Combination Antifungal Therapy for Invasive Aspergillosis

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1 MAJOR ARTICLE Combination Antifungal Therapy for Invasive Aspergillosis Kieren A. Marr, 1,2 Michael Boeckh, 1,2 Rachel A. Carter, 1 Hyung Woo Kim, 1 and Lawrence Corey 1,2 1 Fred Hutchinson Cancer Research Center and 2 University of Washington, Seattle, Washington (See the editorial commentary by Viscoli on pages 803 5) Background. Aspergillosis therapy with amphotericin, azoles, or echinocandins is associated with substantial mortality, ranging from 30% to 80%, depending on the stage of infection and the host s underlying disease. The results of in vitro studies and animal models suggest that combination therapy with azoles and echinocandins may have additive activity against Aspergillus species. Methods. We evaluated the outcomes of patients with aspergillosis who experienced failure of initial therapy with amphotericin B formulations and received either voriconazole ( n p 31 ) or a combination of voriconazole and caspofungin ( n p 16) for salvage therapy. Results. The combination of voriconazole and caspofungin was associated with improved 3-month survival rate, compared with voriconazole alone (hazard ratio [HR], 0.42; 95% confidence interval [CI], ; P p.048). In multivariable models, salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with therapy with voriconazole (HR, 0.28; 95% CI, ; P p.011), independent of other prognostic variables (e.g., receipt of transplant and type of conditioning therapy). The probability of death due to aspergillosis was lowest in patients who received the combination regimen. Conclusions. Randomized trials are warranted to determine whether this combination should be used as primary therapy for aspergillosis. Medical centers worldwide have reported that invasive aspergillosis (IA) has become a leading infection-related cause of death in immunocompromised patients [1 4]. Historically, treatment has been with amphotericin B deoxycholate (AmB-d) or lipid formulations of amphotericin B (LFABs); however, other therapeutic options have recently become available. Voriconazole has been approved for first-line (or primary ) therapy for aspergillosis [5], and caspofungin, which is an echinocandin, has been approved for therapy in patients who experience failure with other antifungal drugs (i.e., approved for salvage therapy) [6]. However, outcomes remain poor, especially in hematopoietic stem cell transplant (HSCT) recipients, with studies demonstrating favorable responses in only 20% 40% of such patients after 3 months of salvage therapy [6, 7]. Received 8 January 2004; accepted 29 April 2004; electronically published 27 August Reprints or correspondence: Dr. Kieren A. Marr, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, D3-100, Seattle, WA (kmarr@fhcrc.org). Clinical Infectious Diseases 2004; 39: by the Infectious Diseases Society of America. All rights reserved /2004/ $15.00 Azoles and echinocandins target different cellular sites, impacting the fungal cell membrane and the cell wall, respectively. Results of in vitro studies, animal models, and case reports of aspergillosis suggest good outcomes when echinocandins are combined with amphotericin formulations or azoles; however, no comparative clinical data have been published [8 14]. Here, we compared the outcomes of salvage therapy for aspergillosis with the combination of voriconazole and caspofungin, compared with voriconazole alone, in a sequential cohort of patients in our center (Fred Hutchinson Cancer Research Center [FHCRC]; Seattle, WA). METHODS Informed consent was obtained from patients or their parents or guardians, and this retrospective review was approved by the FHCRC Institutional Review Board. Patients who developed pulmonary aspergillosis after reciept of HSCT or cytotoxic chemotherapy for a hematologic malignancy at FHCRC were identified by review of microbiology, histopathology, and infectioncontrol records [1, 15]. Only patients with aspergillosis Combination Therapy for Aspergillosis CID 2004:39 (15 September) 797

2 defined as proven or probable according to standardized composite criteria were included [16]. During the review period ( ), standard practice guidelines that were developed by the infectious diseases program were used to direct antifungal therapy. Practice was to initiate therapy with AmB-d ( 1 mg/kg q.d.) and to change to voriconazole (6 mg/kg, followed by 4 mg/kg b.i.d.) for salvage therapy. A change to a salvage regimen was indicated by progressive infection, intolerance to the initial regimen, or renal dysfunction (creatinine clearance of!30 ml/min or creatinine level of 12.5 mg/ml) after 7 days of amphotericin-based therapy. Patients who had preexisting renal dysfunction or a history of AmB-d intolerance could receive LFABs (amphotericin B lipid complex or liposomal amphotericin B, both at a dosage of 5 mg/kg q.d.) prior to receipt of voriconazole as salvage therapy. In February 2001, practice was altered such that caspofungin