Antifungal prophylaxis with itraconazole in neutropenic ... - Nature

Leukemia (1998) 12, 1338–1343  1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu

Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia A Glasmacher1, E Molitor2, C Hahn1, K Bomba1, S Ewig1, C Leutner3, E Wardelmann4, IGH Schmidt-Wolf1, J Mezger1, G Marklein2 and T Sauerbruch1 1

Medizinische Klinik und Poliklinik, 2Institut fu¨r Medizinische Mikrobiologie und Immunologie, 3Radiologische Universita¨tsklinik and Pathologisches Institut, Rheinische Friedrich-Wilhelms-Universita¨t, Bonn, Germany

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The efficacy of antifungal prophylaxis with itraconazole capsules and its serum concentrations were evaluated in patients intensively treated for acute leukaemia. A consecutive group of patients without systemic antifungal prophylaxis (January 1993 to August 1994, period 1) was compared with another consecutive group of patients (period 2) who received itraconazole capsules (September 1994 to April 1995 400 mg/day, from May 1995 onwards 600 mg/day). All patients admitted with acute leukaemia and standard or high-dose chemotherapy were included into the study. Clinical endpoint was mortality from proven fungal infection. Seventy-six patients and 148 courses of cytotoxic chemotherapy were analysed in the control group as well as 47 patients and 112 treatment courses in the intervention group. Antifungal prophylaxis led to a significant decrease of mortality from invasive fungal infections (8.8%– 0.9%, P = 0.005). The median trough concentration of itraconazole of all measurements was 520 ng/ml (range 230–793) in patients who received 400 mg/day and 760 ng/ml (370–1200) in patients receiving a dosage of 600 mg/day (P = 0.002). These findings suggest that itraconazole is an effective drug for antifungal prophylaxis but also that a considerable number of patients do not reach the desired trough levels (⬎500 ng/ml) with itraconazole capsules. Keywords: acute leukaemia; itraconazole; fungal infections; prevention of infections; drug monitoring

Introduction Invasive fungal infections are increasingly recognised as a significant cause of morbidity and mortality in patients with acute leukaemia and have been found at autopsy in about 25% of these patients.1,2 An effective prophylaxis against fungal infections would therefore be an important advance in the supportive therapy of patients with acute leukaemia. Several drugs have been tested, but as yet no consensus on a prophylactic strategy has been reached.3,4 The oral intake of polyenes such as nystatin or amphotericin B has reduced superficial but not invasive fungal infections.5 Intravenous amphotericin B reduced fungal infections to some degree but was associated with considerable toxicity.6,7 Of the newer triazole agents, fluconazole has been studied extensively; a significant reduction of fungal infections, however, could only be shown for patients undergoing allogeneic bone marrow transplanation.8,9 Fluconazole has only marginal activity against Candida krusei and C. glabrata and is not active against Aspergillus spp.10,11 The triazole itraconazole is active against a wide range of yeasts and filamentous fungi.12 Previous studies in patients with acute leukaemia have shown a trend towards a reduction of invasive fungal infections. A major problem in these

Correspondence: A Glasmacher, Medizinische Klinik und Poliklinik, Department of Internal Medicine, Sigmund-Freud-Strasse 25, D53105 Bonn, Germany Received 13 February 1998; accepted 9 June 1998

patients is the limited bioavailability of itraconazole capsules.13 In the present study we evaluated the effect of antifungal prophylaxis with itraconazole capsules on the mortality from invasive mycoses in patients with acute leukaemia. Contrary to randomised trials, where the selection of patients may influence results and high-risk patients too ill to take the medication are often not randomised, our study included all individuals with acute leukaemia, who received standard- or highdose cytostatic treatment in the respective periods independent of their clinical state or their ability to take oral medication. This should allow a more representative assessment of the efficacy of itraconazole capsules in an unselected patient population. Patients and methods

Patients All patients suffering from acute leukaemia and receiving at least one full course of standard-dose or high-dose cytotoxic chemotherapy were evaluated prospectively and consecutively. Patients who received supportive care or low-dose palliative chemotherapy only were not eligible. No patient who fulfilled these criteria was excluded. Therefore, we are able to present an unselected case series. All patients were treated on a single ward at a university hospital not equipped with air filtration facilities.

Control group Seventy-six patients were admitted between January 1993 and August 1994 and fulfilled the inclusion criteria. They served as a consecutive control group (period 1). Although some of these patients received azole antimycotic agents during their treatment for various reasons, no systematic antifungal prophylaxis was given.

