Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial

Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post... Abstract Background Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA. Methods A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count <0.5 × 109/L for >10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed. Results One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P < 0.001; EOT, P < 0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P = 0.002) and numerically higher at day 7 and EOT (P > 0.05 for both). Conclusions Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes. Introduction Invasive aspergillosis (IA) has become the predominant mycosis in patients with haematological cancer and prolonged neutropenia.1 Historically, prolonged neutropenia was associated with a failure to respond to antifungal therapy as well as increased mortality in patients with haematological malignancies, although the data come mostly from older, single-institution, retrospective studies that relied on culture- or histopathology-proven IA cases in which the outcomes were poor.1–3 Pivotal randomized studies for the treatment of IA in the last two decades showed improvement of responses with triazoles,3–5 yet they do not provide an in-depth evaluation of the impact of neutropenia on IA outcomes. The significance of persistent neutropenia for outcomes in IA is a timely question in the era of high-potency new anti-Aspergillus triazoles, such as isavuconazole and voriconazole, and revised guidelines for the diagnosis of probable IA that heavily rely on Aspergillus galactomannan (GM) detection. Specifically, a potential confounder for improved outcome in the latest studies might have been the introduction of Aspergillus GM in serum or bronchoalveolar lavage samples, which is an important step in the early diagnosis of IA.6 The SECURE trial demonstrated the non-inferiority of isavuconazole compared with voriconazole for the treatment of IA and other filamentous fungi.5 In this post hoc analysis of the SECURE trial, we compared the efficacy and safety outcomes in the subset of patients with baseline neutropenia and IA in order to assess the impact of persistent neutropenia on mortality and outcomes in each treatment group. We also examined the impact of baseline GM on outcomes for each treatment arm. Methods Study design The SECURE trial (ClinicalTrials.gov; NCT00412893) was a global, Phase 3, randomized, multicentre, double-blind, comparative-group, non-inferiority trial of isavuconazole versus voriconazole.5 The primary findings of this trial together with methodology and patient eligibility criteria have been reported elsewhere.5 Briefly, patients aged ≥18 years with proven, probable or possible invasive fungal infections, defined according to the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group,7 were randomized 1:1 to receive isavuconazole or voriconazole. Patients assigned to isavuconazole received a loading dose of 372 mg of isavuconazonium sulphate prodrug, equivalent to 200 mg of isavuconazole, three times daily intravenously for the first 2 days, followed by a maintenance once-daily intravenous or oral dose of 200 mg of isavuconazole from day 3 to end of treatment (EOT). Patients assigned to voriconazole received a loading dose of 6 mg/kg every 12 h intravenously on study day 1, followed by a maintenance dose of 4 mg/kg every 12 h intravenously or 200 mg every 12 h orally from day 2 to EOT. Patients were treated for up to a maximum of 84 days. The final follow-up visit was scheduled at 4 weeks ±7 days after the last dose of study drug, which may have occurred before or after day 42 and/or day 84. The primary endpoint of this post hoc analysis was all-cause mortality (ACM) through day 42 following primary treatment with isavuconazole compared with voriconazole in patients with neutropenia and IA. Differences in the primary outcome by neutropenic status and treatment assignment, for patients with neutropenia at baseline that had resolved or remained at day 7, day 42 and EOT, were also assessed. Overall success at EOT was a key secondary endpoint and was based on clinical, mycological and radiological responses as described previously.5 The impact of baseline GM on outcomes in each treatment arm was evaluated. Assessments Mycological assessments were performed locally according to best practice and included samples for fungal culture and isolation and biopsy/biological fluid samples from the infected site for histology/cytology. Serum samples were assessed for Aspergillus infection by GM antigen assay, with a single value ≥0.7 or two consecutive values ≥0.5 by Bio-Rad Platelia™ (Bio-Rad, Hercules, CA, USA) considered a positive result. An independent data review committee (DRC) assessed proven or probable IA status and evaluated clinical, mycological and overall response at EOT based on consensus criteria.8 Specifically, complete or partial clinical success was defined as the complete resolution or partial resolution, respectively, of attributable clinical symptoms and physical findings. Clinical failure was defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening of symptoms or results not available. Mycological success was defined as eradication, or presumed eradication, of infection, and failure as cases of persistence or presumed persistence of infection. Neutropenic status was determined at baseline, day 7, day 42 and EOT. Neutropenia was defined as an absolute neutrophil count (ANC) <0.5 × 109/L for >10 days at baseline. For measurements on or before day 7, unresolved neutropenia was defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement. For day 42 and EOT measurements, unresolved neutropenia was defined as no ANC measurement in patients whose previously available ANC indicated neutropenia, or at least one ANC <0.5 × 109/L measurement from day 35 to day 49, or from 3 days before to 3 days after last treatment dose, respectively. Patients whose neutropenia had resolved were compared with those who remained neutropenic (unresolved neutropenia). A comparison of the efficacy and safety of isavuconazole compared with voriconazole was also carried out for these patient groups. The incidence, nature and severity of treatment-emergent adverse events (TEAEs) were monitored and assessed throughout the study for all patients who received one or more doses of study drug. Analysis populations This analysis was performed using the mycological ITT (myITT) population, which included all patients with neutropenia and proven or probable IA, as assessed by the DRC, who had received at least one dose of study drug. Statistical analyses Demographic and baseline characteristics were summarized for the myITT population. The primary efficacy endpoint of crude ACM through day 42 was assessed from the myITT population, with the between-group treatment difference obtained by subtracting the voriconazole rate from isavuconazole rate. Fisher’s exact test (two-tailed) (R software, University of Aix-Marseille, France) was used to assess differences between treatment groups and between groups with resolved versus unresolved neutropenia and P < 0.05 was considered significant. Results Patient demographics and baseline characteristics Overall, 142 patients with neutropenia received one or more doses of study drug and had either proven or probable IA, and thus constituted the myITT population. The treatment subgroups were mostly well balanced with respect to age and other baseline characteristics (Table 1). The percentage of males was lower among those assigned to the isavuconazole group, compared with those assigned to the voriconazole group. Nearly all patients had underlying haematological malignant disease, with acute leukaemia accounting for >50% cases in each treatment group (Table 1). Most patients had active malignancy at the diagnosis of IA (83.3% and 89.1% in the isavuconazole and voriconazole groups, respectively). The majority of patients only had invasive pulmonary aspergillosis (91.0% in the isavuconazole group and 96.9% in the voriconazole group). More patients in the isavuconazole group (2/78) had disseminated IA compared with the voriconazole group (0/64, P = not significant; Table 1). Table 1. Demographics and baseline characteristics of patients with neutropeniaa and IA (myITT population)b Parameter  Isavuconazole (n = 78)  Voriconazole (n = 64)  Age (years), mean (SD)  51.6 (15.2)  50.0 (15.1)  Male, n (%)  38 (48.7)  39 (60.9)  Race, n (%)       white  62 (79.5)  45 (70.3)   Asian  15 (19.2)  19 (29.7)   other  1 (1.3)  0  Baseline condition, n (%)       primary underlying disease  78 (100.0)  64 (100.0)    AML  37 (47.4)  38 (59.4)    ALL  14 (17.9)  7 (10.9)    refractory anaemia with excess of blasts  6 (7.7)  1 (1.6)    myelodysplastic syndrome  2 (2.6)  4 (6.3)    non-Hodgkin’s lymphoma  6 (7.7)  0    CLL  