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Original Research |

Combination Antifungal Therapy for Invasive Aspergillosis: A Randomized TrialCombination Therapy for Invasive Aspergillosis

Kieren A. Marr, MD; Haran T. Schlamm, MD; Raoul Herbrecht, MD; Scott T. Rottinghaus, MD; Eric J. Bow, MD, MSc; Oliver A. Cornely, MD; Werner J. Heinz, MD; Shyla Jagannatha, PhD; Liang Piu Koh, MBBS; Dimitrios P. Kontoyiannis, MD; Dong-Gun Lee, MD; Marcio Nucci, MD; Peter G. Pappas, MD; Monica A. Slavin, MD; Flavio Queiroz-Telles, MD, PhD; Dominik Selleslag, MD; Thomas J. Walsh, MD; John R. Wingard, MD; and Johan A. Maertens, MD, PhD
[+] Article, Author, and Disclosure Information

From Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland; Pfizer and Weill Cornell Medical Center, Cornell University, New York, New York; Hôpital de Hautepierre, Strasbourg, France; CancerCare Manitoba and the University of Manitoba, Winnipeg, Manitoba, Canada; First Department of Internal Medicine, Clinical Trials Centre Cologne, ZKS Köln, BMBF 01KN1106, Köln, Germany; University of Würzburg Medical Centre, Würzburg, Germany; National University Cancer Institute, National University Health System, Singapore; The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Medicine, The Catholic University of Korea, Seoul, South Korea; University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; University of Alabama at Birmingham Medical Center, Birmingham, Alabama; Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil; Algemeen Ziekenhuis Sint-Jan, Brugge, Belgium; University of Florida, Gainesville, Florida; and Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Leuven, Belgium.

Acknowledgment: The authors thank the patients, coordinators, and nurses involved in the study, and members of the Mycoses Study Group for advice in the design, administrative coordination, and implementation of the DRC. Editorial support was provided by Complete Medical Communications and was funded by Pfizer. The authors thank the site investigators who are listed in Supplement 3.

Grant Support: By the National Institute of Allergy and Infectious Diseases (K24 AI085118; Dr. Marr).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2508.

Reproducible Research Statement:Study protocol: Sections available at www.clinicaltrials.gov/ct2/show/NCT00531479. Statistical code and data set: Applications for access can be made to Pfizer via www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests.

Requests for Single Reprints: Kieren A. Marr, MD, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1064, Baltimore, MD 21205; e-mail, kmarr4@jhmi.edu.

Current Author Addresses: Dr. Marr: Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1064, Baltimore, MD 21205.

Dr. Rottinghaus: Pfizer, 235 East 42nd Street, New York, NY 10017.

Dr. Schlamm: Cidara Therapeutics, 6310 Nancy Ridge Drive, Suite 101, San Diego, CA 92121.

Dr. Herbrecht: Centre Hospitalier Universitaire de Strasbourg, Hôpital de Hautepierre, 1 Avenue Molière, Strasbourg Cedex, France 67098.

Dr. Jagannatha: Johnson & Johnson, 1125 Trenton-Harbourton Road, Titusville, NJ 08560.

Dr. Bow: University of Manitoba, Faculty of Health Sciences, College of Medicine, c/o Infection Control Services, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9, Canada.

Dr. Cornely: University Hospital of Cologne, Kerpener Street 62, Cologne 50937, Germany.

Dr. Heinz: University of Würzburg Medical Centre, Sanderring 2, Würzburg 97080, Germany.

Mr. Koh: National University Cancer Institute, National University Health System, 5 Lower Kent Ridge Road, 119074 Singapore.

Dr. Kontoyiannis: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Dr. Lee: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul, South Korea 137-701.

Dr. Nucci: Hospital Universitario, Universidade Federal do Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco 255, Rio de Janeiro, Brazil 21941-913.

Dr. Pappas: University of Alabama at Birmingham Medical Center, 500 22nd Street South, Birmingham, AL 35233.

