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Using Genetic Risk Factors to Stratify Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia

English title Using Genetic Risk Factors to Stratify Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia
Applicant Bochud Pierre-Yves
Number 179636
Funding scheme Investigator Initiated Clinical Trials (IICT)
Research institution Service des Maladies Infectieuses Département de Médecine Interne CHUV
Institution of higher education University of Lausanne - LA
Main discipline Infectious Diseases
Start/End 01.06.2018 - 30.11.2022
Approved amount 2'205'222.00
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All Disciplines (2)

Discipline
Infectious Diseases
Clinical Cancer Research

Keywords (7)

Acute myeloid leukemia; Myelodysplastic syndrome; Invasive mould infections; Antifungal prophylaxis; Invasive aspergillosis; Antifungal prophylaxis; Genetic risk factors

Lay Summary (French)

Lead
Les patients traités par chimiothérapie intensive pour une leucémie aiguë sont à haut risque de développer des infections fongiques invasives (e. g. aspergilloses). La prophylaxie systématique ne constitue pas une solution optimale, puisqu'un grand nombre de patients sont traités inutilement par des médicaments pouvant avoir des effets indésirables importants et qu'elle peut conduire à l'émergence d'infections résistantes aux antifongiques. Le but de ce projet est d'utiliser l'analyse de ces polymorphismes, afin de réserver la prophylaxie aux patients à haut risque tout en évitant les effets indésirables pour les patients à moindre risque.
Lay summary
Importance

Jusqu'à 15% des patients traités par chimiothérapie intensive pour une leucémie aiguë développent une infection fongique invasive (e. g. aspergillose). Ces infections peuvent être prévenues par l'administration d'une prophylaxie antifongique. Toutefois, cette stratégie est remise en cause, car elle expose un grand nombre d'individus à des effets indésirables inutiles (toxicité, interactions avec d'autres médicaments), et peut entraîner l'émergence d'infections dues à des champignons résistants.

Intervention

Depuis quelques années, on sait que la susceptibilité aux infections fongiques est en partie déterminée par le profil génétique du patient. Dans le cadre de ce projet,  la présence ou l'absence de certains polymorphismes génétiques sera analysée au moment du diagnostic de leucémie, afin de déterminer si le patient est à haut ou bas risque de développer une infection fongique invasive. Les patients seront randomisés dans des groupes de manière différente en fonction de leur profil génétique.

Effet

Si les résultats attendus sont confirmés, l'étude permettra de démontrer qu'on peut optimiser l'administration des antifongiques chez les patient leucémiques, en réservant la prophylaxie à ceux qui sont à haut risque tout en épargnant les effets indésirables à ceux qui sont à moindre risque. Il s'agit d'un des premiers essais cliniques utilisant des facteurs génétiques du patient dans la stratification du risque infectieux, selon un concept souvent cité sous le terme de "médecine de précision".

Les résultats de cette étude pourraient s'appliquer à d'autres catégories de patients, comme les receveurs de transplantation de cellules souches hématopoïétiques (greffes de "moelle osseuse") ou les receveurs de greffes d'organes solides (cœurs ou poumons par exemple).
Direct link to Lay Summary Last update: 04.06.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Pentraxin-3 polymorphisms and invasive mold infections in acute leukemia patients receiving intensive chemotherapy
Brunel Anne-Sophie, Wójtowicz Agnieszka, Lamoth Frédéric, Spertini Olivier, Neofytos Dionysios, Calandra Thierry, Marchetti Oscar, Bochud Pierre-Yves (2018), Pentraxin-3 polymorphisms and invasive mold infections in acute leukemia patients receiving intensive chemotherapy, in Haematologica, 103(11), e527-e530.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual meeting of the Swiss Society for Infectious Diseases Talk given at a conference Personalized medicine, invasive fungal diseases 04.09.2020 Geneva, Switzerland Bochud Pierre-Yves;
9th Advances Against Aspergillosis and Mucormycosis Talk given at a conference Individualized genetic-based approach for IA prophylaxis 27.02.2020 Lugano, Switzerland Bochud Pierre-Yves;
Fongilead Talk given at a conference Infections fongiques invasives. Le déterminisme génétique de l'hôte 20.11.2019 Paris, France Bochud Pierre-Yves;
Trends in Medical Mycology (TIMM) Talk given at a conference Personnalized Medicine. Approach by genetic risk 11.10.2019 Nice, France Bochud Pierre-Yves;
American Transplant Congress Talk given at a conference Personalized Immunosuppression and Infectious Risk; Underlying Infectious Risk: Genetics 01.06.2019 Boston, United States of America Bochud Pierre-Yves;