was administered (70 mg on the first day of therapy, followed by 50 mg q.d.) in combination with voriconazole (6 mg/kg, followed by 4 mg/kg b.i.d.) for salvage therapy. Demographic and treatment data were obtained by review of computerized databases and patient charts. An investigator blinded to treatment arm examined discharge summaries and autopsy records to determine cause of death and indication for salvage therapy. Patient-identifying and therapy data were removed from documents to mask treatment arm for this review. Because aspergillosis-related deaths were an important endpoint, patients with graft-versus-host disease (GVHD) who died with infection were considered to have died due to the infection, not due to GVHD. However, to minimize bias introduced by receipt of additional myelosuppressive therapies, patients with relapsed malignancy were considered to have died due to relapse, not due to the infection. Other outcomes analyzed included survival for 3 months after the diagnosis of aspergillosis and survival for 3 months after the start of salvage therapy. To evaluate the relative safety of the salvage regimens, median total bilirubin, aspartate aminotransferase, and creatinine levels were compared during the course of salvage therapy (from initiation until 90 days after the start of salvage therapy). Survival was estimated with Kaplan-Meier curves [17]. Multivariable analysis was performed to determine the impact of antifungal therapy on 3-month survival. In overall Cox proportional-hazard regression models, candidate variables included antifungal therapy, underlying risk (no transplant received vs. autologous or allogeneic HSCT received), stage of aspergillosis (disseminated vs. pulmonary), and type of antifungal drug administered for primary therapy (AmB-d vs. LFAB). Because prior studies found that outcomes for allogeneic HSCT recipients are dependent on transplant type and GVHD therapy [4, 18], additional models were performed only among allogeneic HSCT recipients, including the variables of conditioning therapy (myeloablative vs. nonmyeloablative) and maximum corticosteroid dose ( 2 mg/kg q.d.). Variables with a P value of.25 were entered into the model and sequentially eliminated in a stepwise backward fashion, with a significance level of!.05 as the criterion for inclusion. RESULTS We analyzed the outcomes for 47 patients who acquired confirmed (proven or probable) aspergillosis from 1997 through Forty-one patients developed infection after receipt of HSCTs, and 6 developed infection after receiving cytotoxic chemotherapy. Patients were well matched with regard to age, sex, underlying disease, type of conditioning therapy, and maximum corticosteroid doses received for GVHD (table 1). The majority of patients in both the voriconazole and combination salvage therapy arms received salvage therapy because they experienced clinical failure (not because of intolerance); however, there was a trend for a greater proportion of patients in the combination therapy arm to have received salvage therapy for progressive aspergillosis ( P p.13, by Fisher s exact test). There were slightly more patients who received combination salvage therapy for extrapulmonary disseminated and proven aspergillosis; however, differences were not statistically significant. The median duration and types of primary antifungal therapy were not significantly different (table 1). Survival after diagnosis of IA among patients receiving voriconazole alone was compared with survival among those receiving the combination regimen. Because salvage therapy was initiated at different times relative to the diagnosis of aspergillosis, we evaluated outcomes relative to both the day of diagnosis and the start of salvage therapy. Overall survival at 3 months after the day of diagnosis of aspergillosis was highest among patients who received the combination regimen (figure 1; P p.048). Similarly, 3-month survival after the start of salvage therapy was greatest among the group of patients who received the combination regimen (hazard ratio [HR], 0.43; 95% CI, ; P p.050). We repeated the analysis after excluding several patients in both treatment groups (4 in the monotherapy group and 2 in the combination therapy group) who received!7 days of salvage therapy; in this limited cohort, there was still a trend to an increased survival rate in the combination therapy group (HR, 0.38; 95% CI, ; P p.058). Finally, the probability of death due to aspergillosis was lower in patients who received combination therapy, compared with voriconazole alone (figure 2; P p.024). Results of the univariate Cox regression model to identify risks for death are shown in table 2. Multivariable models were performed to determine whether the improved survival after combination therapy was independent of other variables. Among the entire cohort of patients (table 3), combination salvage therapy was associated with reduced mortality relative to voriconazole alone (HR, 0.27; 95% CI, ; P p 798 CID 2004:39 (15 September) Marr et al.

