Antifungal Treatment Duration in Hematology Patients With Invasive Mold Infections: A Real-life Update

Abstract Background Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised. Methods This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010–31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation. Results In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5–348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P = .85) or by center (P = .92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P = .004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1–3; range, 1–8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression. Conclusions AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression.

As easy as it may be to initiate empirical or targeted treatment for an invasive mold infection (IMI), discontinuing treatment may be a much more complex and difficult decision to make in clinical practice.Historically, antifungal treatment duration for IMI has been set at 12 weeks in the setting of clinical trials, with real-life data remaining scarce [1][2][3][4][5][6][7][8][9].International guidelines and experts' opinions suggest a minimum of 3 to 6 months of antifungal treatment in patients with invasive aspergillosis (IA) and mucormycosis, respectively, based on treatment response and the patient's net immunosuppression status, with European guidelines referring to treatment durations as long as 50 weeks [10][11][12][13].However, treatment response and assessment of immune function remain poorly defined, allowing for wide interpretations and leading to variable treatment durations [1][2][3]14].Additionally, long treatment courses in complex patient populations, such as patients with hematologic malignancies and recipients of allogeneic hematopoietic cell transplant (HCT), may lead to frequent changes of antifungal agents due to reasons related to clinical efficacy and/or toxicities with potential impact on clinical outcomes [9].In a singlecenter cohort of allogeneic HCT recipients with IMI, 2 changes of antifungal treatment on average (range, 0-8) were reported, with at least 1 antifungal change observed in 86% of cases [9].Various reasons prompted those changes, such as clinical efficacy, toxicity, drug interactions, and logistical reasons.To further investigate the challenges associated with administration of antifungal treatment in a different high-risk patient population, we performed a retrospective study reviewing antifungal therapy courses of patients with acute myelogenous leukemia (AML) diagnosed with an IMI in 3 Swiss hematology centers.

Study Design and Objectives
This observational retrospective multicenter cohort study comprised all consecutive adult patients (≥18 years old) with AML, diagnosed with a proven/probable IMI from 1 January 2010 to 31 December 2022.Patients were identified through the relevant institutional databases from 3 university hospitals in Switzerland (Basel, Geneva, Lausanne).Proven and probable IMIs were defined per consensus definitions [15].For patients who had an allogeneic HCT, only infections diagnosed prior to the HCT were included.For patients with >1 IMI, only the first was considered.The study was approved by the local ethics committees.The primary objective was to describe the duration and number of changes of antifungal treatment.Treatment duration was defined as the time of uninterrupted mold-active agent administration starting with the diagnosis of an IMI.Given the retrospective nature of this study, it was not possible to differentiate between primary antifungal treatment and secondary antifungal prophylaxis, and both were included in the assessment of the overall duration of antifungal treatment for an IMI.For secondary objectives, we describe the reasons for antifungal treatment: adjustment (categorized as clinical efficacy, toxicity, and logistical reasons), continuation beyond 90 and 180 days, and discontinuation.Treatment selection reasons were arbitrarily divided in 3 major categories as previously described by our group and as assessed by the treating physicians and documented in the patients' charts [1].Clinical efficacy reasons prompting a specific treatment selection, as initial treatment or treatment change, included de-escalation for clinical improvement, escalation for clinical deterioration, targeted treatment for a clinical suspicion of IA or non-IA IMI, or a change attributed to subtherapeutic azole trough concentrations.Toxicity leading to treatment selection included liver or renal function impairment, neurotoxicity, or drug interactions.When a certain agent was selected as initial antifungal treatment based on an underlying pathology (eg, renal or liver impairment, potential drug interactions), toxicity was chosen as the reason of initial treatment selection rather than clinical efficacy.Logistical reasons consisted of changes due to insurance coverage or to facilitate patient discharge (eg, when changing intravenously to orally administered treatment).

Data Collection
Pertinent data were retrospectively collected at all 3 centers through electronic medical records and entered into an electronic case report form stored on a REDCap electronic database [16,17].Data were collected for variables related to AML, IMI (antifungal prophylaxis administration within 30 days prior to IMI diagnosis, date of diagnosis, site of infection, pathogen), and antifungal treatment.Chest and/or sinus computed tomography and the following laboratory variables were collected at 90 and 180 days and at end of treatment (EOT): absolute neutrophil count, absolute lymphocyte count, CD4 count, platelet count, immunoglobulins, glomerular filtration rate, alanine aminotransferase, and γ-glutamyltransferase.Finally, chart documentation of treatment discontinuation at EOT by hematology and infectious disease services was recorded.

Statistical Analysis
Study data were collected and managed by REDCap electronic data capture tools hosted at Geneva University Hospital.Descriptive statistics were used to characterize the study sample.Median and IQR were calculated for continuous variables and frequencies and percentages for categorical variables.Statistical analysis was performed with Stata (release 16; StataCorp), and figures were generated with Prism (version 8.0; GraphPad).