1 (1.3)  3 (4.7)    CML  2 (2.6)  2 (3.1)    T cell lymphoma  1 (1.3)  2 (3.1)    aplastic anaemia  1 (1.3)  2 (3.1)    otherc  17 (21.8)  12 (18.8)   active malignancy  65 (83.3)  57 (89.1)   T cell immunosuppressant  27 (34.6)  26 (40.6)   allogeneic bone marrow transplantation  17 (21.8)  7 (10.9)   corticosteroid use  10 (12.8)  9 (14.1)  Location of aspergillosis, n (%)       LRTD only  71 (91.0)  62 (96.9)   LRTD + other organ  4 (5.1)  0   non-LRTD only  3 (3.8)  2 (3.1)  Non-LRTD location, n (%)  7 (9.0)  2 (3.1)   disseminated  2 (2.6)  0   brain  1 (1.3)  0   sinus  5 (6.4)  2 (3.1)   skin  1 (1.3)  0   other  1 (1.3)  0  Parameter  Isavuconazole (n = 78)  Voriconazole (n = 64)  Age (years), mean (SD)  51.6 (15.2)  50.0 (15.1)  Male, n (%)  38 (48.7)  39 (60.9)  Race, n (%)       white  62 (79.5)  45 (70.3)   Asian  15 (19.2)  19 (29.7)   other  1 (1.3)  0  Baseline condition, n (%)       primary underlying disease  78 (100.0)  64 (100.0)    AML  37 (47.4)  38 (59.4)    ALL  14 (17.9)  7 (10.9)    refractory anaemia with excess of blasts  6 (7.7)  1 (1.6)    myelodysplastic syndrome  2 (2.6)  4 (6.3)    non-Hodgkin’s lymphoma  6 (7.7)  0    CLL  1 (1.3)  3 (4.7)    CML  2 (2.6)  2 (3.1)    T cell lymphoma  1 (1.3)  2 (3.1)    aplastic anaemia  1 (1.3)  2 (3.1)    otherc  17 (21.8)  12 (18.8)   active malignancy  65 (83.3)  57 (89.1)   T cell immunosuppressant  27 (34.6)  26 (40.6)   allogeneic bone marrow transplantation  17 (21.8)  7 (10.9)   corticosteroid use  10 (12.8)  9 (14.1)  Location of aspergillosis, n (%)       LRTD only  71 (91.0)  62 (96.9)   LRTD + other organ  4 (5.1)  0   non-LRTD only  3 (3.8)  2 (3.1)  Non-LRTD location, n (%)  7 (9.0)  2 (3.1)   disseminated  2 (2.6)  0   brain  1 (1.3)  0   sinus  5 (6.4)  2 (3.1)   skin  1 (1.3)  0   other  1 (1.3)  0  ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia; LRTD, lower respiratory tract disease. a ANC <0.5 × 109/L for >10 days at baseline. b myITT population: all randomized patients who received at least one dose of study drug and were diagnosed with IA. c Other occurring in a single patient from each or either treatment group: Hodgkin’s disease, acute biphenotypic leukaemia, acute monocytic leukaemia, acute promyelocytic leukaemia, B cell lymphoma, Burkitt’s leukaemia, chloroma, hairy cell leukaemia, leukaemia, lymphoplasmacytoid lymphoma/immunocytoma stage IV, multiple myeloma. Most aspergillosis diagnoses were based only on positive serum GM (74.4% isavuconazole group, 82.8% voriconazole group) versus isolation of Aspergillus spp. alone and Aspergillus spp. plus other filamentous fungi (25.6% isavuconazole group, 17.2% voriconazole group; Table 2). Among those patients with a pathogen identified at baseline, the predominant pathogens causing IA as assessed by the DRC were Aspergillus fumigatus and Aspergillus flavus (Table 2), which accounted for 15.4% of cases in the isavuconazole group and 17.2% of cases in the voriconazole group. Table 2. Baseline pathogens causing IA in patients with neutropeniaa (myITT populationb) Pathogen causing IAc  Isavuconazole (n = 78)  Voriconazole (n = 64)  Aspergillus spp. only, n (%)  17 (21.8)  11 (17.2)   A. fumigatus  8 (10.3)  6 (9.4)   A. flavus  4 (5.1)  5 (7.8)   Aspergillus niger  4 (5.1)  0   Aspergillus terreus  1 (1.3)  0   Aspergillus sydowii  1 (1.3)  0  Aspergillus spp. plus other filamentous fungi, n (%)  3 (3.8)  0  Positive serum GMd, n (%)  58 (74.4)  53 (82.8)  Pathogen causing IAc  Isavuconazole (n = 78)  Voriconazole (n = 64)  Aspergillus spp. only, n (%)  17 (21.8)  11 (17.2)   A. fumigatus  8 (10.3)  6 (9.4)   A. flavus  4 (5.1)  5 (7.8)   Aspergillus niger  4 (5.1)  0   Aspergillus terreus  1 (1.3)  0   Aspergillus sydowii  1 (1.3)  0  Aspergillus spp. plus other filamentous fungi, n (%)  3 (3.8)  0  Positive serum GMd, n (%)  58 (74.4)  53 (82.8)  a Neutropenia: ANC <0.5 × 109/L for >10 days at baseline. b myITT population: all randomized patients who received at least one dose of study drug, with proven or probable IA. c As assessed by the DRC. d Serum GM single value ≥0.7 or two consecutive serum sample values of ≥ 0.5 to < 0.7. Efficacy outcomes In the isavuconazole group, neutropenia persisted in 58/78 (74.4%) patients at day 7, 40/78 (51.3%) patients at day 42 and 37/78 (47.4%) patients at EOT. In the voriconazole group, neutropenia persisted in 47/64 (73.4%) patients at day 7, 31/64 (48.4%) patients at day 42 and 33/64 (51.6%) patients at EOT. How the diagnosis of neutropenia was made is shown in Table S1 (available as Supplementary data at JAC Online). Patients who had resolved their neutropenia at day 7 but subsequently relapsed are shown in Table S2. Overall, 10/20 (50.0%) and 11/17 (64.7%) patients in the isavuconazole and voriconazole groups, respectively, who had resolved neutropenia at day 7 were subsequently diagnosed with unresolved neutropenia at day 42. Similarly, 8/20 (40.0%) and 7/17 (41.2%) patients in the isavuconazole and voriconazole groups, respectively, who had resolved neutropenia at day 7 subsequently were diagnosed with unresolved neutropenia at EOT. The relapse in neutropenia was predominantly due to the lack of availability of absolute neutrophil counts at these timepoints (Table S2). In patients who were neutropenic at baseline, overall ACM at day 42 occurred in 19/78 (24.4%) patients (18/58 patients with unresolved neutropenia at day 7 and 1/20 patients with resolved neutropenia at day 7) in the isavuconazole group and 15/64 (23.4%) patients (14/47 patients with unresolved neutropenia at day 7 and 1/17 patients with resolved neutropenia at day 7) in the voriconazole group (Table 3). Irrespective of treatment assignment, ACM was higher for patients who remained neutropenic at each timepoint [day 7, 32/105 (30.5%); day 42, 32/71 (45.1%); EOT, 30/70 (42.9%)] compared with patients whose neutropenia had resolved at that timepoint [day 7, 2/37 (5.4%); day 42, 0/32; EOT, 2/35 (5.7%)], regardless of whether the diagnosis of IA was by culture plus GM or just GM positivity (culture negative) (Table 3). A separate analysis of the data showed that 5/142 (3.5%) patients died before day 7 [4/78 (5.1%) in the isavuconazole group and 1/64 (1.6%) in the voriconazole group], 28/142 (19.7%) patients died between day 7 and 42 [15/78 (19.2%) in the isavuconazole group and 13/64 (20.3%) in the voriconazole group] and 14/142 (9.9%) patients died between day 43 and day 84 [7/78 (9.0%) in the isavuconazole group and 7/64 (10.9%) in the voriconazole group]. Table 3. ACM at day 42 in patients with unresolved versus resolved neutropenia dependent on day of resolution of neutropenia and diagnosis by culture and GM or by GM alone Neutropeniac status  Culture-based + GM IAa, n/N (%) deaths   GM alone IAb, n/N (%) deaths   Total, n/N (%) deaths   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  6/16 (37.5)  2/6 (33.3)  12/42 (28.6)  12/41 (29.3)  18/58 (31.0)  14/47 (29.8)   resolved  0/4  1/5 (20.0)  1/16 (6.3)  0/12  1/20 (5.0)  1/17 (5.9)   Pe  0.267  1.000  0.087  0.048  0.031  0.053  Day 42f               unresolved  6/13 (46.2)  2/4 (50.0)  12/27 (44.4)  12/27 (44.4)  18/40 (45.0)  14/31 (45.2)   resolved  0/3  0/2  0/15  0/14  0/18  0/16   Pe  0.250  0.467  0.003  0.003  <0.001  0.002  EOTg               unresolved  6/8 (75.0)  0/3  12/29 (41.4)  12/30 (40.0)  18/37 (48.6)  12/33 (36.4)   resolved  0/8  2/3 (66.7)  0/13  0/11  0/21  2/14 (14.3)   Pe  0.007  0.400  0.008  0.018  <0.001  0.175  Neutropeniac status  Culture-based + GM IAa, n/N (%) deaths   GM alone IAb, n/N (%) deaths   Total, n/N (%) deaths   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  6/16 (37.5)  2/6 (33.3)  12/42 (28.6)  12/41 (29.3)  18/58 (31.0)  14/47 (29.8)   resolved  0/4  1/5 (20.0)  1/16 (6.3)  0/12  1/20 (5.0)  1/17 (5.9)   Pe  0.267  1.000  0.087  0.048  0.031  0.053  Day 42f               unresolved  6/13 (46.2)  2/4 (50.0)  12/27 (44.4)  12/27 (44.4)  18/40 (45.0)  14/31 (45.2)   resolved  0/3  0/2  0/15  0/14  0/18  0/16   Pe  0.250  0.467  0.003  0.003  <0.001  0.002  EOTg               unresolved  6/8 (75.0)  0/3  12/29 (41.4)  12/30 (40.0)  18/37 (48.6)  12/33 (36.4)   resolved  0/8  2/3 (66.7)  0/13  0/11  0/21  2/14 (14.3)   Pe  0.007  0.400  0.008  0.018  <0.001  0.175  a Diagnosis of IA culture positive and GM positive. b Diagnosis of IA culture negative but GM positive. c Neutropenia: ANC <0.5 × 109/L for >10 days at baseline. d Unresolved neutropenia: no ANC measurement available or at least one ANC <0.5 × 109/L measurement from day 2 to day 7. e P, Fisher’s two-tailed exact test for unresolved versus resolved neutropenia. f Unresolved neutropenia at day 42 defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement from day 35 to day 49. g Unresolved neutropenia at EOT defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement from 3 days before last dose to 3 days after last