Infectious Medicine

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

Abstract

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at 7.5 mg kg−1 per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P0.001) and 11% for combination therapy (P<0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8–32.5; P<0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P0.02) and hepatotoxicity (P<0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Introduction

Invasive aspergillosis is one of the most common and most life-threatening invasive fungal infections occurring in patients with hematologic malignancies and patients who have undergone hematopoietic stem cell transplant.1, 2, 3 In these patients, invasive aspergillosis continues to be associated with a mortality rate that exceeds 50%,3, 4 and treatment with conventional antifungal agents such as amphotericin B is associated with a high level of toxicity and intolerance.5, 6

Posaconazole is a potent extended-spectrum triazole shown to have activity in vitro and in animal studies against Aspergillus spp., including amphotericin B-resistant Aspergillus terreus.7, 8, 9 In a multicenter clinical study that predated the use of echinocandins, posaconazole salvage therapy for invasive aspergillosis in patients with diverse underlying diseases was found to be superior to conventional antifungal therapy (consisting mainly of an amphotericin B-based regimen, itraconazole or both) in a historical control group.10

Several studies have suggested that a high-dose lipid formulation of amphotericin B (HD-LPD/AMB; 10 mg kg−1 per day) improves the survival rate in patients with invasive aspergillosis.11, 12, 13, 14, 15, 16 Anecdotal experience at our institution supported these studies' findings and this led to the widespread use of HD-LPD/AMB as salvage treatment for invasive aspergillosis in hematologic malignancy patients.17 In addition, in vitro studies suggesting that the echinocandin caspofungin has synergistic activity with amphotericin B for at least half of the Aspergillus isolates tested18 and clinical studies showing that this combination had a response rate exceeding 55% in patients with invasive aspergillosis19, 20 led to our use of HD-LPD/AMB plus caspofungin. From 1999 to 2005, hematologic malignancy patients with invasive aspergillosis at our tertiary-care cancer center were included in compassionate-use trials of posaconazole as salvage therapy. This study evaluated the efficacy and safety of posaconazole as salvage therapy in this patient population and compared posaconazole retrospectively with HD-LPD/AMB alone or in combination with caspofungin.

Materials and methods

Posaconazole salvage therapy trials

Between August 1999 and January 2005, 53 hematologic malignancy patients were enrolled in compassionate-use trials of posaconazole salvage therapy. Patients had to have documented invasive aspergillosis, defined in accordance with the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria.21 Only proven and probable cases with respective histopathology or microbiologic evidence of aspergillosis were included. Possible cases were not included. Patients received posaconazole salvage therapy only after having had at least 7 days of other antifungal therapy to which they were refractory (defined by disease progression or failure to improve) or intolerant (defined by severe infusion-related toxicity, renal impairment (serum creatinine level double the baseline value or more than two times the upper limit of normal) or other organ dysfunction). The daily posaconazole dose consisted of 800 mg, given orally or via an enteral feeding tube in 200-mg doses four times daily while in the hospital and in 400-mg doses twice daily outside the hospital. Patients were instructed to take posaconazole following a fatty meal and were followed up for at least 6 months.

The following clinical information was obtained on all study patients: gender, age, underlying hematologic malignancy, history of hematopoietic stem cell transplant within the past year (autologous or allogeneic), presence of graft-versus-host disease, mean duration of neutropenia, persistence of neutropenia during therapy, high-dose steroid use (defined as the equivalent of 600 mg of prednisone), tacrolimus use, prior antifungal therapy and reason for discontinuation, additional therapy during infection (including white blood cell transfusions), admission to the intensive care unit (ICU; including duration of stay in the ICU) and need for mechanical ventilation (including duration of mechanical ventilation). Information pertaining to the type of infection, site of infection, prior antifungal prophylaxis and mean duration of posaconazole therapy was also obtained. Adverse events were determined for study patients, with special attention given to changes in renal and liver function during therapy. Outcomes were assessed as described below.

HD-LPD/AMB salvage therapy

Between August 1994 and December 2005, 382 patients with hematologic malignancies were diagnosed as having invasive aspergillosis based on the EORTC/MSG criteria. Fifty-two of these patients received HD-LPD/AMB (7.5 mg kg−1 per day) as salvage therapy for invasive aspergillosis and fulfilled all the inclusion criteria for salvage therapy used in the posaconazole trials and were included in this study as a control group. An additional 38 patients with hematologic malignancies and invasive aspergillosis who met the criteria outlined for the posaconazole trials received a combination of HD-LPD/AMB (7.5 mg kg−1 per day) and caspofungin (70 mg on day 1 and 50–100 mg per day) and also were included in the control group. These control patients' medical records were retrospectively reviewed to extract the clinical information outlined above.