DISCUSSION
This retrospective multicenter study demonstrates the complexity and challenges associated with the treatment of IMI in high-risk populations, such as patients with AML.Our observations suggest that prolonged treatment courses are frequently administered in hematology patients with IMI.We report that treatment duration was on average >6 months, at times as long as 1 year, regardless of the type of IMI or treating center.This is consistent with previous real-life data reported in allogeneic HCT recipients [9].In fact, treatment was much longer in patients who underwent an allogeneic HCT vs patients with AML who did not undergo transplantation.In the latter, treatment might have been discontinued because they died before an HCT or they had a favorable AML prognosis with treatment completion by the end of chemotherapy with resolution of neutropenia, the major risk factor in this patient group.In contrast, patients with AML and a subsequent allogeneic HCT might have continued treatment due to prolonged severe immunosuppression associated with their underlying malignancy, conditioning regimen, and posttransplant complications such as graft-vs-host disease (GvHD) and treatment.As is well known, HCT recipients with GvHD undergoing treatment with highdose corticosteroids or other immunosuppressive therapies are at higher risk for IMI, including primary or relapsing infections.This might be one of the reasons for continuing antifungal treatment in this subgroup of patients.In fact, treatment was continued beyond 90 and 180 days in most patients owing b P value compares IA vs non-IA.c Information for 1 patient with non-IA IMI was limited to 3 days of monotherapy; additional information after day 3 was not available.This patient was included under monotherapy and accounted for a total treatment duration of 3 days.d One patient with non-IA IMI was treated with combination therapy including liposomal amphotericin-B and an echinocandin.e Clinical efficacy reasons prompting a specific treatment selection, either as initial treatment or as treatment change, included de-escalation for clinical improvement, escalation for clinical deterioration, targeted treatment for a clinical suspicion of IA or non-IA IMI, or a change due to subtherapeutic azole trough concentrations.Toxicity leading to treatment selection included liver or renal function impairment, neurotoxicity, or drug interactions.When a certain agent was selected as an initial antifungal treatment based on an underlying pathology (eg, renal or liver impairment, potential drug interactions), toxicity, rather than clinical efficacy, was chosen as the reason of initial treatment selection.Other reasons included changes due to insurance coverage or to facilitate patient discharge (eg, when changing from intravenously to orally administered treatment).f Concomitant invasive candidiasis (n = 1), neutropenic enterocolitis (n = 1), and unknown reason (n = 4).g Information was available for 61 patients overall.
to transition to an allogeneic HCT and/or continuation of an administered immunosuppressive treatment.Considering the large number of patients with a clinical response in our series, treatment prolongation was predominately based on persistent immunosuppression.This is consistent with current guidelines suggesting that treatment discontinuation be tailored by clinical response and the patient's immunosuppression status, although this combination has never been validated in the context of clinical trials, where a duration of 12 weeks of treatment has been historically and uniquely studied [4-8, 10-13, 18].
Prolonging administration of antifungal agents after treatment completion may represent secondary prophylaxis, used to prevent infection relapse in states of persistent immunosuppression [18].Although a term frequently used, secondary antifungal prophylaxis remains poorly defined and requires clarification in terms of administration (when, how, and for how long) [18].Notably, international guidelines suggest that secondary prophylaxis be administered in patients with continued immunosuppression.However, we are lacking clear-cut definitions for what are the degree and duration of immunosuppression that would warrant prolongation of antifungal agent administration.This is a field that requires continuous efforts and research to optimally define the net state of immunosuppression that would be considered safe enough to discontinue antifungal treatment or prevention.Given the retrospective nature of this study, it was not feasible to discern from patients' charts at which point treatment was transitioned to secondary prophylaxis.In a recent cross-sectional internet-based questionnaire survey from Europe, the majority of clinicians treating hematology patients with IMI employed secondary prophylaxis, in most cases until the end of the immunosuppressive   regimen [3].The study clearly showed that, whether it refers to antifungal treatment or secondary prophylaxis, treatment interruption remains problematic for most physicians, who would appreciate an algorithm to help decision making in the setting [3].