Itraconazole prophylaxis group Between September 1994 and May 1996, 47 patients were eligible for antifungal prophylaxis with itraconazole capsules and were followed prospectively (period 2). Until April 1995 only patients with defined risk factors (treatment with highdose cytarabine, (pre-) treatment with corticosteroids, fungal colonisation or previous invasive fungal infections) received 400 mg/day (200 mg twice daily) itraconazole capsules after meals (Sempera, Janssen-Cilag, Neuss, Germany). In 18 (34%) of 53 treatment cycles during this interval itraconazole was not given due to the following reasons: chemotherapy with vincristine, one; no high-risk factors or inability to take any

Antifungal prophylaxis with itraconazole A Glasmacher et al

oral medication, 17. From May 1995 onwards the dosage was raised to 600 mg/day itraconazole (200 mg three times daily) and itraconazole was given to all patients who did not receive vincristine. In eight (14%) of these 59 treatment cycles patients did not receive itraconazole (chemotherapy with vincristine, three; inability to take any oral medication, five). Again, no patient was excluded from the analysis. In total, 31 patients received itraconazole in 86 courses in period 2. Itraconazole was given from the beginning of cytotoxic chemotherapy treatment either up to the end of neutropenia (leukocyte count ⬎ 1.0 G/l) or the start of antimycotic treatment with intravenous amphotericin B.

Concomitant anti-infective therapy All patients received oral polyene antimycotics (nystatin 24 × 106 U/day or amphotericin B 2.4 g/day) and antibacterial prophylaxis with cotrimoxazole plus colistine. Weekly surveillance cultures were taken from mouth, nose and anus. When a temperature above 38.5°C was measured, broad-spectrum antibiotic therapy was initiated immediately. Intravenous amphotericin B was given on day 4 if no defervescence occurred. Patients disclosing pulmonary infiltrates on chest radiography were investigated by fiberoptic bronchoscopy and lavage if the fever did not resolve within 72 h. Bronchoalveolar fluid was cultured for bacteria, fungi, mycobacteria and viruses, and was stained for Pneumocystis carinii. In the second period, patients with pulmonary infiltrates were additionally examined with high-resolution computed tomography (HR-CT) scans.

Drug monitoring Serum concentrations of itraconazole were measured at trough levels (fasting, in the morning) by high performance liquid chromatography (HPLC).14 Two determinations during the chemotherapy course were made in the patient group receiving 400 mg/day and weekly determinations in patients receiving 600 mg/day. Values obtained on days 5–24 after the start of the prophylaxis were used for analysis. For some patients measurements were not available due to logistical reasons.

Definition of endpoints The study endpoint was mortality from proven invasive fungal infection defined as follows: (1) Histological and/or microbiological proof of invasive infection or (2) Radiological evidence of pneumonia and microbiological isolation of a fungus in blood cultures or in bronchoalveolar lavage fluid. The overall mortality was not defined as an endpoint.

Statistical analysis The evaluation is based on an ‘intention-to-treat’ analysis, eg that patients were evaluated even if they did not receive itraconazole during period 2 or rejected the proposed medi-

cation. The results of the drug monitoring were evaluated according to the two dosage groups (400 mg/day and 600 mg/day); for analysis of outcome patients in the two dosage groups were combined. The statistical analysis was performed with SPSS for Windows, Rel. 6.1.2, (SPSS, Munich, Germany). Data are given as median (range). Comparisons were made with Fisher’s exact test, Pearson’s ␹2 test and the Mann–Whitney U Wilcoxon rank sum test where appropriate. A logistic regression analysis was performed using the variables age (⬍60 or ⭓60 years), sex, relapse of leukaemia, duration of neutropenia (⬍20 or ⭓20 days), presence of myelodysplastic features in the bone marrow, high-risk cytogenetics, high-dose chemotherapy and the treatment period to predict death from invasive fungal infection. All P values are two-tailed.