Definitions of responses

The following definitions were used in determining the response to salvage antifungal therapy:

  1. 1)

    Favorable response: complete (complete resolution of clinical, radiographic and microbiologic abnormalities present at study entry) or partial (significant improvement) response to salvage antifungal therapy.

  2. 2)

    Failure: progressive or stable disease in response to salvage antifungal therapy or toxicity that required discontinuation of the therapy.

Response was assessed at the end of antifungal therapy or at 12 weeks after the initiation of therapy, whichever came first.

Aspergillosis was considered to have contributed to the death of a patient within 12 months after initiation of salvage therapy if the patient died with clinical, radiographic or postmortem evidence of aspergillosis and had not had a persistent favorable response to the salvage therapy.

Statistical analysis

Categorical variables were compared by χ2-test or Fisher's exact test as appropriate. Continuous variables were compared by Student's t-test. In addition, a multiple logistic regression technique was applied to evaluate the independent effect of salvage therapy and other factors on response. First, univariate analyses were performed to evaluate the predictive effect of each factor alone. Then, any factor with a P-value <0.25 in the univariate analyses was included in a full multiple logistic regression model. Finally, the full model was reduced one factor at a time such that all factors remaining in the model were statistically significant at a 5% significance level. The patients were followed up for 12 weeks from initiating salvage therapy. The Kaplan–Meier method was used to estimate the overall survival probability of each treatment group, and the log-rank test was used for comparisons of overall survival. P-values <0.05 were considered statistically significant in the analysis. Data analyses were performed using SPSS version 12.0 software (SPSS Inc., Chicago, IL, USA).

Results

Characteristics of patients

A total of 143 patients were included in this study divided among three subgroups: 53 patients were treated with posaconazole, 52 treated with HD-LPD/AMB and 38 treated with HD-LPD/AMB plus caspofungin. Among the three subgroups 21–40% had proven (or definite) aspergillosis and the rest (60–79%) were diagnosed to have probable aspergillosis in accordance with the EORTC/MSG criterion.21

As shown in Table 1, patients treated with posaconazole were similar to those treated with HD-LPD/AMB in terms of gender, age, sites of invasive aspergillosis, underlying malignancy, type of transplant, steroid use, presence of neutropenia at the onset of infection, mean duration of neutropenia, persistence of neutropenia during therapy, mean duration of stay in the ICU and mean duration of mechanical ventilation. Furthermore, the distribution of Aspergillus spp. causing the invasive fungal infections was similar in the two groups. The two groups were also similar in terms of prior antifungal prophylaxis with fluconazole or itraconazole.

Table 1 Clinical characteristics of patients receiving posaconazole or HD-LPD/AMB

The patients treated with posaconazole and those treated with HD-LPD/AMB plus caspofungin were also similar for all characteristics except three, that is, the mean duration of neutropenia from diagnosis of invasive aspergillosis was significantly longer for patients treated with posaconazole, the mean duration of mechanical ventilation was significantly longer for patients treated with HD-LPD/AMB and caspofungin and the proportion of the patients who had ICU stay (Table 2).

Table 2 Clinical characteristics of patients receiving posaconazole or HD-LPD/AMB with caspofungin

The most common primary antifungal therapy received by study subjects was a regular-dose (3–5 mg kg−1 per day) lipid formulation of amphotericin B (LPD/AMB) (Table 3). Other regimens used as primary therapy included LPD/AMB with itraconazole or caspofungin, caspofungin alone, itraconazole alone, non-lipid amphotericin B or voriconazole consisting regimen.

