A retrospective study investigating the incidence of invasive fungal disease (IFD) in patients with AML receiving intensive chemotherapy

The AML Global Portal previously reported on a retrospective study by Portugal et al., (1) who described adverse events associated with high-dose daunorubicin, particularly gastrointestinal problems and invasive fungal disease (IFD). IFD is an infectious complication of AML patients who have intense chemotherapy and/or allogeneic hematopoietic stem cell transplantation (allo-HSCT) resulting in protracted and serious neutropenia.

IFD leads to increases in morbidity and mortality so AML patients may benefit from treatments to prevent IFD. The study indicated that there was no clear benefit of high-dose over low-dose daunorubicin, particularly in light of the increased incidence of adverse events.  The AML Global Portal has also reported on the protective effect of antifungal prophylaxis (with posaconazole) in patients undergoing allo-HSCT. A recent study assessing treatment associated IFD has been published by Rodriguez-Veiga and Montesinos et al., in the Annals of Hematology, which retrospectively analyzed the incidence and clinical outcome of IFD in AML patients treated with chemotherapy, further details are below (2).

Study design:

• A retrospective analysis of all adult patients with newly diagnosed AML between January 2004 and December 2015 at the Hospital Universitario y Politécnico La Fe de Valencia, Spain
• Eligible patients: newly diagnosed AML (excluding acute promyelocytic leukemia), aged ≤65 years old, and had received intensive induction chemotherapy
• Chemotherapy regimens;
  • Intensive induction: either a combination of idarubicin (12 mg/m² for 3 days) and cytarabine (Ara-C; 200 mg/m² continuous perfusion for 7 days), termed 3+7, or mitoxantrone (MTZ) plus Ara-C (MTZ+Ara-C)
  • First consolidation was either the same as induction chemotherapy (3+7 or MTZ+Ara-C) or high-dose cytarabine (HiDAC; 3 g/m²/12 h days 1, 3, 5;1.5 g/m² for patients >60 years old)
  • Second consolidation (and subsequent consolidation) courses of chemotherapy were HiDAC only
• Diagnosis and classification of any IFD was as per the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) revised definitions of 2008 (possible, probable, proven) (3)
• Antifungal prophylaxis (given from chemotherapy initiation until myeloid recovery) consisted of;
  • Oral fluconazole (100 mg/daily) – January 2004 to December 2005
  • Intravenous itraconazole (200mg/daily) – January 2006 to December 2012
  • Oral voriconazole (200mg/twice daily) – January 2013 to December 2015
• Treatment of suspected IFD was by caspofungin (50mg once a day) or liposomal amphotericin (3mg/kg once a day), monotherapy or combination therapy
• Primary end-point: crude incidence of IFD (possible, probable and proven) in all episodes of intensive chemotherapy
• Secondary end-points included: the type of IFD (according to microbiological isolates, site of infection, and EORTC criteria (possible, probable, proven) (3)) and dose-limiting toxicities (DLT) of voriconazole, itraconazole, or fluconazole prophylaxis (defined as dose adjustment or withdrawal of the antifungal agent due to related toxicity)
• The main clinical outcomes were: mortality during each chemotherapy phase, mortality due to IFD, induction of complete remission rate (CR) with or without full hematologic recovery (CRi) according to the revised Cheson criteria, use of empirical or adapted antifungal therapy, and length of hospitalization duration.
• All patients were followed up until discharge of each chemotherapy episode or death during hospitalization

Results:

• A total of 285 consecutive patients were recruited which was a total of 589 episodes of intensive chemotherapy. This included:
  • 285 first induction courses (47%)
    • 3+7 (278, 47%)
    • MTZ+Ara-C (7, 1%)
  • 304 consolidation courses (53%)
    • 3+7 (149, 25%)
    • HiDAC (127, 22%)
    • MTZ+Ara-c (28, 5%)
  • Antifungal prophylaxis:
    • Oral fluconazole in 72 (12%) chemotherapy episodes
    • Intravenous itraconazole in 233 (40%)
    • Oral voriconazole in 264 (45%)
    • An echinocandin or low-dose liposomal amphotericin B in 20 episodes (3%)

