for successful allogeneic stem cell transplantation (alloHSCT). As specific immune response is profoundly suppressed during the first months after transplantation, the components of innate immunity are expected to play important role in protection against infections and modulation of GvHD. The goal of this prospective study was to evaluate the impact of NOD2/CARD15 gene, toll-like receptors (TLR), and interleukin-23 receptor (IL-23R) single nucleotide polymorphisms (SNPs), on outcome of alloHSCT, including the incidence of infectious complications and acute GvHD. All these factors were documented to take part in innate immunity. PATIENTS: One-hundred-twenty-five consecutive patients, mainly with hematological malignancies, aged 32 (18–58)y, treated with alloHSCT from HLA-matched related (n=43) or matched unrelated donor (MUD) (n=82) were analyzed. The conditioning regimen was myeloablative, GVHD prophylaxis consisted of cyclosporin, metotrexate, and, in case of MUD-HSCT, pre-transplant anti-thymocyte globulin. METHODS: Donors and recipients were tested for SNP8,12,13 of the NOD2/CARD15 gene, TLR2/753, TLR4/299, TLR4/399, TLR5/C1174T, and TLR9/1635 SNPs, as well as IL23R/11209026 SNP. Study end-points included the incidence of bacterial, fungal and clinically relevant viral infections. Infections were recognized based on clinical symptoms, microbial cultures, chest X-rays for pneumonia confirmation and in case of CMV and EBV- PCR screening. We analyzed separately infections occurring in the early, cytopenic phase and those occurring after engraftment. Additionally, the incidence of acute GvHD and survival was evaluated. RESULTS: Presence of NOD2/CARD15 SNP8 in recipient resulted in higher frequency of neutropenic pneumonia (40% vs. 6%, p=0.045) and bacterial pharyngitis (100% vs. 50%, p=0.06), as well as increased incidence of grade III-IV acute GVHD (40% vs. 7%, p=0.05), which translated into increased non-relapse mortality (60% vs. 14%, p=0.005) and decreased 2-year overall survival (20% vs. 71%, p=0.003). TLR4/299 SNP in recipient tended to increase the risk of neutropenic fever (FUO) (67% vs. 30%, p=0.06) and decrease survival (71% vs. 48%, p=0.09). TLR2/753 SNP in donor was associated with higher incidence of FUO (83% vs. 30%, p-0.01), while TLR5/C1174T SNP in recipient resulted in increased incidence of EBV infection (25% vs. 4%, p-0.05). Presence of IL23R/11209026 SNP in donor tended to increase the incidence of neutropenic pneumonias (29% vs. 6%, p=0.09). CONCLUSIONS: NOD2/CARD15, TLR, and IL23R SNPs appear to influence outcome of alloHSCT contributing to increased incidence of infections, and in case of NOD2/CARD15 SNP8 in recipient to increased risk of severe acute GVHD. The genomic analysis may allow elaboration of adequate preventive strategies based on individual risk assessment. Our results encourage for further, extended studies.

scholarly journals Diagnosis of invasive fungal infections

2012 ◽  
Vol 3 (1S) ◽  
pp. 15
Author(s):  
Anna Maria Barbui ◽  
Corrado Girmenia ◽  
Giorgio Limerutti
Keyword(s):  
Multidisciplinary Approach ◽  
Medical Decision Making ◽  
Immune Status ◽  
Fungal Infections ◽  
Underlying Disease ◽  
Infectious Complications ◽  
Invasive Fungal Infections ◽  
Disease Stage ◽  
Medical Decision ◽  
Diagnostic Strategy

A proper diagnostic strategy of invasive fungal infections (IFI) is a very important component in the management of infectious complications in hematological patients. A good diagnostic approach should be adapted to the patient in relation to the underlying disease, stage of disease, localization of infection and immune status. None of the diagnostic markers can be entirely adopted for medical decision making, and sometimes it’s useful to use the combination of several microbiological tests.The diagnosis of IFI must therefore have a multidisciplinary approach that includes clinical suspicion, microbiological results and radiological evidence.

scholarly journals Diagnosis of invasive fungal infections

2012 ◽  
Vol 3 (1S) ◽  
pp. 15-25
Author(s):  
Anna Maria Barbui ◽  
Corrado Girmenia ◽  
Giorgio Limerutti
Keyword(s):  
Multidisciplinary Approach ◽  
Medical Decision Making ◽  
Immune Status ◽  
Fungal Infections ◽  
Underlying Disease ◽  
Infectious Complications ◽  
Invasive Fungal Infections ◽  
Disease Stage ◽  
Medical Decision ◽  
Diagnostic Strategy

A proper diagnostic strategy of invasive fungal infections (IFI) is a very important component in the management of infectious complications in hematological patients. A good diagnostic approach should be adapted to the patient in relation to the underlying disease, stage of disease, localization of infection and immune status. None of the diagnostic markers can be entirely adopted for medical decision making, and sometimes it’s useful to use the combination of several microbiological tests.The diagnosis of IFI must therefore have a multidisciplinary approach that includes clinical suspicion, microbiological results and radiological evidence.