Results

Clinical characteristics The clinical characteristics of 123 patients evaluated during the study are shown in Table 1. The patients received between one and six courses of cytotoxic chemotherapy during the study periods. Patients in period 1 received a median of one (1–5) course during the study whereas patients in period 2 received two (1–6) courses in median (P = 0.019). This difference is due to an intensification in the consolidation therapy of patients with acute leukaemia in period 2. There were no other significant differences of base-line variables (including diagnosis) between the patients in both time periods as shown in Table 1. Furthermore, no difference could be found in the pretreatment values for haemoglobin, platelet count, creatinine and total serum protein (data not shown). One hundred and forty-eight courses were evaluated in period 1 and 112 in period 2. Important clinical data are shown in Table 2. Again, base-line variables were not different. There was a non-significant trend towards more intensive chemotherapy (based on the use of high-dose cytarabine) in period 2 and, consequently, the duration of neutropenia (⬍0.5 G/l) was significantly longer (median 3 days) in period 2.

Antifungal prophylaxis Eighty-six (76.8%) of 112 courses of cytotoxic therapy were applied with concomitant itraconazole administration; 43% of these patients received 400 mg/day and 53.5% 600 mg/day. Single patients were given 200 mg/day and 300 mg/day and two patients received 800 mg/day. The median cumulative dose of itraconazole was 11 200 mg (400–33 000 mg) per course. In 83.7% of the chemotherapy courses with prophylactic use of itraconazole the cumulative dose was at least 2800 mg (eg at least 7 days with 400 mg/day). Table 3 shows the microbiological findings in both periods. There were 112 fungal isolates in period 1 and 65 in period 2 with no significant difference between the number of positive surveillance cultures (Table 3). The number of ‘other’ fungi showed a trend towards a higher rate in period 2 (Table 3). The following species were found more than once in period 1: C. norvegensis (3×), C. keyfir (3×), C. tropicalis (2×) and C. krusei (2×). A total of 12 species were found in period 2 with the following isolated more than once: C. krusei (5×), C. parapsilosis (2×) and C. sake (2×). The increase of C. krusei

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Table 1

Base-line characteristics of patients

Period 1 control group (01/93–08/94)

No. of patients No. of courses in total No. of courses per patient Age (years) Male (%) Diagnosis (%) Acute myeloid leukaemia Acute lymphoblastic leukaemia Blast crisis of chronic myeloid leukaemia

Table 2

Period 2 intervention group (09/94–05/96)

76 148 1 (1–5) 54.5 (18–89) 68.4

47 112 2 (1–6) 57.0 (19–84) 57.4

81.3 11.5 5.4

60.8 21.6 4.5

P

0.019 0.833 0.248 0.339

Clinical data on 260 treatment courses


No. of courses Disease status before treatment course Induction/consolidation of 1st remission % 1st relapse ⭓2nd relapse WBC before cytostatic therapy (G/l) LDH before cytostatic therapy (U/l) Intensity of cytostatic therapy % Standard-dosea cytostatic therapy High-dosea cytostatic therapy Duration of neutropeniab (day)


148

112

72.3 18.9 8.8 5.2 (0.2–214) 263 (98–5273)

80.4 10.7 8.9 7.0 (0.3–234) 245 (106–4458)

70.9 29.1 19 (1–41)

61.6 38.4 22 (2–62)

P

0.188

0.244 0.738 0.143 0.012

a

Standard-dose therapy is defined as cytarabine (less than 1.3 g/m2 total dose per course) plus a standard dose of daunorubicin (60 mg/m2 for 3 days) or idarubicin (8–12 mg/m2 for 3 days). High-dose therapy is defined as high-dose cytarabine (at least 6.0 g/m2 total dose per course) plus mitoxantrone (10 mg/m2 for 3–4 days) or idarubicin (8–12 mg/m2 for 3 days). b Calculated in patients surviving the chemotherapy course only.

Table 3

Microbiological findings and infectious complications in 260 treatment courses


No. of courses Courses with surveillance cultures with any fungal growth (%) Candida albicansa Candida glabrataa Other fungia Courses with ⭓1 febrile episode % Duration of 1st febrile episode (day) Courses with 2 febrile episodes %


P

148 78 (52.7)

112 71 (63.4)

0.125

49 (46.7) 44 (41.9) 12 (11.4) 74.3 4 (1–32) 23.0

50 (50.0) 31 (31.0) 19 (19.0) 67.9 4 (1–34) 19.6

0.093 0.680 0.052 0.269 0.846 0.546

a

Percentages are based on the number of isolates in each period.

isolations from surveillance cultures was not significant (P = 0.109).

