Incidence of Breakthrough Invasive Fungal Infections after Posaconazole Prophylaxis in Allogeneic Stem Cell Transplant Patients
Authors: Ahmed Rayaz , Thakur Sanghmitra , Kapoor Jyotsna , Agrawal Narendra , Mehta Pallavi , Thekuddan Shinto Francis , Garg Ambar , Bhurani Dinesh 
Published: October 2019

Abstract
Background - Invasive fungal infection (IFI) is a complication found in most of the allogeneic stem cell transplant (AlloSCT) recipients leading to high number of morbidity and mortality. Posaconazole, a broad spectrum, second generation triazole compound with antifungal activity, was approved by the FDA for prophylactic use against invasive Aspergillus and Candida infections in immunocompromised patients. The aim of this retrospective observational single centre study is to investigate the incidence of IFI and to determine the various risk factors for IFI in patients within 30 days of AlloSCT who had received posaconazoleprophylaxis in Indian subcontinent.
Methods - This study includes the data of all adult patients (>18 years) without history of fungal infection who underwent AlloSCT at the Rajiv Gandhi Cancer Institute and Research Centre- tertiary cancer care center, New Delhi, between January 2015 and December 2017, and received antifungal prophylactic therapy with thrice daily posaconazole in the form of syrup since day +5 of AlloSCT till the antifungal therapy is changed to Amphotericin or Caspofungin for empirical or probable/ possible/proven IFI. All IFI's were classified in accordance with EORTC/MSG criteria into possible, probable or proven IFI. Statistical analyses were performed using SPSS version 21 (IBM, Armonk, NY, USA).
Results - During the study period, 50 patients were found to be eligible out of 181. The median(range) of eligible patients was 37 (18-58) years with a male to female ratio of 2.6 :1 (Table 1). Ninety six percent of patients achieved engraftment at a median of 15(11-30) days. Within 30 days of AlloSCT, 78% patients developed prolonged neutropenia (neutropenia for more than 7 days), while 86% patients developed febrile neutropenia . Mucositis, VOD, GVHD, pulmonary complications within 30 days developed in 56%, 6%,8%, and 16% of patients respectively. Bacterial infection and CMV reactivation within 30 days developed in 62% and 20% of patients respectively.
Incidence of breakthrough IFI was 10% (n=5) of patients [possible IFI= 60% (n=3), probable IFI= 40% (n=2)], which developed at a median of 17 (9-29) days. Antifungal therapy was changed in 15 patients (30%) because of oral and abdominal mucositis, emperical treatment for febrile neutropenia, TRALI (Acute lung injury), and breakthrough IFI in 5 (10%), 4 (8%), 1 (2%) and5 (10%)patients respectively.IFI resolved in 4 patients (80%), while 1 patient expired due to regimen related toxicity (10%). After 30 days of AlloSCT, 94% of patients were alive, while 6% (n=3) patients expired because of bacterial infection (n=1) and regimen related toxicity (n =2). At a median follow up of 337 (32-1139) days, estimated 2-year Overall Survival (OS) is 56%. IFI did not had any significant difference on the OS and Event Free Survival (EFS). On univariate analysis, no significant difference was found in the development of IFI on the basis of sex mismatched, blood group mismatched, related transplants, matched transplants, conditioning regimen (Myeloablative + reduced intensity vs non myeloablative), presence of prolonged neutropenia, pulmonary complications, hemorrhagic cystitis, acute GVHD ( grade II-IV), mucositis. Bacterial infection within 30 days was found to have a trend towards development of IFI (p=0.06).
Conclusion - Results from this retrospective analysis from a single centre showed the lesser incidence of IFI after posaconazole prophylaxis derived from a small sample size within 30 days of AlloSCT. Therefore, we may conclude that posaconazole prophylaxis may serve as an antifungal prophylactic choice for alloSCT recipients without prior fungal infection. Incidence of breakthrough IFI reported here are similar to that reported in comparative studies of fluconazole and posaconazole prophylaxis in alloSCT recipients.

Disclosures
No relevant conflicts of interest to declare.