Table 2. Reasons Leading to Changes of Antifungal Treatment in 71 Patients With Acute Myelogenous Leukemia With Proven/Probable Invasive Mold Infections
Notably and although suggested by guidelines and commonly used in clinical practice, immune status assessment remains loosely defined.In addition to the administration of immunosuppressive treatments such as chemotherapy and GvHD prophylaxis or treatment, laboratory tests may occasionally be used to help clinicians better evaluate the net immune status of their patients.For instance, CD4 counts have been routinely used in the evaluation of patients with HIV as a surrogate of their immune function.We reviewed white blood cell, absolute neutrophil, absolute lymphocyte, platelet, and CD4 counts as well as immunoglobulins of patients treated for an IMI at EOT and by 3 and 6 months postdiagnosis.Although most patients had robust white blood cell, absolute neutrophil, and platelet counts, they remained lymphopenic even at EOT.However, higher absolute lymphocyte and CD4 counts were noted at EOT as compared with day 90 and 180 after treatment initiation.The latter may merely represent the natural evolution of lymphocyte count reconstitution at a distance posttransplant.There are no current data on the threshold of absolute lymphocyte or CD4 count or the doses of immunosuppressive treatment beyond which treatment could be safely discontinued.This is a field where more data are needed to better define easy-to-use tools of immune reconstitution evaluation in the decisionmaking process of antifungal treatment discontinuation.Most patients in our cohort had at least 1 treatment change, with a range of up to 8 changes during their treatment, similar to findings reported by Roth et al [9].Variability was observed in the number of changes reported at different centers, likely reflecting differences in patient populations and local clinical practices.No significant differences were observed in the number of changes between IA and non-IA IMI, although there was a trend for fewer changes in AML cases without an allogeneic HCT as compared with those with one.This could be, in part, attributed to the longer survival of the latter patient group and the potential drug interactions between azoles and conditioning regimens observed in transplant recipients.In fact, drug interactions accounted for most toxicity-related causes that prompted treatment changes.
This study has many limitations, such as the small number of patients, retrospective design, and lack of data for all patients at all time points.In addition, information on neutropenia duration was not collected or reported.However, considering the long duration of antifungal treatment administration, it is less likely that the latter was associated to persistence of neutropenia but rather the other factors listed in this study, including administration of immunosuppressive treatment due to an allogeneic HCT and/ or GvHD.Yet, it remains one of the few real-life studies describing the complexities and current issues in antifungal treatment of IMI in high-risk patients.Our data point to the urgent need for better tools, definitions, and clinical algorithms to support clinicians to decide when and how to stop antifungal treatment.Of particular interest remains the field of assessing the clinical response and immune status of high-risk patients treated for IMI and the definition of treatment vs secondary prophylaxis in that context.

Antifungal
Treatment and Duration in Hematology Patients • OFID • 1Open Forum Infectious DiseasesM A J O R A R T I C L E

Figure 1 .
Figure 1.Presentation of antifungal treatment duration: A, type of invasive mold infection (IA vs not; P = .85);B, administration of an allogeneic HCT or not (P = .004);C, center (P = .92).Results are presented as whisker plots, with lines representing the median and 25% and 75% percentiles.CHUV, University Hospital of Lausanne; HCT, hematopoietic cell transplant; HUG, University Hospital of Geneva; IA, invasive aspergillosis; USB, University Hospital of Basel.

Figure 2 .
Figure 2. Presentation of antifungal treatment number of changes: A, diagnosis of invasive mold infection (IA vs not; P = .42);B, administration of an allogeneic HCT or not (P = .12);C, center (P = .001).Results are presented as whisker plots, with lines representing the median and 25% and 75% percentiles.CHUV, University Hospital of Lausanne; HCT, hematopoietic cell transplant; HUG, University Hospital of Geneva; IA, invasive aspergillosis; USB, University Hospital of Basel.

NotesFigure 3 .
Figure 3. Kaplan-Meier survival curves depicting all-cause mortality at 1-year after IMI diagnosis in patients: A, administration of an allogeneic HCT or not (log-rank test, P = .01);B, center (log-rank test, P = .28).CHUV, University Hospital of Lausanne; HCT, hematopoietic cell transplant; HUG, University Hospital of Geneva; USB, University Hospital of Basel.

Table 1 . Antifungal Treatment Administered in 71 Patients With Acute Myelogenous Leukemia Diagnosed With Proven or Probable Invasive Mold Infections
Data are presented as median (IQR) or No. (%).Abbreviations: IA, invasive aspergillosis; IMI, invasive mold infection.a There were 2 mixed infections due to Aspergillus fumigatus and Mucorales, which are considered in the non-IA group in this table.

Table 3 . Clinical and Immunologic Parameters at EOT and for Patients Whose Treatment Continued Beyond Day 90 and 180
Abbreviations: EOT, end of treatment; IA, invasive aspergillosis; ID, infectious diseases.aDatawere not available for all patients at EOT or by day 90 and 180 after treatment initiation.bTreatmentcontinuation reasons were not mutually exclusive, meaning that treatment could have been continued due to >1 reason per patient.Allogeneic hematopoietic cell transplant and disease relapse were included as part of continued immunosuppressive treatment.cThefollowing were the only statistically significant results comparing laboratory variables: EOT vs day 90 for absolute lymphocyte count, P = .008;EOT vs day 180 for absolute lymphocyte count, P = .05;EOT vs day 90 for CD4 count, P = .04;EOT vs day 180 for CD4 count, P = .02.All other comparisons were not statistically significant and are not presented on this table.d Corticosteroids included administration of daily dose of prednisone >10 mg.Antifungal Treatment and Duration in Hematology Patients • OFID • 7