3 Table 1. Demographic and clinical characteristics of patients receiving salvage therapy with either voriconazole alone (voriconazole group) or voriconazole and caspofungin (combination group). Variable Voriconazole group (n p 31) Combination group (n p 16) P Age, median years (range) 49 (16 66) 45 (18 66).77 Female sex 17 (55) 12 (75).22 Type of HSCT Autologous 3 (10) 1 (6).36 Allogeneic HLA-MR 11 (35) 6 (38) MM-URD 15 (48) 5 (31) Other a 2 (6) 4 (25) Conditioning therapy b Myeloablative 27 (87) 12 (75).42 Nonmyeloablative 4 (13) 4 (25) Underlying disease c AML 5 (16) 6 (38).12 CML 9 (29) 1 (6) MDS 8 (26) 2 (13) MM 3 (10) 1 (6) NHL 3 (10) 1 (6) Other 3 (10) 5 (3) Maximum corticosteroid dose, mg/kg per day (61) 8 (50) (39) 8 (50) Stage of aspergillosis d Pulmonary only 28 (90) 12 (75).21 Disseminated 3 (10) 4 (25) Certainty of diagnosis e Proven 18 (58) 12 (75).34 Probable 13 (42) 4 (25) Indication for salvage therapy f Progression of infection 20 (71) 14 (93).13 Renal insufficiency/other g 8 (29) 1 (7) Duration of therapy, median days (range) Primary therapy 14 (4 59) 14 (2 334).42 Salvage therapy 33 (2 205) 68 (3 248).14 Type of primary therapy AmB-d 13 (42) 4 (25).34 LFAB 18 (58) 12 (75) NOTE. Data are no. (%) of patients, unless otherwise indicated. AmB-d, amphotericin B deoxycholate; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; HLA- MR, human leukocyte antigen matched related donor; HSCT, hematopoietic stem cell transplant; LFAB, lipid formulations of amphotericin B; MDS, myelodysplastic syndrome; MM, multiple myeloma, MM-URD, human leukocyte antigen mismatched or unrelated donor; NHL, non-hodgkin lymphoma. a Indicates patients who had not yet received HSCT but had received cytotoxic chemotherapy for an underlying malignant disorder. b Administered as described elsewhere [27, 28]. c The most common other diagnoses include aplastic anemia (2 patients), acute and chronic lymphocytic leukemia (2), and Hodgkin disease (1). d Stage of aspergillosis at time of diagnosis; disease was considered disseminated (i.e., extrapulmonary) if proven by histological examination or probable by radiographic appearance. e Defined according to published consensus criteria [16]. f Indication for change of therapy was not available for 3 patients in the voriconazole group and 1 patient in the combination group. g Other indicates prior intolerance to amphotericin B formulations (attributed to allergic reactions in 1 patient).