Drug monitoring The monitoring of itraconazole serum trough concentrations showed a difference between patients receiving 400 mg/day

and those receiving 600 mg/day (Table 4). This was significant for trough levels determined at days 5–14 in both dosage groups. This difference persisted, albeit not statistically significantly, throughout the next 10 days (Table 4). If 500 ng/ml is assumed as the minimal trough level, 52% of the 400 mg/day group and 41% of the 600 mg/day group did not reach this threshold up to day 14 (P = 0.440). Although there is a trend towards higher levels in patients with higher doses


Table 4

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Itraconazole trough concentrations (ng/ml) during prophylaxis in period 2

All measurements on days 5–24 of prophylaxis (400 mg/day: n = 33; 600 mg/day: n = 80) All measurements on days 5–14 of prophylaxis (400 mg/day: n = 21; 600 mg/day: n = 51) All measurements on days 15–24 of prophylaxis (400 mg/day: n = 12; 600 mg/day: n = 29)

Itraconazole 400 mg/day

Itraconazole 600 mg/day

520 (270–760)

730 (350–1110)

0.0152

410 (200–590)

610 (310–1080)

0.0257

520 (178–693)

860 (530–1150)

0.2400

and a trend towards an increase of itraconazole trough concentrations during the treatment course (Table 4), a considerable portion of patients never achieved trough levels above 500 ng/ml.

P

cation because of nausea and was successfully treated with intravenous amphotericin B, the other had taken itraconazole during 16 days of neutropenia and achieved a trough level of 350 ng/ml when the pneumonia occurred. He was successfully treated with liposomal amphotericin B.

Invasive fungal infections Adverse effects Antifungal prophylaxis with itraconazole resulted in a significant reduction of fatal invasive fungal infections (Table 5). There was also a trend towards a reduction of the overall mortality, which was 7.1% lower in period 2. As the death rate from causes other than invasive fungal infection remained constant in the two study periods, it can be concluded that the reduction of the overall mortality is due to the reduction of lethal fungal infections (Table 4). The statistically significant reduction of mortality from invasive fungal infections could be equally demonstrated when the analysis was restricted to patients with acute myeloid leukaemia (Table 5) and when it was performed on a per patient instead of a per course basis (data not shown). In a multivariate logistic regression analysis looking for variables predicting death from invasive fungal infection only the treatment period (less events in period 2; r = 0.1850), P = 0.0166) and the application of high-dose chemotherapy (more events after high-dose chemotherapy; r = 0.1579, P = 0.0298) contributed significantly to the statistical model. One patient died from invasive fungal infection in period 2. Suffering from severe nausea and mucositis she could not take any oral medications from the start of the chemotherapy course. Fever unresponsive to broad-spectrum antibiotics occurred and intravenous amphotericin B was administered. C. glabrata was found in a tracheal specimen and she died from respiratory failure. In two patients during period 2, pulmonary lesions strongly suggesting invasive aspergillosis on HR-CT scans were detected. One of these patients had not taken any oral mediTable 5

No severe adverse effects (necessitating an interruption of prophylaxis) clearly attributable to itraconazole were seen in this population of patients intensively treated with chemotherapy, especially no severe hepatotoxicity. Although it could not be quantitated due to many confounding factors there was a clinical impression that more hypokalaemia occurred in patients with itraconazole. Potassium supplements or potassium-sparing agents were sufficient to restore normokalaemia. Discussion This study compares two consecutive, unselected and wellbalanced groups including all patients admitted with acute leukaemia and treated with standard or high-dose chemotherapy in the respective periods. In these patients antifungal prophylaxis with itraconazole capsules significantly reduced the mortality from invasive fungal infections. Our study also reports close drug monitoring of itraconazole during the antifungal prophylaxis showing that a considerable portion of patients did not reach the desired serum concentration (⬎500 ng/ml). Until now, six other studies of antifungal prophylaxis with itraconazole in patients with acute leukaemia have been published. One is a small randomised, controlled trial with 400 mg/day itraconazole that showed a non-significant reduction of invasive fungal infections from 18 to 11%.15 The statistical power of the study was too small to prove that the

Outcome of antifungal prophylaxis in 260 treatment courses


No. of courses Death from any cause (%) Death from proven invasive fungal infection (%) Death from all other causes (%) Death from proven invasive fungal infection in patients with AML onlya (%) a


P

148 37 (25.0) 13 (8.8) 24 (17.8)

112 20 (17.9) 1 (0.9) 19 (17.1)

0.177 0.005 1.000

10 (8.1)

1 (1.1)

0.025

123 treatment courses in period 1, 87 treatment courses in period 2.