dose. In analyses by treatment group (Table 3), ACM was comparable in both the isavuconazole and voriconazole groups who remained neutropenic at day 7 [18/58 (31.0%) and 14/47 (29.8%), respectively], day 42 [18/40 (45.0%) and 14/31 (45.2%), respectively] and EOT [18/37 (48.6%) and 12/33 (36.4%), respectively]. ACM was statistically significantly lower in isavuconazole-treated patients whose neutropenia had resolved compared with isavuconazole-treated patients with unresolved neutropenia at day 7 [1/20 (5.0%) compared with 18/58 (31.0%), P = 0.031], day 42 [0/18 compared with 18/40 (45.0%), P < 0.001] and EOT [0/21 compared with 18/37 (48.6%), P < 0.001]. In voriconazole-treated patients, ACM was significantly lower for resolved, compared with unresolved, neutropenia at day 42 [0/16 compared with 14/31 (45.2%), P = 0.002] but not at day 7 [1/17 (5.9%) compared with 14/47 (29.8%), P = 0.053] or at EOT [2/14 (14.3%) compared with 12/33 (36.4%), P = 0.175] (Table 3). Although the numbers were small, ACM was slightly higher in patients with unresolved neutropenia regardless of treatment arm at day 7 and day 42 when diagnosis was based upon culture plus GM positivity, compared with culture-negative GM positivity (day 7, 8/22 versus 24/83; day 42, 8/17 versus 24/54, respectively; Table 3). There was a statistically significant association between baseline GM values and the risk of mortality in the isavuconazole group at day 42, with 0/12 patients in the ≥0.5 to ≤1.0 group, compared with 15/44 (34.1%) (P = 0.024) in the >1.0 group, and at EOT with 0/12 patients in the ≥0.5 to ≤1.0 group, compared with 18/44 (40.9%) (P = 0.006) in the >1.0 group, progressing to death (Table 4). In contrast, no significant link was observed in the voriconazole group. Table 4. Analysis of ACM at day 42 and EOT by baseline GM values (myITT population) Serum GM values  Isavuconazole (n = 78), n/N (%) deaths  Voriconazole (n = 64), n/N (%) deaths  Day 42       two consecutive values ≥0.5 but ≤1.0  0/12  4/15 (26.7)   at least one value of ≥ 0.7 but <1.0  2/9 (22.2), P = 0.171b  2/6 (33.3), P = 1.000b   at least one value ≥1.0  15/44 (34.1), P = 0.024b  8/38 (21.1), P = 0.722b   no serum GM values checkeda  2/13 (15.4)  1/5 (20.0)  EOT       two consecutive values ≥0.5 but ≤1.0  0/12  5/15 (33.3)   at least one value of ≥ 0.7 but <1.0  4/9 (44.4), P = 0.021b  4/6 (66.7), P = 0.331b   at least one value ≥1.0  18/44 (40.9), P = 0.006b  12/38 (31.6), P = 1.000b   no serum GM values checkeda  4/13 (30.8)  1/5 (20.0)  Serum GM values  Isavuconazole (n = 78), n/N (%) deaths  Voriconazole (n = 64), n/N (%) deaths  Day 42       two consecutive values ≥0.5 but ≤1.0  0/12  4/15 (26.7)   at least one value of ≥ 0.7 but <1.0  2/9 (22.2), P = 0.171b  2/6 (33.3), P = 1.000b   at least one value ≥1.0  15/44 (34.1), P = 0.024b  8/38 (21.1), P = 0.722b   no serum GM values checkeda  2/13 (15.4)  1/5 (20.0)  EOT       two consecutive values ≥0.5 but ≤1.0  0/12  5/15 (33.3)   at least one value of ≥ 0.7 but <1.0  4/9 (44.4), P = 0.021b  4/6 (66.7), P = 0.331b   at least one value ≥1.0  18/44 (40.9), P = 0.006b  12/38 (31.6), P = 1.000b   no serum GM values checkeda  4/13 (30.8)  1/5 (20.0)  a GM-positive result but no titre data available. b P, versus two consecutive values ≥0.5 but ≤1.0 (Fisher’s two-tailed exact test). In line with the ACM results, the finding of DRC-assessed treatment success at EOT was greater in patients with resolved, compared with those with unresolved, neutropenia at all timepoints, regardless of treatment group. Isavuconazole achieved rates of success similar to those of voriconazole in those stratified according to unresolved or resolved neutropenia status at day 7 and at day 42 but not at EOT (Table 5). At EOT, voriconazole appeared to have a greater success rate among those with unresolved neutropenia while isavuconazole appeared to have a greater success rate in those with resolved neutropenia. Overall, there were no differences between treatment groups at EOT [success in the isavuconazole group 19/58 (32.8%) versus voriconazole 16/47 (34.0%)]. Table 5. DRC-assessed overall success at EOT (myITT population) Neutropeniac status  Culture + GM IAa, n/N (%) success   GM only IAb, n/N (%) success   Total, n/N (%) success   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  5/16 (31.3)  1/6 (16.7)  14/42 (33.3)  15/41 (36.6)  19/58 (32.8)  16/47 (34.0)   resolved  4/4 (100.0)  3/5 (60.0)  7/16 (43.8)  7/12 (58.3)  11/20 (55.0)  10/17 (58.8)   Pe  0.026  0.242  0.546  0.202  0.110  0.091  Day 42f             unresolved  3/13 (23.1)  0/4  4/27 (14.8)  6/27 (22.2)  7/40 (17.5)  6/31 (19.4)   resolved  2/3 (66.7)  1/2 (50.0)  10/15 (66.7)  9/14 (64.3)  12/18 (66.7)  10/16 (62.5)   Pe  0.214  0.400  0.001  0.015  0.001  0.008  EOTg               unresolved  0/8  1/3 (33.3)  4/29 (13.8)  10/30 (33.3)  4/37 (10.8)  11/33 (33.3)   resolved  5/8 (62.5)  0/3  10/13 (76.9)  5/11 (45.5)  15/21 (71.4)  5/14 (35.7)   Pe  0.026  1.000  <0.001  0.491  <0.001  1.000  Neutropeniac status  Culture + GM IAa, n/N (%) success   GM only IAb, n/N (%) success   Total, n/N (%) success   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  5/16 (31.3)  1/6 (16.7)  14/42 (33.3)  15/41 (36.6)  19/58 (32.8)  16/47 (34.0)   resolved  4/4 (100.0)  3/5 (60.0)  7/16 (43.8)  7/12 (58.3)  11/20 (55.0)  10/17 (58.8)   Pe  0.026  0.242  0.546  0.202  0.110  0.091  Day 42f             unresolved  3/13 (23.1)  0/4  4/27 (14.8)  6/27 (22.2)  7/40 (17.5)  6/31 (19.4)   resolved  2/3 (66.7)  1/2 (50.0)  10/15 (66.7)  9/14 (64.3)  12/18 (66.7)  10/16 (62.5)   Pe  0.214  0.400  0.001  0.015  0.001  0.008  EOTg               unresolved  0/8  1/3 (33.3)  4/29 (13.8)  10/30 (33.3)  4/37 (10.8)  11/33 (33.3)   resolved  5/8 (62.5)  0/3  10/13 (76.9)  5/11 (45.5)  15/21 (71.4)  5/14 (35.7)   Pe  0.026  1.000  <0.001  0.491  <0.001  1.000  a Diagnosis of IA culture positive and GM positive. b Diagnosis of IA culture negative but GM positive. c Neutropenia: ANC <0.5 × 109/L for >10 days at baseline. d Unresolved neutropenia: no ANC measurement available or at least one ANC <0.5 × 109/L measurement from day 2 to day 7. e P, Fisher’s two-tailed exact test for unresolved versus resolved neutropenia. f Unresolved neutropenia at day 42 defined as no ANC measurement available or at least one ANC <0.5 × 09/L measurement from day 35 to day 49. g Unresolved neutropenia at EOT defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement from 3 days before last dose to 3 days after last dose. Discussion Using a post hoc analysis of the large Phase 3 SECURE trial, we report the largest contemporary dataset to date assessing the impact of neutropenia resolution on outcomes in patients with IA treated with the modern triazoles, isavuconazole and voriconazole, that are endorsed by guidelines as the preferred first-line agents.1 Failure to resolve neutropenia was a major factor for ACM regardless of the treatment group and is a major finding of our study. We also found that isavuconazole had similar efficacy to voriconazole in patients with baseline neutropenia, irrespective of whether neutropenia had resolved or remained at day 7, day 42 or EOT. However, poorer outcomes were observed for both drugs in the setting of persistent neutropenia. This suggests that neutropenia continues to be a predictor of poor outcomes in patients with IA, and that persistence of neutropenia could potentially influence outcomes in clinical trials. A number of studies have identified neutropenia as a risk factor for mortality and response to therapy in IA.9–14 Neutrophils are crucial for host protection against aspergillosis as they have a direct role in the destruction of hyphae and prevent germination of conidia.15,16 Delayed engraftment after stem cell transplantation and prolonged neutropenia are strong predictors of both IA and poor outcome.17 In a study of patients with haematological malignancies, Reuter et al.18 found that patients with neutropenia of ≤5 days had a 12 month survival rate of 92%, compared with 58% for those with persistent neutropenia of >10 days. Our study emphasizes the importance of resolving neutropenia in patients with IA, even in the era of early GM-based diagnosis of IA and the use of potent triazoles. Indeed, there was no further ACM at day 42 in patients whose neutrophil counts recovered. Therefore, early restoration of neutrophil count is an important consideration in the management of patients with IA. Whether the inferior outcomes of neutropenia reflect the fact that voriconazole and isavuconazole are static drugs in the doses currently used against Aspergillus spp. is a theoretical, yet tenable, hypothesis.19–21 In our analysis of patients who were neutropenic at baseline, the overall day 42 ACM rates of 24.4% (isavuconazole) and 23.4% (voriconazole) were slightly lower than those of previous studies that reported 