4 Figure 1. Kaplan-Meier probability of survival after diagnosis of proven or probable invasive aspergillosis (IA) in patients treated with voriconazole alone (voriconazole group) or voriconazole with caspofungin (combination group). P p.048, calculated from the likelihood ratio test using Cox regression. The number of patients evaluable during each time period is indicated..008). Patients who had not yet received a transplant had an increased risk for death, although the number of such patients was small (HR, 3.8; 95% CI, ; P p.032). Use of nonmyeloablative conditioning therapy appeared to reduce the 90- day mortality according to the univariate analysis, but the effect was not significant after adjusting for antifungal therapy and receipt of transplant (HR, 0.36; 95% CI, ). After restricting the model to allogeneic HSCT recipients, receipt of combination therapy was again associated with reduced mortality, compared with voriconazole alone (HR, 0.25; 95% CI, ; P p.029). In this multivariable model, there was again a trend to increased survival in patients who received nonmyeloablative conditioning therapy (HR, 0.44; 95% CI, ; P p.22) when controlling for antifungal therapy. Stage of aspergillosis was not predictive of survival in multivariable models. Combination therapy was associated with a decreased risk of death, independent of the type of primary therapy (AmB-d vs. LFAB), which was not significant in any model. The relative safety of the 2 salvage regimens was assessed by comparing several laboratory parameters of hepatic and renal function during the first 3 months of salvage therapy. There was no difference in total bilirubin level between patients receiving voriconazole (median, 4.1 mg/ml; range, mg/ml) and those receiving combination therapy (median, 3.8 mg/ml; range, mg/ml). Similarly, aspartate aminotransferase levels did not differ during salvage therapy with voriconazole (median, 45.6 U/L; range, U/L), compared with the combination of drugs (median, 34.2 U/L; range, U/L). There was also no difference in serum creatinine level in recipients of voriconazole (median, 2.2 mg/dl; range, mg/dl), compared with combination therapy (median, 1.5 mg/dl; range, mg/dl). DISCUSSION Comparison of the most objective parameter of therapeutic success survival showed that the combination of voriconazole and caspofungin was associated with better outcomes, compared with voriconazole administered alone, for patients receiving salvage therapy to treat aspergillosis. These data support the use of the combination regimen in treating patients who require salvage therapy, but given the retrospective nature of this study, a randomized trial will be necessary to determine whether combination regimens will be effective for primary therapy for aspergillosis. Combination antifungal therapy has been of interest because of the poor outcomes associated with treatment with either azole antifungals or amphotericin B formulations alone, especially in HSCT recipients. Although combination regimens that include amphotericin formulations and azoles have not Figure 2. Probability of death due to invasive aspergillosis (IA) after diagnosis of IA in patients treated with a salvage therapy regimen of voriconazole alone (voriconazole group) or voriconazole with caspofungin (combination group). Patients with IA and graft-versus-host disease were considered to have died due to IA; to minimize bias from receipt of myelosuppressive therapies, patients with relapsed malignancy were considered to have died due to relapse [25]. P p.024, calculated from the test for comparing groups in the presence of competing risks [26]. The number of patients evaluable during each time period is indicated. 800 CID 2004:39 (15 September) Marr et al.

5 Table 2. Risk of death in patients with invasive aspergillosis receiving salvage therapy with either voriconazole alone or a combination of voriconazole and caspofungin, according to univariate Cox regression models. Variable HR (95% CI) P Antifungal therapy received Voriconazole Combination 0.42 ( ) Receipt of transplant Yes No 1.9 ( ) Stage of aspergillosis Pulmonary only Disseminated 0.35 ( ) Primary therapy received LFAB AmB-d 1.1 ( ) Conditioning therapy received Myeloablative Nonmyeloablative 0.30 ( ) Maximum corticosteroid dose, mg/kg per day ( ) NOTE. AmB-d, amphotericin B deoxycholate; HR, hazard ratio; LFAB, lipid formulation of amphotericin B. resulted in favorable responses in either in vitro studies or animal models [19], this combination has frequently been used as a result of clinical desperation. Regimens that combine azoles or amphotericin with echinocandins may be more compelling than others because of their unique mechanisms of action. Recent in vitro studies and animal models evaluating therapy with caspofungin combined with amphotericin [8], voriconazole [9, 10], or ravuconazole [20] demonstrated favorable responses against Aspergillus species. Cases of successful therapy using caspofungin and