Table 3 Prior primary antifungal therapy

Response and survival

As shown in Table 4, the overall rate of favorable response to posaconazole was 40%, compared to only 8 and 11% for HD-LPD/AMB alone or in combination with caspofungin, respectively (P<0.01). Furthermore, patients treated with posaconazole had a significantly lower Aspergillus-related mortality rate and a lower rate of death within 12 weeks after the initiation of salvage therapy (P0.02). The rate of favorable response to at least 7 days of salvage treatment in non-ICU patients was significantly higher for the posaconazole group than the two other groups (P0.03). Because the mean duration of mechanical ventilation among critically ill patients was longer in the HD-LPD/AMB plus caspofungin group than in the posaconazole group, we examined the response rate among the non-critically ill (non-ICU) patients in the three groups who received at least 7 days of salvage therapy. As shown in Table 4, the favorable response rate among non-critically ill patients who received at least 7 days of salvage treatment was significantly higher for posaconazole than for the other two groups (P0.03). For critically ill (ICU) patients who received at least 7 days of salvage treatment, the favorable response rate in posaconazole group was 27%, as compared to 6% in HD-LPD/AMB group (P=0.27) and also 6% in HD-LPD/AMB plus caspofungin group (P=0.14).

Table 4 Response to therapy, duration of therapy and death

The rate of favorable response to HD-LPD/AMB alone was not significantly different from that to HD-LPD/AMB plus caspofungin.

As shown in Table 5, multiple logistic regression analysis showed that posaconazole salvage therapy was associated with a significantly higher likelihood of a favorable response than HD-LPD/AMB alone (odds ratio (OR), 9.5; 95% confidence interval (CI), 2.8–32.5; P<0.001) and HD-LPD/AMB plus caspofungin (OR, 4.0; 95% CI, 1.1–14.5; P=0.03). In the posaconazole versus HD-LPD/AMB model, white blood cell transfusion was independently associated with a poor response, possibly reflecting the poor response associated with profound neutropenia. In the posaconazole versus combination therapy model, admission to the ICU and persistent neutropenia were independently associated with a poor response.

Table 5 Factors associated with favorable response in multiple logistic regression analysis

As shown in Figure 1, within the 12 weeks of follow-up posaconazole therapy was associated with a significantly higher overall survival rate than HD-LPD/AMB alone or in combination with caspofungin (P0.04).

Figure 1
figure1

(a) Kaplan–Meier overall survival curves for patients receiving posaconazole versus high-dose lipid formulation of amphotericin B (HD-LPD/AMB). (b) Kaplan–Meier overall survival curves for patients receiving posaconazole versus HD-LPD/AMB+caspofungin.

Toxicity and duration of therapy

HD-LPD/AMB alone or in combination with caspofungin was associated with significantly higher rates of hepatic toxicity (twofold or greater increase in bilirubin, and aspartate transaminase) and renal toxicity (twofold or greater increase in serum creatinine) compared with posaconazole (P0.02, Table 6).

Table 6 Renal and hepatic toxicity related to salvage therapy

The duration of salvage therapy was significantly longer with posaconazole than with HD-LPD/AMB alone or combined with caspofungin (Table 4). This might be a reflection of the fact that posaconazole was better tolerated as well as being associated with better response and survival rates with posaconazole.

Discussion

This study indicates that posaconazole is an effective option for salvage therapy for invasive aspergillosis in patients with hematologic malignancies. Oral posaconazole therapy achieved a higher rate of favorable responses when given as salvage therapy for invasive aspergillosis in hematologic malignancy patients than did HD-LPD/AMB alone or in combination with caspofungin. Furthermore, posaconazole was associated with a higher overall survival rate and a significantly lower rate of aspergillosis-related death than the other two regimens. In addition, posaconazole was associated with significantly lower rates of renal and hepatic toxicity.

Our study confirms the findings of other studies that triazoles with anti-mold activity are superior to the polyene antifungal agents (such as amphotericin B) in the treatment of invasive aspergillosis.5, 10 In particular, our study confirms the multi-institutional trial findings of Walsh et al.10 that posaconazole is associated with better overall response and survival when compared to amphotericin B-based regimen in the treatment of invasive aspergillosis. However, our current study has several distinctive features. First, it involved only patients with hematologic malignancies rather than a diverse patient population studied previously.10 Second, the comparison groups received HD-LPD/AMB alone or in combination with caspofungin, whereas the previous study predated the use of the echinocandins and included control patients who mostly received regular-dose amphotericin B-based regimens with or without itraconazole. Third, more than half of the patients included in the current study were neutropenic at baseline (51–71%), whereas only 20–30% included in the previous study were neutropenic at baseline. Hence, our patient population was sicker than that which was studied previously.10

