Invasive Fungal Infections in Acute Promyelocytic Leukemia Patients. Results of a Prospective Multicenter Study in Italy
Authors: Stamouli Maria , Busca Alessandro , Verga Luisa , Candoni Anna , Cattaneo Chiara , Nadali Gianpaolo , Mitra Maria Enza , Delia Mario , Storti Sergio , Spadea Antonio , De Paolis Maria Rosaria , Vacca Adriana , Salutari Prassede , Nosari Annamaria , Caramatti Cecilia , Castagnola Carlo , Chierichini Anna , Melillo Lorella , Facchini Luca , Di Blasi Roberta , Cesarini Monica , Garzia Maria Grazia , Martino Bruno , Perriello Vincenzo , Offidani Massimo , Picardi Marco , Vianelli Nicola , Caira Morena , Aversa Franco , Mancini Valentina , Potenza Leonardo , Fanci Rosa , Sanna Marco , Ferrari Antonella , Venditti Adriano , Pavone Vincenzo , Tumbarello Mario , Pagano Livio 
Published: October 2019

Abstract
OBJECTIVES
Aim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia.
PATIENTS AND METHODS
From January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases.
RESULTS
1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study.
Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded.
Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy.
IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment.
A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. Table 1Comparison between APL and npAML in induction phaseAPLnpAMLpNumber of pts103881Mean age51550.01m/f50/53448/433N.S.Performance status (WHO)0-1>1. 76 27. 284 597. <0.0001Central venous catheter52 (50%)687 (78%)<0.0001Neutropenia (<1000/mm3)103 (100%)874 (99%)N.S.Mean duration of neutropenia (<1000/mm3)23 days25 days0.1Mean duration of deep neutropenia (<500/mm3)17.5 days24 days0.04Antifungal prophylaxis94 (91%)837 (95%)N.S.Topical antifungal prophylaxis 17 (17%)60 (7%)0.0005Drug in prophylaxisfluconazoleitraconazoleposaconazoleother.33 (32%)13 (12%)38 (37%)1 (1%).168 (19%)117 (13%)513 (58%)23 (3%).0.002N.S. <0.0001IFIsall casesproven/probable.8 (8%)4 (4%).214 (24%)77 (9%).0.00010.08moldsall casesproven/probable.8 (8%)4 (4%).191 (22%)55 (6%).0.0006N.S.yeastsall cases.0.23 (3%). <0.0001Antifungal treatmentMean duration11 (11%)17 days275 (31%)14 days<0.0001 N.S.Overall mortality at 30 days8 (8%)110 (12%)N.S.Mortality due to IFI at 30 days1 (1%)25 (3%)N.S.
Comparing APL among them in order to identify parameters that could be correlated to IFI presentation, no significant factors were identified.
DISCUSSION
In our prospective study we specifically analyzed the incidence and the type of IFI in APL during a prolonged follow-up. Only 10 cases of IFI were documented and in most cases (6 pts) the infection was only possible. Comparing APL to npAML a lower incidence of overall IFI was observed despite less use of mold active drugs as prophylaxis. It could be attributed to the different chemotherapy (less aggressive in APL) and to lower duration of deep neutropenia. No yeast infection was observed in APL. On the basis of this study, APLs may be considered at low risk of IFI so probably the use of a mold active antifungal prophylaxis could be omitted.

Disclosures
No relevant conflicts of interest to declare.