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difference of 7% was statistically significant. Unfortunately, drug monitoring was not done. Tricot et al16 and Thunnissen et al17 published two smaller trials comparing 400 mg/day itraconazole vs historical controls receiving ketoconazole or nystatin. Both trials clearly showed a marked reduction of invasive fungal infections. The largest study until now was reported by Todeschini et al,18 who compared 164 patients with 200 mg/day itraconazole and nasal amphotericin B to a historical group of 290 patients with no antifungal prophylaxis. The rate of proven invasive aspergillosis fell from 4 to 0% (P = 0.004). Prentice et al19 used 200 mg/day itraconazole as antifungal prophylaxis in 111 treatment episodes and found a reduction of invasive fungal infections from 25 to 12% P ⬍ 0.02). Bo¨hme et al20 compared 197 patients who had received 400 mg/day itraconazole with a historical group of 223 patients who had received oral amphotericin B and found no significant reduction of invasive fungal infections. Our findings are in line with these previous studies. Furthermore, it could be shown that 600 mg/day itraconazole resulted in significantly higher serum trough concentrations in the first 2 weeks (days 5–14) than 400 mg/day, the dose that has been used previously. Our patients were evaluated on an ‘intention-to-treat’ basis in two unselected and consecutive groups that were highly comparable with respect to important risk factors for invasive fungal infections. Due to an overall intensification of treatment schedules patients in period 2 received more and more intensive (high-dose) therapy than in period 1 which also resulted in significantly longer duration of neutropenia in this patient group. As shown by the logistic regression analysis this increased the risk of invasive fungal infections in period 2. There is no consensus on a minimal serum concentration required for effective antifungal prophylaxis with itraconazole. We have argued that trough concentrations should be at least 500 ng/ml itraconazole measured by HPLC.13 In vitro most Candida spp. and Aspergillus spp. are inhibited at itraconazole concentrations of 1000 ng/ml.12 Hydroxy-itraconazole is a comparably active metabolite of itraconazole and in steadystate conditions it reaches concentrations up to two times higher than the mother compound.21,22 Due to its lipophilicity itraconazole accumulates in most target tissues such as lung, kidney and liver.21 Therefore, a serum concentration of at least 500 ng/ml itraconazole should be sufficient to inhibit more than 90% of the relevant strains. This hypothesis is supported by an in vivo animal model.23 Itraconazole inhibits its own metabolism and therefore reaches steady-state concentrations only after 14 days.22 In our study, this was reflected by the continuous rise of trough concentrations during the first weeks of administration (Table 4). It has been argued that itraconazole capsules are not reliably absorbed in neutropenic patients. Therefore, monitoring of drug concentrations was an important feature of our trial. In this study, 44% of measurements in patients receiving 400 mg/day itraconazole revealed trough concentrations below 500 ng/ml. The median serum concentration was significantly higher between days 5 and 14 in the 600 mg/day group. However, even in this dosage group a remarkable proportion of measurements (35%) did not reach the optimal target value. We assume that this is due to compliance problems and reduced absorption of capsules in patients suffering from nausea and mucositis. Use of the itraconazole cyclodextrin solution may help to overcome this difficulty.24,25 The rate of positive surveillance cultures did not decline in period 2 despite the fact that there were less fatal fungal infec-

tions. Itraconazole does not reach effective concentrations in the mucosa of the gastrointestinal tract and is found in low concentrations in the saliva.21 Furthermore, the capsules (in contrast to the itraconazole solution) cannot exert a local antimycotic effect. Our study was not designed to draw conclusions on these findings but one could speculate that despite unchanged fungal growth in the gastrointestinal tract sufficient blood concentrations of itraconazole prevented invasive infections. We conclude that itraconazole seems to be an effective drug for the prevention of invasive fungal infections in patients with acute leukaemia receiving intensive cytostatic chemotherapy. For itraconazole capsules a dosage of at least 600 mg/day seems more appropriate – but not yet satisfactory – to achieve trough concentrations above 500 ng/ml.

Acknowledgements We gratefully acknowledge that itraconazole concentrations were determined by Dr Dagmar Lampe, Berlin. Helpful comments came from Dr F Odds, Beerse, Belgium, and Dr C Whitelaw, Edinburgh. This work was supported by Leuka¨mieInitiative Bonne ev.

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