Main selected patient characteristics are detailed in Table 1 below

Table 1. Patient and disease characteristics

ECOG, Eastern Cooperative Oncology Group performance status; WBC, white blood cell; CR, complete remission; CRi, complete remission with incomplete blood counts; PR, partial remission
Characteristic	Overall N=285 n (%)
Total	285 (100)
Age, years, mean (range)	51 (17-65)
Male gender	158 (55)
ECOG 0–1 (N=281)	229 (82)
Secondary AML	51 (18)
FAB subtype (N=279)                    M0                    M1                    M2                                M4                    M5                    M6                    M7                    Other	16 (6) 54 (19) 62 (22) 52 (19) 38 (14) 15 (5) 4 (1) 30 (10)
WBC x 109/L, mean (range)	10.5 (0.3–434)
Hemoglobin g/dL, mean (range)	8.9 (3.8–15.5)
Extramedullary disease, (N=271)	62 (23)
Cytogenetics                    Core-binding factor                    Normal karyotype                    Intermediate                    Unfavorable                    No metaphases/unknown	34 (12) 121 (43) 39 (14) 70 (25) 21 (7)
Response to induction                    CR/CRi                    Resistance/PR                    Induction death	185 (65) 71 (25) 29 (10)

• The median duration of grade 4 neutropenia during induction chemotherapy was 20 days (range 11 - 63 days) from the end of 3+7, but 10% of evaluable patients had a grade 4 neutropenia shorter than 15 days
• In total, 56 episodes of IFD during the 589 episodes of intensive chemotherapy (10% crude incidence):
  • 29 were possible (52%)
  • 17 probable (30%)
  • 10 proven (18%)
• Crude incidence of IFD by chemotherapy regimen is detailed in Table 2, shows that IFD (possible/probable/proven and probable/proven) was significantly lower during HiDAC consolidation when compared to anthracycline-containing chemotherapy regimens (2% 11%, p = 0.001, and 0% vs. 5%, p = 0.002, respectively)

Table 2. Incidence of IFD and clinical outcomes according to the chemotherapy schedule

Table 3 Incidence of IFD and main clinical outcomes according to antifungal prophylaxisOutcomes of death during chemotherapy, hospitalization duration among survivors, and use of empirical or directed antifungal therapy were also more favorable in the HiDAC group

Table 3 details the crude incidence of IFD according to antifungal prophylaxis treatment

• IFD incidence (possible/probable/proven) was significantly lower under voriconazole prophylaxis when compared to itraconazole and fluconazole, but this was not the case when only looking at probable and proven IFD incidence
• Hospital stay duration was shorter in the voriconazole group, and the use of empirical or directed antifungal therapy was less frequent
• DLT was observed in the itraconazole courses (1 case of hepatotoxicity and 1 of cardiotoxicity) and in the vorconazole courses (4 hepatotoxicity, 1 neurotoxicity, and 1 cardiotoxicity)
• Multivariate analysis incorporating several patient and treatment characteristics found that voriconazole prophylaxis and HiDAC chemotherapy were independently associated with a decreased risk of IFD (possible/probable/proven)

Conclusion

IFD is a frequent complication in patients with AML undergoing intensive chemotherapy and/or allo-HSCT. .Rodríguez-Veiga R. & Montesinos P. et al., showed that voriconazole prophylaxis was feasible and associated with a lower risk of IFD as compared with intravenous itraconazole or oral fluconazole schedules. The study results are in line with other reports on the incidence of IFD: Ananja-Rajah et al., (4) reported possible/probable/proven IFD rates of 13% with fluconazole prophylaxis, 20% with itraconazole, and 8% with voriconazole and posaconazole; overall crude incidence for this study was 10% possible/probable/proven IFD. In terms of probable/proven IFD incidence rates, other studies reported 8% with fluconazole or itraconazole prophylaxis (5), 3% with voriconazole (6) and 5.3% with itraconazole (7), and this study found a 5% overall incidence rate.

The authors also noted that this was possibly the first study to identify anthacycline-containing chemotherapy as a risk factor for the development for IFD.