6 and 12 week mortality data on the order of 27%–30% when voriconazole was used as primary monotherapy treatment of IA in patients with haematological diseases and haematopoietic stem cell transplantation,3,4,22 although not all patients in these older studies had neutropenia. In the current study, similar overall treatment success rates at EOT were observed between isavuconazole- and voriconazole-treated patients with neutropenia. At EOT, success was greater in those with resolved versus persistent neutropenia. Although the numbers were small, intriguingly, voriconazole appeared to have a better success rate among those with unresolved neutropenia while isavuconazole appeared to have a greater success rate in those with resolved neutropenia. Whether there are differences in the intracellular concentration of each azole in neutrophils and its immunomodulatory effect (favouring isavuconazole) or a more inherent fungicidal effect of voriconazole in the absence of neutrophils (favouring voriconazole) is a complex question that requires careful experimental testing. Alternatively, this might reflect some imbalances in the population. For example, disseminated IA was more common in the isavuconazole group, compared with the voriconazole group, and may not have been balanced between the resolved and unresolved neutropenia groups. Not surprisingly, most of the patients in our study had haematological cancer and had a diagnosis of probable IA, on the basis of a positive GM in serum and/or bronchoalveolar lavage. A number of studies have shown that GM values may be a surrogate marker for mortality due to IA, with high GM values being a predictor of mortality in patients with neutropenia.6,23–26 Furthermore, a diagnosis based on a positive culture together with GM positivity has been shown in a multivariate analysis to be independently associated with an increased risk of death.27 Our study did not show any significant differences in the risk of death between culture-positive and GM-alone diagnosis. In our study, irrespective of neutropenia status, there was a link between baseline GM values and ACM in patients receiving isavuconazole, but not in patients who received voriconazole. Furthermore, others have shown that patients with IA regardless of neutropenia status whose GM values normalize after initiation of antifungal therapy, including isavuconazole, have significantly better outcomes compared with patients with persistently positive GM values.6,23–26,28 Future clinical trials on IA should consider sequential GM values during treatment as a possible surrogate marker for success. As a post hoc analysis, this study has inherent limitations, including a limited analysis population that may have resulted in sampling bias and/or introduced imbalances and a lack of powering to support firm conclusions. In addition, as the study enrolment criteria excluded patients who were severely ill, and with comorbidities such as renal or hepatic dysfunction, there might be limitations in the generalizability of our findings. In conclusion, the findings of this post hoc analysis of the Phase 3 SECURE trial suggest that isavuconazole has comparable efficacy to voriconazole in the primary treatment of IA in patients with either resolved or unresolved neutropenia. These data confirm the durable influence of resolving neutropenia on improving antifungal treatment success and outcomes in patients with haematological cancer and IA. Similar observations of the profound influence of neutrophil recovery on outcome have been made for the other clinically important, yet less common non-Aspergillus moulds that cause invasive fungal infections in this patient population.29–31 Future studies should carefully analyse and report outcomes of agents by taking the issue of persistent neutropenia into account. Finally, whether there are meaningful differences in the activity of voriconazole compared with isavuconazole in patients with IA and unresolved neutropenia would require further study. Acknowledgements We are grateful for the contributions of Nkechi Azie, formerly of Astellas Pharma Global Development, to the development of the manuscript. Funding This study was funded by Astellas Pharma, Inc. Medical writing support was also funded by Astellas Pharma, Inc. Transparency declarations D. P. K. has received support from Astellas, Pfizer and Merck. D. S. has received support from Astellas, Pfizer and Merck. K. M. has received support from Astellas, Anson, Chimerix, Cubist, Optimer, Merck, Rebiotix, ViroPharma and Pfizer. O. A. C. has received support from Astellas, Cubist, Optimer, Pfizer, Gilead, Merck, 3M, Basilea, F2G, ViroPharma, GSK, Actelion, Sanofi Pasteur, Quintiles, Summit, Vifor, Celgene, Genzyme and Miltenyi. W. H. has received support from Astellas, Pfizer, Gilead, F2G, Amplyx and Basilea. O. L. has received support from Astellas, Pfizer, Gilead and Merck. R. C.-D. and C. L. are employees of Astellas Pharma Global Development, Inc. M. E. is an employee of Basilea Pharmaceutica International Ltd, Basel, Switzerland. T. F. P. has received support from Amplyx, Astellas, Basilea, Gilead, Merck, Pfizer, Toyama, Scynexis, Vical and Viamet.  Isavuconazole has been co-developed by Astellas and Basilea Pharmaceutica International Ltd.  Medical writing support was provided by John Clarke, a medical writer at Envision Scientific Solutions. Supplementary data Tables S1 and S2 are available as Supplementary data at JAC Online. References 1 Patterson TF, Thompson GR3rd, Denning DW et al.   Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis  2016; 63: e1– 60. Google Scholar CrossRef Search ADS PubMed  2 Burch PA, Karp JE, Merz WG et al.   Favorable outcome of invasive aspergillosis in patients with acute leukemia. J Clin Oncol  1987; 5: 1985– 93. Google Scholar CrossRef Search ADS PubMed  3 Marr KA, Schlamm HT, Herbrecht R et al.   Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med  2015; 162: 81– 9. Google Scholar CrossRef Search ADS PubMed  4 Herbrecht R, Denning DW, Patterson TF et al.   Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med  2002; 347: 408– 15. Google Scholar CrossRef Search ADS PubMed  5 Maertens JA, Raad I, Marr KA et al.   Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet  2016; 387: 760– 9. Google Scholar CrossRef Search ADS PubMed  6 Cordonnier C, Botterel F, Ben Amor R et al.   Correlation between galactomannan antigen levels in serum and neutrophil counts in haematological patients with invasive aspergillosis. Clin Microbiol Infect  2009; 15: 81– 6. Google Scholar CrossRef Search ADS PubMed  7 De Pauw B, Walsh TJ, Donnelly JP et al.   Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis  2008; 46: 1813– 21. Google Scholar CrossRef Search ADS PubMed  8 Segal BH, Herbrecht R, Stevens DA et al.   Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria. Clin Infect Dis  2008; 47: 674– 83. Google Scholar CrossRef Search ADS PubMed  9 Baddley JW, Andes DR, Marr KA et al.   Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis  2010; 50: 1559– 67. Google Scholar CrossRef Search ADS PubMed  10 Neofytos D, Horn D, Anaissie E et al.   Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis  2009; 48: 265– 73. Google Scholar CrossRef Search ADS PubMed  11 Nivoix Y, Velten M, Letscher-Bru V et al.   Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis  2008; 47: 1176– 84. Google Scholar CrossRef Search ADS PubMed  12 Pagano L, Caira M, Candoni A et al.   Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study. Haematologica  2010; 95: 644– 50. Google Scholar CrossRef Search ADS PubMed  13 Parody R, Martino R, Sanchez F et al.   Predicting survival in adults with invasive aspergillosis during therapy for hematological malignancies or after hematopoietic stem cell transplantation: single-center analysis and validation of the Seattle, French, and Strasbourg prognostic indexes. Am J Hematol  2009; 84: 571– 8. Google Scholar CrossRef Search ADS PubMed  14 Upton A, Kirby KA, Carpenter P et al.   Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis  2007; 44: 531– 40. Google Scholar CrossRef Search ADS PubMed  15 Bonnett CR, Cornish EJ, Harmsen AG et al.   Early neutrophil recruitment and aggregation in the murine lung inhibit germination of Aspergillus fumigatus conidia. Infect Immun  2006; 74: 6528– 39. Google Scholar CrossRef Search ADS PubMed  16 Zarember KA, Sugui JA, Chang YC et al.   Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J Immunol  2007; 178: 6367– 73. Google Scholar CrossRef Search ADS PubMed  17 Mikulska M, Raiola AM, Bruno B et al.   Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients. Bone Marrow Transplant  2009; 44: 361– 70. Google Scholar CrossRef Search ADS PubMed  18 Reuter S, Kern W, Zenz C et al.   