Lipid formulations of amphotericin B have been shown to have less toxicity than conventional amphotericin B.22, 23 However, there are no comparative data to demonstrate whether lipid formulations of amphotericin B are more efficacious than conventional amphotericin B in the treatment of invasive aspergillosis in patients with hematologic malignancies. Animal data have demonstrated that HD-LPD/AMB is associated with a higher survival rate and a significant decrease in fungal biomass compared with regular-dose conventional amphotericin B or regular-dose LPD/AMB.11, 12 Furthermore, anecdotal clinical reports have suggested that HD-LPD/AMB is safe, well tolerated and associated with a relatively high response rate (greater than 55%) in patients with invasive aspergillosis.13, 14, 15, 16 Walsh et al.13 reported that patients with invasive pulmonary invasive aspergillosis who received HD-LPD/AMB (7.5 mg kg−1 per day) had an overall response rate of 71%, and Ryan et al.15 reported a 75% response rate to HD-LPD/AMB among eight patients with invasive aspergillosis who had hematologic malignancies. In a prospective, randomized study that compared regular-dose LPD/AMB plus caspofungin (3 mg kg−1 per day) with HD-LPD/AMB (10 mg kg−1 per day) in 30 patients with invasive aspergillosis, HD-LPD/AMB monotherapy was associated with an 86% response rate, whereas the combination was associated with a 100% favorable response rate.16

In the current study, the overall favorable response rate to HD-LPD/AMB salvage monotherapy was 8%, which is unexpectedly low. In those non-critically ill patients who received at least 7 days of treatment, the overall response rate was 18%. This unexpectedly low response rate might be related to several factors. First, compared with earlier studies,13, 14, 15, 16 the current study included a sicker population of hematologic malignancy patients, most of whom were neutropenic at the onset of infection and almost half of whom had undergone hematopoietic stem cell transplant. In addition, 78% of the transplant patients who received HD-LPD/AMB had graft-versus-host disease. In a prospective, randomized, multicenter trial comparing voriconazole to conventional amphotericin B in the treatment of invasive aspergillosis, the response rate to amphotericin B was as low as 13% in patients who had received allogeneic stem cell transplants and as high as 32% in non-neutropenic patients with no hematologic malignancy.5 Second, more than 60% of patients who received HD-LPD/AMB monotherapy in our study had failed to respond to regular-dose LPD/AMB; although the rate is comparable to that in patients who received posaconazole, escalating the dose of the same drug might not be as effective as switching to a different agent such as posaconazole. Third, 15–42% of the patients in this study were infected with A. terreus, which has decreased susceptibility to amphotericin B.9, 24, 25

Several studies have shown that caspofungin is an effective option for salvage therapy in patients with invasive aspergillosis who are refractory to or intolerant of conventional antifungal agents.26, 27 However, the response to salvage monotherapy using caspofungin in stem cell transplant recipients has been reported to be as low as 14%.26 Arikan et al.18 have reported the in vitro synergy of caspofungin and amphotericin B against Aspergillus. In addition, several investigators have reported a response rate greater than 50% for the combination of caspofungin and amphotericin B in the treatment of invasive aspergillosis.19, 20 However, a previous study from our cancer center that used caspofungin plus LPD/AMB for salvage therapy for invasive aspergillosis showed that the combination had an 18% response rate, no better than LPD/AMB monotherapy.28 In the current study, the combination of HD-LPD/AMB with caspofungin was not associated with a higher response or survival rate than HD-LPD/AMB monotherapy. Posaconazole was superior to the combination of caspofungin and HD-LPD/AMB in terms of overall response rate, survival rate, Aspergillus-related mortality rate and toxicity.

Concerns have been raised as to the bioavailability of posaconazole, which is administered orally (or via nasogastric tube). To enhance drug absorption, posaconazole is administered immediately after ingestion of a high-lipid meal. Bioavailability is particularly important because pharmacokinetic studies have revealed that higher plasma concentrations of posaconazole are associated with a greater response rate.10 However, studies have shown that orally administered posaconazole can achieve plasma concentrations that exceed the minimum inhibitory concentration for Aspergillus.29, 30 In addition, Krishna et al.31 have shown that oral posaconazole in allogeneic stem cell transplant patients with graft-versus-host disease achieves efficacious plasma concentrations and is not affected by variables such as body weight or grade of graft-versus-host disease. In the patient population evaluated in this study, almost half of whom underwent stem cell transplant, with the majority of those having graft-versus-host disease, posaconazole was not expected to demonstrate superiority in terms of response and survival to parenteral antifungal therapy. Given that the absorption of posaconazole is partly dependent on its intake with a fatty meal,32 it is possible that the compliance of our patients with instructions to take it immediately after a high-fat meal could have contributed to good bioavailability and thus to the favorable outcomes.