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

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

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

2021 ◽  
Vol 8 ◽  
pp. 204993612198954
Author(s):  
Isabel Ruiz-Camps ◽  
Juan Aguilar-Company
Keyword(s):  
Hematological Malignancies ◽  
Opportunistic Infections ◽  
Respiratory Infections ◽  
Fungal Infections ◽  
Checkpoint Inhibitors ◽  
Janus Kinase ◽  
Prolonged Treatment ◽  
Solid Organ ◽  
Risk Of Infection ◽  
Increased Risk

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.

scholarly journals (1, 3)-β-D-glucan assay for diagnosing invasive fungal infections in critically ill patients with hematological malignancies

Oncotarget ◽  
2016 ◽  
Vol 7 (16) ◽  
pp. 21484-21495 ◽  
Author(s):  
Elie Azoulay ◽  
Nicolas Guigue ◽  
Michael Darmon ◽  
Djamel Mokart ◽  
Virginie Lemiale ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Hematological Malignancies ◽  
Fungal Infections ◽  
Invasive Fungal Infections

scholarly journals Association of ABO haplotypes with the risk of venous thrombosis: impact on disease risks estimation

Blood ◽  
2020 ◽  
Author(s):  
Louisa Goumidi ◽  
Florian Thibord ◽  
Kerri L. Wiggins ◽  
Ruifang Li-Gao ◽  
Michael R Brown ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Blood Group ◽  
Plasma Levels ◽  
Odds Ratio ◽  
Prediction Models ◽  
Genetic Risk Score ◽  
Individual Risk ◽  
Abo Blood Group ◽  
Increased Risk ◽  
The Impact

Genetic risk score (GRS) analysis is an increasingly popular approach to derive individual risk prediction models for complex diseases. In the context of venous thrombosis (VT), any GRS shall integrate information at the ABO blood group locus, the latter being one of the major susceptibility locus for this disease. However, there is yet no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when one is interested in properly assessing the association of ABO locus with VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in up to 5,425 cases and 8,445 controls from 6 studies, we demonstrated that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal as 5% of rs8176719-delG carriers are not exposed at higher VT risk. Instead, we recommend to use 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B) and rs41302905 (O2) in any analysis aimed at assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared to O1 haplotype that can be inferred from these 4 SNPs, the A2 haplotype is associated with a modest increase in VT risk (odds ratio ~1.2), A1 and B haplotypes are associated with a ~1.8 fold increased risk while O2 tend to be slightly protective (odds ratio ~0.80). In addition, our analyses clearly showed that while the A1 an B blood group are associated with increased vWF and FVIII plasma levels only the A1 blood group is associated wih ICAM plasma levels but in an opposite direction, leaving additional avenues to be explored in order to fully understand the whole spectrum of biological effect of ABO locus on cardiovascular traits.

Allogeneic Leukocyte-Reduced Red Blood Cell Transfusion Is Associated with Postoperative Infectious Complications and Cancer Recurrence after Colon Cancer Resection

2019 ◽  
Vol 37 (2) ◽  
pp. 163-170 ◽  
Author(s):  
Andrew-Paul Deeb ◽  
Christopher T. Aquina ◽  
John R.T. Monson ◽  
Neil Blumberg ◽  
Adan Z. Becerra ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Cancer Recurrence ◽  
Infectious Complications ◽  
Oncologic Outcomes ◽  
Red Blood Cell Transfusion ◽  
Elective Resection ◽  
Increased Risk ◽  
The Impact

Background/Aims: Transfusion rates in colon cancer surgery are traditionally very high. Allogeneic red blood cell (RBC) transfusions are reported to induce immunomodulation that contributes to infectious morbidity and adverse oncologic outcomes. In an effort to attenuate these effects, the study institution implemented a universal leukocyte reduction protocol. The purpose of this study was to examine the impact of leukocyte-reduced (LR) transfusions on postoperative infectious complications, recurrence-free survival, and overall survival (OS). Methods: In a retrospective study, patients with stage I–III adenocarcinoma of the colon from 2003 to 2010 who underwent elective resection were studied. The primary outcome measures were postoperative infectious complications and recurrence-free and OS in patients that received a transfusion. Bivariate and multivariable regression analyses were performed for each endpoint. Results: Of 294 patients, 66 (22%) received a LR RBC transfusion. After adjustment, transfusion of LR RBCs was found to be independently associated with increased infectious complications (OR 3.10, 95% CI 1.24–7.73), increased odds of cancer recurrence (hazard ratio [HR] 3.74, 95% CI 1.94–7.21), and reduced OS when ≥3 units were administered (HR 2.24, 95% CI 1.12–4.48). Conclusion: Transfusion of LR RBCs is associated with an increased risk of infectious complications and worsened survival after elective surgery for colon cancer, irrespective of leukocyte reduction.

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