Prognostic factors for invasive aspergillosis in patients with haematological malignancies. Scand J Infect Dis  2009; 41: 483– 90. Google Scholar CrossRef Search ADS PubMed  19 Meletiadis J, Al-Saigh R, Velegraki A et al.   Pharmacodynamic effects of simulated standard doses of antifungal drugs against Aspergillus species in a new in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother  2012; 56: 403– 10. Google Scholar CrossRef Search ADS PubMed  20 Ananda-Rajah MR, Kontoyiannis D. Isavuconazole: a new extended spectrum triazole for invasive mold diseases. Future Microbiol  2015; 10: 693– 708. Google Scholar CrossRef Search ADS PubMed  21 Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet  2006; 45: 649– 63. Google Scholar CrossRef Search ADS PubMed  22 Herbrecht R, Patterson TF, Slavin MA et al.   Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group. Clin Infect Dis  2015; 60: 713– 20. Google Scholar CrossRef Search ADS PubMed  23 Maertens J, Buve K, Theunissen K et al.   Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients. Cancer  2009; 115: 355– 62. Google Scholar CrossRef Search ADS PubMed  24 Park SH, Choi SM, Lee DG et al.   Serum galactomannan strongly correlates with outcome of invasive aspergillosis in acute leukaemia patients. Mycoses  2011; 54: 523– 30. Google Scholar CrossRef Search ADS PubMed  25 Miceli MH, Grazziutti ML, Woods G et al.   Strong correlation between serum Aspergillus galactomannan index and outcome of aspergillosis in patients with hematological cancer: clinical and research implications. Clin Infect Dis  2008; 46: 1412– 22. Google Scholar CrossRef Search ADS PubMed  26 Woods G, Miceli MH, Grazziutti ML et al.   Serum Aspergillus galactomannan antigen values strongly correlate with outcome of invasive aspergillosis: a study of 56 patients with hematologic cancer. Cancer  2007; 110: 830– 4. Google Scholar CrossRef Search ADS PubMed  27 Lortholary O, Gangneux JP, Sitbon K et al.   Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). Clin Microbiol Infect  2011; 17: 1882– 9. Google Scholar CrossRef Search ADS PubMed  28 Kovanda LL, Kolamunnage-Dona R, Neely M et al.   Pharmacodynamics of isavuconazole for invasive mold disease: role of galactomannan for real-time monitoring of therapeutic response. Clin Infect Dis  2017; 64: 1557– 63. Google Scholar CrossRef Search ADS PubMed  29 Ben-Ami R, Lewis RE, Raad II et al.   Phaeohyphomycosis in a tertiary care cancer center. Clin Infect Dis  2009; 48: 1033– 41. Google Scholar CrossRef Search ADS PubMed  30 Campo M, Lewis RE, Kontoyiannis DP. Invasive fusariosis in patients with hematologic malignancies at a cancer center: 1998-2009. J Infect  2010; 60: 331– 7. Google Scholar CrossRef Search ADS PubMed  31 Kontoyiannis DP, Wessel VC, Bodey GP et al.   Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis  2000; 30: 851– 6. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: a post hoc analysis of the SECURE trial

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Abstract

Abstract Background Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA. Methods A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count <0.5 × 109/L for >10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed. Results One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P < 0.001; EOT, P < 0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P = 0.002) and numerically higher at day 7 and EOT (P > 0.05 for both). Conclusions Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes. Introduction Invasive aspergillosis (IA) has become the predominant mycosis in patients with haematological cancer and prolonged neutropenia.1 Historically, prolonged neutropenia was associated with a failure to respond to antifungal therapy as well as increased mortality in patients with haematological malignancies, although the data come mostly from older, single-institution, retrospective studies that relied on culture- or histopathology-proven IA cases in which the outcomes were poor.1–3 Pivotal randomized studies for the treatment of IA in the last two decades showed improvement of responses with triazoles,3–5 yet they do not provide an in-depth evaluation of the impact of neutropenia on IA outcomes. The significance of persistent neutropenia for outcomes in IA is a timely question in the era of high-potency new anti-Aspergillus triazoles, such as isavuconazole and voriconazole, and revised guidelines for the diagnosis of probable IA that heavily rely on Aspergillus galactomannan (GM) detection. Specifically, a potential confounder for improved outcome in the latest studies might have been the introduction of Aspergillus GM in serum or bronchoalveolar lavage samples, which is an important step in the early diagnosis of IA.6 The SECURE trial demonstrated the non-inferiority of isavuconazole compared with voriconazole for the treatment of IA and other filamentous fungi.5 In this post hoc analysis of the SECURE trial, we compared the efficacy and safety outcomes in the subset of patients with baseline neutropenia and IA in order to assess the impact of persistent neutropenia on mortality and outcomes in each treatment group. We also examined the impact of baseline GM on outcomes for each treatment arm. Methods Study design The SECURE trial (ClinicalTrials.gov; NCT00412893) was a global, Phase 3, randomized, multicentre, double-blind, comparative-group, non-inferiority trial of isavuconazole versus voriconazole.5 The primary findings of this trial together with methodology and patient eligibility criteria have been reported elsewhere.5 Briefly, patients aged ≥18 years with proven, probable or possible invasive fungal infections, defined according to the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group,7 were randomized 1:1 to receive isavuconazole or voriconazole. Patients assigned to isavuconazole received a loading dose of 372 mg of isavuconazonium sulphate prodrug, equivalent to 200 mg of isavuconazole, three times daily intravenously for the first 2 days, followed by a maintenance once-daily intravenous or oral dose of 200 mg of isavuconazole from day 3 to end of treatment (EOT). Patients assigned to voriconazole received a loading dose of 6 mg/kg every 12 h intravenously on study day 1, followed by a maintenance dose of 4 mg/kg every 12 h intravenously or 200 mg every 12 h orally from day 2 to EOT. Patients were treated for up to a maximum of 84 days. The final follow-up visit was scheduled at 4 weeks ±7 days after the last dose of study drug, which may have occurred before or after day 42 and/or day 84. The primary endpoint of this post hoc analysis was all-cause mortality (ACM) through day 42 following primary treatment with isavuconazole compared with voriconazole in patients with neutropenia and IA. Differences in the primary outcome by neutropenic status and treatment assignment, for patients with neutropenia at baseline that had resolved or remained at day 7, day 42 and EOT, were also assessed. Overall success at EOT was a key secondary endpoint and was based on clinical, mycological and radiological responses as described previously.5 The impact of baseline GM on outcomes in each treatment arm was evaluated. Assessments Mycological assessments were performed locally according to best practice and included samples for fungal culture and isolation and biopsy/biological fluid samples from the infected site for histology/cytology. Serum samples were assessed for Aspergillus infection by GM antigen assay, with a single value ≥0.7 or two consecutive values ≥0.5 by Bio-Rad Platelia™ (Bio-Rad, Hercules, CA, USA) considered a positive result. An independent data review committee (DRC) assessed proven or probable IA status and evaluated clinical, mycological and overall response at EOT based on consensus criteria.8 Specifically, complete or partial clinical success was defined as the complete resolution or partial resolution, respectively, of attributable clinical symptoms and physical findings. Clinical failure was defined as no resolution of any attributable clinical symptoms and physical findings and/or worsening of symptoms or results not available. Mycological success was defined as eradication, or presumed eradication, of infection, and failure as cases of persistence or presumed persistence of infection. Neutropenic status was determined at baseline, day 7, day 42 and EOT. Neutropenia was defined as an absolute neutrophil count (ANC) <0.5 × 109/L for >10 days at baseline. For measurements on or before day 7, unresolved neutropenia was defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement. For day 42 and EOT measurements, unresolved neutropenia was defined as no ANC measurement in patients whose previously available ANC indicated neutropenia, or at least one ANC <0.5 × 109/L measurement from day 35 to day 49, or from 3 days before to 3 days after last treatment dose, respectively. Patients whose neutropenia had resolved were compared with those who remained