The clinical and microbiologic characteristics of the three groups in this study were similar except for the fact that posaconazole was less often used in critically ill patients and patients on mechanical ventilation when compared to patients receiving HD-LPD/AMB alone or with plus caspofungin. This difference is to be expected since posaconazole is available only as an oral formulation. However, the multivariate and univariate analyses excluding ICU patients as well as mechanical ventilation patients also demonstrated superior response associated with this novel triazole.

The novel triazoles are associated with minimal renal toxicity but a low to moderate level of hepatic toxicity.33, 34 In the current study, posaconazole was well tolerated and associated with lower hepatic and renal toxicity rates than HD-LPD/AMB alone or in combination with caspofungin. Toxicity has an impact on cost. The LPD/AMB formulations are substantially more expensive than other agents, including conventional amphotericin B, but are believed to have a better safety profile.22, 23 In the current study, however, posaconazole seemed to have a better efficacy and safety profile in addition to being less expensive than HD-LPD/AMB alone or in combination with caspofungin. The daily cost of the posaconazole regimen (800 mg per day) used in this study at our institution is $110, whereas the daily cost of HD-LPD/AMB alone or with caspofungin ranges from $1680 to 3033.

In this current study, patients treated with posaconazole had a longer duration of therapy when compared with HD-LPD/AMB given with or without caspofungin (P<0.001). To what extent this is a function of the better safety and tolerability of posaconazole when compared to HD-LPD/AMB (as shown in Table 6) versus its contribution to a better response and survival is unknown. Posaconazole's safety has been shown to be comparable to fluconazole35 which leads to its long-term (>6 months) use in the treatment of refractory invasive fungal infections.36 This better safety profile could have contributed to the improved response and survival among recipients of this drug in this current study, particularly, since toxicity that resulted in discontinuation of the drug was considered as failure and more prolonged survival leads to cumulative longer duration of therapy.

Potential limitations of this study include the use of a non-randomized, retrospective control group in comparing the efficacy of posaconazole to that of the HD-LPD/AMB regimens. Second, more than 75% of the patients who received HD-LPD/AMB had already failed therapy with regular doses of the same drug, which could have biased the response results in favor of posaconazole. This might explain the low response rate associated with HD-LPD/AMB secondary salvage therapy in his current study compared to a response rate of 46% to HD-LPD/AMB primary therapy in patients who did not receive any prior antifungal therapy.37 Third, because posaconazole was available only as an oral formulation, it was less often used in critically ill patients particularly those receiving mechanical ventilation, which also could have biased the outcome in favor of posaconazole. However, posaconazole continued to demonstrate a superior response rate when the critically ill ventilated patients were excluded from the analysis and when multivariate analysis was performed.

In conclusion, posaconazole is a potent antifungal agent with clinical activity against aspergillosis. In this study, we demonstrated the efficacy of posaconazole in the salvage treatment of aspergillosis in patients with hematologic malignancies and stem cell transplant recipients. Posaconazole was well tolerated and associated with a better safety profile than HD-LPD/AMB alone or in combination with caspofungin. Further studies evaluating an intravenous formulation of posaconazole alone or in combination with an echinocandin are warranted.

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Acknowledgements

Issam I Raad designed the study and wrote the paper. Hend Hanna did the statistical analysis. Maha Boktour and Harrys Torres coordinated the data collection. Claude Afif and Dimitrios P Kontoyiannis followed up on the patients. Ray Y Hachem coordinated the study and assisted Issam I Raad in writing the paper. Grant support received from Schering-Plough Research Institute, Merck & Co., Enzon, Fujisawa (Astellas).

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Correspondence to I I Raad.

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Raad, I., Hanna, H., Boktour, M. et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia 22, 496–503 (2008). https://doi.org/10.1038/sj.leu.2405065

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Keywords

  • hematologic malignancy
  • posaconazole
  • caspofungin
  • invasive aspergillosis

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