itraconazole [12] and caspofungin and LFABs [11, 13, 14] have also been reported. In this comparative analysis of clinical outcomes, we observed a survival advantage in patients treated with the combination of voriconazole and caspofungin, compared with voriconazole alone. Responses were not a function of primary therapy, because patients in both arms received equivalent durations and types of amphotericin B formulations. Multivariable analyses confirmed that combination therapy was associated with improved survival, even though a greater proportion of patients had disseminated and/or progressive aspergillosis at baseline in the combination arm than in the monotherapy arm. The multivariable analyses attempted to control for differences in host variables that may have changed over the time period during which the outcomes were observed. To this end, the impact of antifungal therapies appeared independent of the type of conditioning therapy and the receipt of corticosteroids, both of which are factors that have Table 3. Risk of death in patients with invasive aspergillosis receiving salvage therapy with either voriconazole alone or a combination of voriconazole and caspofungin, according to multivariate Cox regression models. Cox regression, variable HR (95% CI) P Bivariate Antifungal therapy received Voriconazole Combination 0.27 ( ) Receipt of transplant Yes No 3.8 (1.2 12) Trivariate Antifungal therapy received Voriconazole Combination 0.28 ( ) Receipt of transplant Yes No 3.2 (1.0 10) Conditioning therapy received Myeloablative Nonmyeloablative 0.36 ( ) NOTE. HR, hazard ratio. been shown to be important prognostic variables in other studies [4, 21 23]. However, the retrospective and noncontemporaneous nature of this comparison limits the conclusions that can be drawn, because other changes in transplantation or supportivecare practices could account for the differences in outcome. Some of these variables may not be apparent or quantifiable in this small observational study. In this study, the 3-month survival rate of patients treated with voriconazole was 40%, which does not differ from the survival rate of patients treated at our institution in earlier years [15]. Assigning attributable mortality in patients with opportunistic infections is difficult, given the presence of multiple comorbidities. Cause-of-death analysis revealed that 20% 50% of patients died as a result of aspergillosis within 3 months after diagnosis. The finding that combination therapy was associated with a decreased mortality rate suggests that a large proportion of poor outcomes can be ameliorated with improved antifungal regimens for both prevention and therapy. The persistently high mortality rate associated with aspergillosis, even among patients treated with voriconazole for salvage therapy, prompted our exploration of combination therapy. Although we evaluated outcomes in a relatively large group of patients and made efforts to equalize the composition of treatment arms with use of both entry criteria and multivariable models, the conclusions of this study are limited by its retrospective design. An appropriately powered randomized trial is warranted to determine whether this combination would be optimal first-line therapy for aspergillosis. Such a trial is im- Combination Therapy for Aspergillosis CID 2004:39 (15 September) 801

6 perative, given the added toxicities, drug interactions, and costs that may be encountered when administering combinations of antifungal drugs. Design of such a trial will require careful consideration; as reviewed in a recent editorial, 570 evaluable subjects will be required in order to show a 10% difference in survival with use of predictions based on data for patients receiving voriconazole monotherapy [24]. The survival advantage we observed may support the use of the combination regimen in the select group of patients who are experiencing treatment failure with other therapies. For these patients, it appears that the combination regimen, compared with voriconazole monotherapy, is at least not associated with worse outcomes. Acknowledgments We acknowledge the efforts of the Fred Hutchinson Cancer Research Center Program in Infectious Diseases (Seattle, WA) research nurses and database coordinators, as well as the efforts of clinicians, microbiologists, and pathologists, who have assisted in the conduct of the clinical trials and the formation of the fungal infection database. Financial support. National Institutes of Health (grants CA18029 and CA15704). Conflict of interest. K.A.M. has served as a consultant for Pfizer, Merck, Fujisawa, Enzon, Ortho Biotechnologies, Schering Plough, and Vicuron. M.B. has served as a consultant for Pfizer and Enzon. All other authors: No conflict. References 1. Marr K, Carter R, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: Grow W, Moreb J, Roque D, et al. Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital. 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