neutropenic (unresolved neutropenia). A comparison of the efficacy and safety of isavuconazole compared with voriconazole was also carried out for these patient groups. The incidence, nature and severity of treatment-emergent adverse events (TEAEs) were monitored and assessed throughout the study for all patients who received one or more doses of study drug. Analysis populations This analysis was performed using the mycological ITT (myITT) population, which included all patients with neutropenia and proven or probable IA, as assessed by the DRC, who had received at least one dose of study drug. Statistical analyses Demographic and baseline characteristics were summarized for the myITT population. The primary efficacy endpoint of crude ACM through day 42 was assessed from the myITT population, with the between-group treatment difference obtained by subtracting the voriconazole rate from isavuconazole rate. Fisher’s exact test (two-tailed) (R software, University of Aix-Marseille, France) was used to assess differences between treatment groups and between groups with resolved versus unresolved neutropenia and P < 0.05 was considered significant. Results Patient demographics and baseline characteristics Overall, 142 patients with neutropenia received one or more doses of study drug and had either proven or probable IA, and thus constituted the myITT population. The treatment subgroups were mostly well balanced with respect to age and other baseline characteristics (Table 1). The percentage of males was lower among those assigned to the isavuconazole group, compared with those assigned to the voriconazole group. Nearly all patients had underlying haematological malignant disease, with acute leukaemia accounting for >50% cases in each treatment group (Table 1). Most patients had active malignancy at the diagnosis of IA (83.3% and 89.1% in the isavuconazole and voriconazole groups, respectively). The majority of patients only had invasive pulmonary aspergillosis (91.0% in the isavuconazole group and 96.9% in the voriconazole group). More patients in the isavuconazole group (2/78) had disseminated IA compared with the voriconazole group (0/64, P = not significant; Table 1). Table 1. Demographics and baseline characteristics of patients with neutropeniaa and IA (myITT population)b Parameter  Isavuconazole (n = 78)  Voriconazole (n = 64)  Age (years), mean (SD)  51.6 (15.2)  50.0 (15.1)  Male, n (%)  38 (48.7)  39 (60.9)  Race, n (%)       white  62 (79.5)  45 (70.3)   Asian  15 (19.2)  19 (29.7)   other  1 (1.3)  0  Baseline condition, n (%)       primary underlying disease  78 (100.0)  64 (100.0)    AML  37 (47.4)  38 (59.4)    ALL  14 (17.9)  7 (10.9)    refractory anaemia with excess of blasts  6 (7.7)  1 (1.6)    myelodysplastic syndrome  2 (2.6)  4 (6.3)    non-Hodgkin’s lymphoma  6 (7.7)  0    CLL  1 (1.3)  3 (4.7)    CML  2 (2.6)  2 (3.1)    T cell lymphoma  1 (1.3)  2 (3.1)    aplastic anaemia  1 (1.3)  2 (3.1)    otherc  17 (21.8)  12 (18.8)   active malignancy  65 (83.3)  57 (89.1)   T cell immunosuppressant  27 (34.6)  26 (40.6)   allogeneic bone marrow transplantation  17 (21.8)  7 (10.9)   corticosteroid use  10 (12.8)  9 (14.1)  Location of aspergillosis, n (%)       LRTD only  71 (91.0)  62 (96.9)   LRTD + other organ  4 (5.1)  0   non-LRTD only  3 (3.8)  2 (3.1)  Non-LRTD location, n (%)  7 (9.0)  2 (3.1)   disseminated  2 (2.6)  0   brain  1 (1.3)  0   sinus  5 (6.4)  2 (3.1)   skin  1 (1.3)  0   other  1 (1.3)  0  Parameter  Isavuconazole (n = 78)  Voriconazole (n = 64)  Age (years), mean (SD)  51.6 (15.2)  50.0 (15.1)  Male, n (%)  38 (48.7)  39 (60.9)  Race, n (%)       white  62 (79.5)  45 (70.3)   Asian  15 (19.2)  19 (29.7)   other  1 (1.3)  0  Baseline condition, n (%)       primary underlying disease  78 (100.0)  64 (100.0)    AML  37 (47.4)  38 (59.4)    ALL  14 (17.9)  7 (10.9)    refractory anaemia with excess of blasts  6 (7.7)  1 (1.6)    myelodysplastic syndrome  2 (2.6)  4 (6.3)    non-Hodgkin’s lymphoma  6 (7.7)  0    CLL  1 (1.3)  3 (4.7)    CML  2 (2.6)  2 (3.1)    T cell lymphoma  1 (1.3)  2 (3.1)    aplastic anaemia  1 (1.3)  2 (3.1)    otherc  17 (21.8)  12 (18.8)   active malignancy  65 (83.3)  57 (89.1)   T cell immunosuppressant  27 (34.6)  26 (40.6)   allogeneic bone marrow transplantation  17 (21.8)  7 (10.9)   corticosteroid use  10 (12.8)  9 (14.1)  Location of aspergillosis, n (%)       LRTD only  71 (91.0)  62 (96.9)   LRTD + other organ  4 (5.1)  0   non-LRTD only  3 (3.8)  2 (3.1)  Non-LRTD location, n (%)  7 (9.0)  2 (3.1)   disseminated  2 (2.6)  0   brain  1 (1.3)  0   sinus  5 (6.4)  2 (3.1)   skin  1 (1.3)  0   other  1 (1.3)  0  ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia; LRTD, lower respiratory tract disease. a ANC <0.5 × 109/L for >10 days at baseline. b myITT population: all randomized patients who received at least one dose of study drug and were diagnosed with IA. c Other occurring in a single patient from each or either treatment group: Hodgkin’s disease, acute biphenotypic leukaemia, acute monocytic leukaemia, acute promyelocytic leukaemia, B cell lymphoma, Burkitt’s leukaemia, chloroma, hairy cell leukaemia, leukaemia, lymphoplasmacytoid lymphoma/immunocytoma stage IV, multiple myeloma. Most aspergillosis diagnoses were based only on positive serum GM (74.4% isavuconazole group, 82.8% voriconazole group) versus isolation of Aspergillus spp. alone and Aspergillus spp. plus other filamentous fungi (25.6% isavuconazole group, 17.2% voriconazole group; Table 2). Among those patients with a pathogen identified at baseline, the predominant pathogens causing IA as assessed by the DRC were Aspergillus fumigatus and Aspergillus flavus (Table 2), which accounted for 15.4% of cases in the isavuconazole group and 17.2% of cases in the voriconazole group. Table 2. Baseline pathogens causing IA in patients with neutropeniaa (myITT populationb) Pathogen causing IAc  Isavuconazole (n = 78)  Voriconazole (n = 64)  Aspergillus spp. only, n (%)  17 (21.8)  11 (17.2)   A. fumigatus  8 (10.3)  6 (9.4)   A. flavus  4 (5.1)  5 (7.8)   Aspergillus niger  4 (5.1)  0   Aspergillus terreus  1 (1.3)  0   Aspergillus sydowii  1 (1.3)  0  Aspergillus spp. plus other filamentous fungi, n (%)  3 (3.8)  0  Positive serum GMd, n (%)  58 (74.4)  53 (82.8)  Pathogen causing IAc  Isavuconazole (n = 78)  Voriconazole (n = 64)  Aspergillus spp. only, n (%)  17 (21.8)  11 (17.2)   A. fumigatus  8 (10.3)  6 (9.4)   A. flavus  4 (5.1)  5 (7.8)   Aspergillus niger  4 (5.1)  0   Aspergillus terreus  1 (1.3)  0   Aspergillus sydowii  1 (1.3)  0  Aspergillus spp. plus other filamentous fungi, n (%)  3 (3.8)  0  Positive serum GMd, n (%)  58 (74.4)  53 (82.8)  a Neutropenia: ANC <0.5 × 109/L for >10 days at baseline. b myITT population: all randomized patients who received at least one dose of study drug, with proven or probable IA. c As assessed by the DRC. d Serum GM single value ≥0.7 or two consecutive serum sample values of ≥ 0.5 to < 0.7. Efficacy outcomes In the isavuconazole group, neutropenia persisted in 58/78 (74.4%) patients at day 7, 40/78 (51.3%) patients at day 42 and 37/78 (47.4%) patients at EOT. In the voriconazole group, neutropenia persisted in 47/64 (73.4%) patients at day 7, 31/64 (48.4%) patients at day 42 and 33/64 (51.6%) patients at EOT. How the diagnosis of neutropenia was made is shown in Table S1 (available as Supplementary data at JAC Online). Patients who had resolved their neutropenia at day 7 but subsequently relapsed are shown in Table S2. Overall, 10/20 (50.0%) and 11/17 (64.7%) patients in the isavuconazole and voriconazole groups, respectively, who had resolved neutropenia at day 7 were subsequently diagnosed with unresolved neutropenia at day 42. Similarly, 8/20 (40.0%) and 7/17 (41.2%) patients in the isavuconazole and voriconazole groups, respectively, who had resolved neutropenia at day 7 subsequently were diagnosed with unresolved neutropenia at EOT. The relapse in neutropenia was predominantly due to the lack of availability of absolute neutrophil counts at these timepoints (Table S2). In patients who were neutropenic at baseline, overall ACM at day 42 occurred in 19/78 (24.4%) patients (18/58 patients with unresolved neutropenia at day 7 and 1/20 patients with resolved neutropenia at day 7) in the isavuconazole group and 15/64 (23.4%) patients (14/47 patients with unresolved neutropenia at day 7 and 1/17 patients with resolved neutropenia at day 7) in the voriconazole group (Table 3). Irrespective of treatment assignment, ACM was higher for patients who remained neutropenic at each timepoint [day 7, 32/105 (30.5%); day 42, 32/71 (45.1%); EOT, 30/70 (42.9%)] compared with patients whose neutropenia had resolved at that timepoint [day 7, 2/37 (5.4%); day 42, 0/32; EOT, 2/35 (5.7%)], regardless of whether the diagnosis of IA was by culture plus GM or just GM positivity (culture