Associated projects

Number Title Start Funding scheme
127613 Innate Immunogenetic Study of Invasive Aspergillosis in Hematopoietic Cells Transplant Recipients 01.11.2009 Project funding (Div. I-III)
192616 Immunogenetics of Viral Infections - Focus on human herpes simplex virus I 01.04.2020 Project funding (special)

Abstract

Background. Invasive mold infections (IMIs, mainly due to Aspergillus spp) are a major concern in hematological patients, such as those with acute myeloid leukemia (AML) or those undergoing hematopoietic cell transplantation (HCT), with incidence and mortality rates ranging between 3-15% and 25-45%, respectively. Primary antifungal prophylaxis has become the standard of care in such patients. Historically, fluconazole (inactive against Aspergillus spp.) was first used as prophylaxis. More recently, posaconazole (a broad-spectrum azole active against Aspergillus spp. and other non-Aspergillus filamentous molds) was approved for primary antifungal prophylaxis in high-risk patient categories. However, universal prophylaxis with posaconazole has been challenged, based on the relatively low incidence of IMI and the large number of patients needed to treat. Moreover, administration of broad-spectrum azoles is costly and associated with a large number of complications. Hence, there is an urgent need to optimize antifungal prophylaxis by identifying those patients with the highest risk for IMI to receive a broad-spectrum azole. Pentraxin-3 (PTX3), a pattern recognition receptor, recognizes and binds to Aspergillus conidia, facilitates opsonization and subsequently leads to complement and phagocyte activation. Specific PTX3 genetic single nucleotide polymorphisms (SNPs) have been identified as strong predictors for invasive aspergillosis (IA) in both animal and human studies. What makes PTX3 SNPs different and important in clinical practice is: (i) the extent and reproducibility of basic science data with regards to PTX3 and IA, (ii) the validation of PTX SNP3 associations with IA in many different patient populations, and (iii) the high frequency of minor allele in the general population. We hypothesize that PTX3 SNPs could be used to identify patients at high risk for IA, who will benefit the most by antifungal prophylaxis with broad-spectrum azoles.Aims. We will evaluate the efficacy of a stratified posaconazole antifungal prophylaxis based on IA risk by PTX3 SNPs, with the aim of optimizing protection against IA and other IMI due to non-Aspergillus filamentous molds, hereafter IMI for the purposes of this protocol. Methodology. In this Swiss multi-center prospective stratified randomised clinical trial, patients with a new diagnosis of AML will be stratified in two unbalanced strata, based on their PTX3 SNPs : stratum A (high-risk PTX3 SNPs) to be randomized 2:1 in favor of posaconazole prophylaxis vs non-posaconazole and stratum-B (low-risk PTX3 SNPs) to be randomized 1:2 in favor of non-posaconazole. Patients in the non-posaconazole arms will receive fluconazole, as standard primary antifungal prophylaxis. Patients will be enrolled at the following 5 centers in Switzerland: Cantonal Hospital of Aarau, University Hospital of Basel, University Hospital of Geneva, Cantonal Hospital of Fribourg, and University Hospital of Lausanne. In order to meet recruitment requirements, the trial associates two European academic hospitals which are highly recognized in the field: Hôpital Henri Mondor, in Créteil, France and University Hospital of Leuven in Leuven Belgium. It is estimated that 100 new patients with AML will be enrolled yearly at all these institutions. Enrolment will be performed for three years. Significance of research: The results of this study may contribute to the optimization of pri-mary antifungal prophylaxis, by preventing IA while limiting the use of broad-spectrum azoles, thus decreasing complications and costs. This study is one of the first interventional clinical trials to use genetic factors for risk stratification in the field of hematology and infectious diseases, a concept frequently emphasized, however barely transcribed in practice, as precision medicine. Furthermore, the scope of the proposed study expands beyond the specific patient population. The results of this study could be used in the design and initiation of similar efforts in other high-risk patients categories, including allogeneic HCT and solid organ transplant (SOT) recipients.
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