negative) (Table 3). A separate analysis of the data showed that 5/142 (3.5%) patients died before day 7 [4/78 (5.1%) in the isavuconazole group and 1/64 (1.6%) in the voriconazole group], 28/142 (19.7%) patients died between day 7 and 42 [15/78 (19.2%) in the isavuconazole group and 13/64 (20.3%) in the voriconazole group] and 14/142 (9.9%) patients died between day 43 and day 84 [7/78 (9.0%) in the isavuconazole group and 7/64 (10.9%) in the voriconazole group]. Table 3. ACM at day 42 in patients with unresolved versus resolved neutropenia dependent on day of resolution of neutropenia and diagnosis by culture and GM or by GM alone Neutropeniac status  Culture-based + GM IAa, n/N (%) deaths   GM alone IAb, n/N (%) deaths   Total, n/N (%) deaths   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  6/16 (37.5)  2/6 (33.3)  12/42 (28.6)  12/41 (29.3)  18/58 (31.0)  14/47 (29.8)   resolved  0/4  1/5 (20.0)  1/16 (6.3)  0/12  1/20 (5.0)  1/17 (5.9)   Pe  0.267  1.000  0.087  0.048  0.031  0.053  Day 42f               unresolved  6/13 (46.2)  2/4 (50.0)  12/27 (44.4)  12/27 (44.4)  18/40 (45.0)  14/31 (45.2)   resolved  0/3  0/2  0/15  0/14  0/18  0/16   Pe  0.250  0.467  0.003  0.003  <0.001  0.002  EOTg               unresolved  6/8 (75.0)  0/3  12/29 (41.4)  12/30 (40.0)  18/37 (48.6)  12/33 (36.4)   resolved  0/8  2/3 (66.7)  0/13  0/11  0/21  2/14 (14.3)   Pe  0.007  0.400  0.008  0.018  <0.001  0.175  Neutropeniac status  Culture-based + GM IAa, n/N (%) deaths   GM alone IAb, n/N (%) deaths   Total, n/N (%) deaths   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  6/16 (37.5)  2/6 (33.3)  12/42 (28.6)  12/41 (29.3)  18/58 (31.0)  14/47 (29.8)   resolved  0/4  1/5 (20.0)  1/16 (6.3)  0/12  1/20 (5.0)  1/17 (5.9)   Pe  0.267  1.000  0.087  0.048  0.031  0.053  Day 42f               unresolved  6/13 (46.2)  2/4 (50.0)  12/27 (44.4)  12/27 (44.4)  18/40 (45.0)  14/31 (45.2)   resolved  0/3  0/2  0/15  0/14  0/18  0/16   Pe  0.250  0.467  0.003  0.003  <0.001  0.002  EOTg               unresolved  6/8 (75.0)  0/3  12/29 (41.4)  12/30 (40.0)  18/37 (48.6)  12/33 (36.4)   resolved  0/8  2/3 (66.7)  0/13  0/11  0/21  2/14 (14.3)   Pe  0.007  0.400  0.008  0.018  <0.001  0.175  a Diagnosis of IA culture positive and GM positive. b Diagnosis of IA culture negative but GM positive. c Neutropenia: ANC <0.5 × 109/L for >10 days at baseline. d Unresolved neutropenia: no ANC measurement available or at least one ANC <0.5 × 109/L measurement from day 2 to day 7. e P, Fisher’s two-tailed exact test for unresolved versus resolved neutropenia. f Unresolved neutropenia at day 42 defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement from day 35 to day 49. g Unresolved neutropenia at EOT defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement from 3 days before last dose to 3 days after last dose. In analyses by treatment group (Table 3), ACM was comparable in both the isavuconazole and voriconazole groups who remained neutropenic at day 7 [18/58 (31.0%) and 14/47 (29.8%), respectively], day 42 [18/40 (45.0%) and 14/31 (45.2%), respectively] and EOT [18/37 (48.6%) and 12/33 (36.4%), respectively]. ACM was statistically significantly lower in isavuconazole-treated patients whose neutropenia had resolved compared with isavuconazole-treated patients with unresolved neutropenia at day 7 [1/20 (5.0%) compared with 18/58 (31.0%), P = 0.031], day 42 [0/18 compared with 18/40 (45.0%), P < 0.001] and EOT [0/21 compared with 18/37 (48.6%), P < 0.001]. In voriconazole-treated patients, ACM was significantly lower for resolved, compared with unresolved, neutropenia at day 42 [0/16 compared with 14/31 (45.2%), P = 0.002] but not at day 7 [1/17 (5.9%) compared with 14/47 (29.8%), P = 0.053] or at EOT [2/14 (14.3%) compared with 12/33 (36.4%), P = 0.175] (Table 3). Although the numbers were small, ACM was slightly higher in patients with unresolved neutropenia regardless of treatment arm at day 7 and day 42 when diagnosis was based upon culture plus GM positivity, compared with culture-negative GM positivity (day 7, 8/22 versus 24/83; day 42, 8/17 versus 24/54, respectively; Table 3). There was a statistically significant association between baseline GM values and the risk of mortality in the isavuconazole group at day 42, with 0/12 patients in the ≥0.5 to ≤1.0 group, compared with 15/44 (34.1%) (P = 0.024) in the >1.0 group, and at EOT with 0/12 patients in the ≥0.5 to ≤1.0 group, compared with 18/44 (40.9%) (P = 0.006) in the >1.0 group, progressing to death (Table 4). In contrast, no significant link was observed in the voriconazole group. Table 4. Analysis of ACM at day 42 and EOT by baseline GM values (myITT population) Serum GM values  Isavuconazole (n = 78), n/N (%) deaths  Voriconazole (n = 64), n/N (%) deaths  Day 42       two consecutive values ≥0.5 but ≤1.0  0/12  4/15 (26.7)   at least one value of ≥ 0.7 but <1.0  2/9 (22.2), P = 0.171b  2/6 (33.3), P = 1.000b   at least one value ≥1.0  15/44 (34.1), P = 0.024b  8/38 (21.1), P = 0.722b   no serum GM values checkeda  2/13 (15.4)  1/5 (20.0)  EOT       two consecutive values ≥0.5 but ≤1.0  0/12  5/15 (33.3)   at least one value of ≥ 0.7 but <1.0  4/9 (44.4), P = 0.021b  4/6 (66.7), P = 0.331b   at least one value ≥1.0  18/44 (40.9), P = 0.006b  12/38 (31.6), P = 1.000b   no serum GM values checkeda  4/13 (30.8)  1/5 (20.0)  Serum GM values  Isavuconazole (n = 78), n/N (%) deaths  Voriconazole (n = 64), n/N (%) deaths  Day 42       two consecutive values ≥0.5 but ≤1.0  0/12  4/15 (26.7)   at least one value of ≥ 0.7 but <1.0  2/9 (22.2), P = 0.171b  2/6 (33.3), P = 1.000b   at least one value ≥1.0  15/44 (34.1), P = 0.024b  8/38 (21.1), P = 0.722b   no serum GM values checkeda  2/13 (15.4)  1/5 (20.0)  EOT       two consecutive values ≥0.5 but ≤1.0  0/12  5/15 (33.3)   at least one value of ≥ 0.7 but <1.0  4/9 (44.4), P = 0.021b  4/6 (66.7), P = 0.331b   at least one value ≥1.0  18/44 (40.9), P = 0.006b  12/38 (31.6), P = 1.000b   no serum GM values checkeda  4/13 (30.8)  1/5 (20.0)  a GM-positive result but no titre data available. b P, versus two consecutive values ≥0.5 but ≤1.0 (Fisher’s two-tailed exact test). In line with the ACM results, the finding of DRC-assessed treatment success at EOT was greater in patients with resolved, compared with those with unresolved, neutropenia at all timepoints, regardless of treatment group. Isavuconazole achieved rates of success similar to those of voriconazole in those stratified according to unresolved or resolved neutropenia status at day 7 and at day 42 but not at EOT (Table 5). At EOT, voriconazole appeared to have a greater success rate among those with unresolved neutropenia while isavuconazole appeared to have a greater success rate in those with resolved neutropenia. Overall, there were no differences between treatment groups at EOT [success in the isavuconazole group 19/58 (32.8%) versus voriconazole 16/47 (34.0%)]. Table 5. DRC-assessed overall success at EOT (myITT population) Neutropeniac status  Culture + GM IAa, n/N (%) success   GM only IAb, n/N (%) success   Total, n/N (%) success   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  5/16 (31.3)  1/6 (16.7)  14/42 (33.3)  15/41 (36.6)  19/58 (32.8)  16/47 (34.0)   resolved  4/4 (100.0)  3/5 (60.0)  7/16 (43.8)  7/12 (58.3)  11/20 (55.0)  10/17 (58.8)   Pe  0.026  0.242  0.546  0.202  0.110  0.091  Day 42f             unresolved  3/13 (23.1)  0/4  4/27 (14.8)  6/27 (22.2)  7/40 (17.5)  6/31 (19.4)   resolved  2/3 (66.7)  1/2 (50.0)  10/15 (66.7)  9/14 (64.3)  12/18 (66.7)  10/16 (62.5)   Pe  0.214  0.400  0.001  0.015  0.001  0.008  EOTg               unresolved  0/8  1/3 (33.3)  4/29 (13.8)  10/30 (33.3)  4/37 (10.8)  11/33 (33.3)   resolved  5/8 (62.5)  0/3  10/13 (76.9)  5/11 (45.5)  15/21 (71.4)  5/14 (35.7)   Pe  0.026  1.000  <0.001  0.491  <0.001  1.000  Neutropeniac status  Culture + GM IAa, n/N (%) success   GM only IAb, n/N (%) success   Total, n/N (%) success   isavuconazole  voriconazole  isavuconazole  voriconazole  isavuconazole  voriconazole  Day 7d               unresolved  5/16 (31.3)  1/6 (16.7)  14/42 (33.3)  15/41 (36.6)  19/58 (32.8)  16/47 (34.0)   resolved  4/4 (100.0)  3/5 (60.0)  7/16 (43.8)  7/12 (58.3)  11/20 (55.0)  10/17 (58.8)   Pe  0.026  0.242  0.546  0.202  0.110  0.091  Day 42f             unresolved  3/13 (23.1)  0/4  4/27 (14.8)  6/27 (22.2)  7/40 (17.5)  6/31 (19.4)   resolved  2/3 (66.7)  1/2 (50.0)  10/15 (66.7)  9/14 (64.3)  12/18 (66.7)  10/16 (62.5)   Pe  0.214  0.400  0.001  0.015  0.001  0.008  EOTg               unresolved  0/8  1/3 (33.3)  4/29 (13.8)  10/30 (33.3)  4/37 (10.8)  11/33 (33.3)   resolved  5/8 (62.5)  0/3  10/13 (76.9)  5/11 (45.5)  15/21 (71.4)  5/14 (35.7)   Pe  0.026  1.000  <0.001  0.491  <0.001  1.000  a Diagnosis of IA culture positive and GM positive. b Diagnosis of IA culture negative but GM positive. c Neutropenia: ANC <0.5 × 109/L for >10 days at baseline. d Unresolved neutropenia: no ANC measurement available or at least one ANC <0.5 × 109/L measurement from day 2 to day 7. e P, Fisher’s two-tailed exact test for unresolved versus resolved neutropenia. f Unresolved neutropenia at day 42 defined as no ANC measurement available or at least one ANC <0.5 × 09/L measurement from day 35 to day 49. g Unresolved neutropenia at EOT defined as no ANC measurement available or at least one ANC <0.5 × 109/L measurement from 3 days before last dose to 3 days after last dose. Discussion Using a post hoc analysis of the large Phase 3 SECURE trial, we report the largest contemporary dataset to date assessing the impact of neutropenia resolution on outcomes in patients with IA treated with the modern triazoles, isavuconazole and voriconazole, that are endorsed by guidelines as the preferred first-line agents.1 Failure to resolve neutropenia was a major factor for ACM regardless of the treatment group and is a major finding of our study. We also found that isavuconazole had similar efficacy to voriconazole in patients with baseline neutropenia, irrespective of whether neutropenia had resolved or remained at day 7, day 42 or EOT. However, poorer outcomes were observed for both drugs in the setting of persistent neutropenia. This suggests that neutropenia continues to be a predictor of poor outcomes in patients with IA, and that persistence of neutropenia could potentially influence outcomes in clinical trials. A number of studies have identified neutropenia as a risk factor for mortality and response to therapy in IA.9–14 Neutrophils are crucial for host protection against aspergillosis as they have a direct role in the destruction of hyphae and prevent germination of conidia.15,16 Delayed engraftment after stem cell transplantation and prolonged neutropenia are strong predictors of both IA and poor outcome.17 In a study of patients with haematological malignancies, Reuter et al.18 found that patients with neutropenia of ≤5 days had a 12 month survival rate of 92%, compared with 58% for those with persistent neutropenia of >10 days. Our study emphasizes the importance of resolving neutropenia in patients with IA, even in the era of early GM-based diagnosis of IA and the use of potent triazoles. Indeed, there was no further ACM at day 42 in patients whose neutrophil counts recovered. Therefore, early restoration of neutrophil count is an important consideration in the management of patients with IA. Whether the inferior outcomes of neutropenia reflect the fact that voriconazole and isavuconazole are static drugs in the doses currently used against Aspergillus spp. is a theoretical, yet tenable, hypothesis.19–21 In our analysis of patients who were neutropenic at baseline, the overall day 42 ACM rates of 24.4% (isavuconazole) and 23.4% (voriconazole) were slightly lower than those of previous studies that reported 6 and 12 week mortality data on the order of 27%–30% when voriconazole was used as primary monotherapy treatment of IA in patients with haematological diseases and haematopoietic stem cell transplantation,3,4,22 although not all patients in these older studies had neutropenia. In the current study, similar overall treatment success rates at EOT were observed between isavuconazole- and voriconazole-treated patients with neutropenia. At EOT, success was greater in those with resolved versus persistent neutropenia. Although the numbers were small, intriguingly, voriconazole appeared to have a better success rate among those with unresolved neutropenia while isavuconazole appeared to have a greater success rate in those with resolved neutropenia. Whether there are differences in the intracellular concentration of each azole in neutrophils and its immunomodulatory effect (favouring isavuconazole) or a more inherent fungicidal effect of voriconazole in the absence of neutrophils (favouring voriconazole) is a complex question that requires careful experimental testing. Alternatively, this might reflect some imbalances in the population. For example, disseminated IA was more common in the isavuconazole group, compared with the voriconazole group, and may not have been balanced between the resolved and unresolved neutropenia groups. Not surprisingly, most of the patients in our study had haematological cancer and had a diagnosis of probable IA, on the basis of a positive GM in serum and/or bronchoalveolar lavage. A number of studies have shown that GM values may be a surrogate marker for mortality due to IA, with high GM values being a predictor of mortality in patients with neutropenia.6,23–26 Furthermore, a diagnosis based on a positive culture together with GM positivity has been shown in a multivariate analysis to be independently associated with an increased risk of death.27 Our study did not show any significant differences in the risk of death between culture-positive and GM-alone diagnosis. In our study, irrespective of neutropenia status, there was a link between baseline GM values and ACM in patients receiving isavuconazole, but not in patients who received voriconazole. Furthermore, others have shown that patients with IA regardless of neutropenia status whose GM values normalize after initiation of antifungal therapy, including isavuconazole, have significantly better outcomes compared with patients with persistently positive GM values.6,23–26,28 Future clinical trials on IA should consider sequential GM values during treatment as a possible surrogate marker for success. As a post hoc analysis, this study has inherent limitations, including a limited analysis population that may have resulted in sampling bias and/or introduced imbalances and a lack of powering to support firm conclusions. In addition, as the study enrolment criteria excluded patients who were severely ill, and with comorbidities such as renal or hepatic dysfunction, there might be limitations in the generalizability of our findings. In conclusion, the findings of this post hoc analysis of the Phase 3 SECURE trial suggest that isavuconazole has comparable efficacy to voriconazole in the primary treatment of IA in patients with either resolved or unresolved neutropenia. These data confirm the durable influence of resolving neutropenia on improving antifungal treatment success and outcomes in patients with haematological cancer and IA. Similar observations of the profound influence of neutrophil recovery on outcome have been made for the other clinically important, yet less common non-Aspergillus moulds that cause invasive fungal infections in this patient population.29–31 Future studies should carefully analyse and report outcomes of agents by taking the issue of persistent neutropenia into account. Finally, whether there are meaningful differences in the activity of voriconazole compared with isavuconazole in patients with IA and unresolved neutropenia would require further study. Acknowledgements We are grateful for the contributions of Nkechi Azie, formerly of Astellas Pharma Global Development, to the development of the manuscript. Funding This study was funded by Astellas Pharma, Inc. Medical writing support was also funded by Astellas Pharma, Inc. Transparency declarations D. P. K. has received support from Astellas, Pfizer and Merck. D. S. has received support from Astellas, Pfizer and Merck. K. M. has received support from Astellas, Anson, Chimerix, Cubist, Optimer, Merck, Rebiotix, ViroPharma and Pfizer. O. A. C. has received support from Astellas, Cubist, Optimer, Pfizer, Gilead, Merck, 3M, Basilea, F2G, ViroPharma, GSK, Actelion, Sanofi Pasteur, Quintiles, Summit, Vifor, Celgene, Genzyme and Miltenyi. W. H. has received support from Astellas, Pfizer, Gilead, F2G, Amplyx and Basilea. O. L. has received support from Astellas, Pfizer, Gilead and Merck. R. C.-D. and C. L. are employees of Astellas Pharma Global Development, Inc. M. E. is an employee of Basilea Pharmaceutica International Ltd, Basel, Switzerland. T. F. P. has received support from Amplyx, Astellas, Basilea, Gilead, Merck, Pfizer, Toyama, Scynexis, Vical and Viamet.  Isavuconazole has been co-developed by Astellas and Basilea Pharmaceutica International Ltd.  Medical writing support was provided by John Clarke, a medical writer at Envision Scientific Solutions. Supplementary data Tables S1 and S2 are available as Supplementary data at JAC Online. References 1 Patterson TF, Thompson GR3rd, Denning DW et al.   Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis  2016; 63: e1– 60. Google Scholar CrossRef Search ADS PubMed  2 Burch PA, Karp JE, Merz WG et al.   Favorable outcome of invasive aspergillosis in patients with acute leukemia. J Clin Oncol  1987; 5: 1985– 93. 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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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