Dr. Slavin: Peter MacCallum Cancer Centre, St. Andrews Place East Melbourne, Victoria 3002, Australia.

Dr. Queiroz-Telles: Hospital de Clínicas, Universidade Federal do Paraná, Rua XV de Novembro, 1299-Centro, Curitiba, Paraná 80060-000, Brazil.

Dr. Selleslag: Algemeen Ziekenhuis Sint-Jan, Ruddershove 10, 8000 Brugge, Belgium.

Dr. Walsh: Weill Cornell Medical Center, Cornell University, 1300 York Avenue, New York, NY 10065.

Dr. Wingard: University of Florida, 1600 Southwest Archer Road, Gainesville, FL 32610.

Dr. Maertens: Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Brusselsestraat 69, 3000 Leuven 3000, Belgium.

Author Contributions: Conception and design: K.A. Marr, H.T. Schlamm, R. Herbrecht, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, M. Nucci, M.A. Slavin, J.R. Wingard, J.A. Maertens.

Analysis and interpretation of data: K.A. Marr, H.T. Schlamm, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, S. Jagannatha, L.P. Koh, P.G. Pappas, M.A. Slavin, D. Selleslag, T.J. Walsh, J.R. Wingard.

Drafting of the article: K.A. Marr, H.T. Schlamm, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, D.G. Lee, M.A. Slavin, F. Queiroz-Telles, T.J. Walsh, J.A. Maertens.

Critical revision of the article for important intellectual content: K.A. Marr, H.T. Schlamm, R. Herbrecht, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, D.P. Kontoyiannis, D.G. Lee, M. Nucci, P.G. Pappas, M.A. Slavin, D. Selleslag, T.J. Walsh, J.R. Wingard, J.A. Maertens.

Final approval of the article: K.A. Marr, H.T. Schlamm, R. Herbrecht, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, L.P. Koh, D.P. Kontoyiannis, D.G. Lee, M. Nucci, P.G. Pappas, M.A. Slavin, F. Queiroz-Telles, D. Selleslag, T.J. Walsh, J.R. Wingard, J.A. Maertens.

Provision of study materials or patients: R. Herbrecht, E.J. Bow, O.A. Cornely, W.J. Heinz, L.P. Koh, D.P. Kontoyiannis, M. Nucci, P.G. Pappas, D. Selleslag, J.A. Maertens.

Statistical expertise: E.J. Bow, S. Jagannatha.

Obtaining of funding: P.G. Pappas.

Administrative, technical, or logistic support: S.T. Rottinghaus, E.J. Bow, P.G. Pappas.

Collection and assembly of data: K.A. Marr, H.T. Schlamm, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, S. Jagannatha, L.P.K., D.P. Kontoyiannis, M.A. Slavin, F. Queiroz-Telles, T.J. Walsh, J.R. Wingard, J.A. Maertens.


Ann Intern Med. 2015;162(2):81-89. doi:10.7326/M13-2508
Text Size: A A A

This article has been corrected. The original version (PDF) is appended to this article as a Supplement.

Background: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy.

Objective: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA.

Design: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479)

Setting: 93 international sites.

Patients: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed.

Measurements: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures.

Results: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, −8.2 percentage points [95% CI, −19.0 to 1.5]; P  = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, −11.5 percentage points [CI, −22.7 to −0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different.

Limitations: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability.

Conclusion: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority.

Primary Funding Source: Pfizer.

Figures

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Figure 1.

Study flow diagram.

ITT = intention-to-treat; mITT = modified intention-to-treat.

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Figure 2.

Cumulative incidence of death in the modified intention-to-treat population.

Log-rank, P = 0.086.

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Figure 3.

Outcomes in the positive galactomannan subgroup.

Top. Cumulative incidence of death in the modified intention-to-treat population with probable invasive aspergillosis based on radiographic abnormalities and positive galactomannan antigen. Log-rank, P = 0.049. Bottom. 6-week mortality rate by range of maximum serum galactomannan index values at baseline. The middle boxes indicate the point estimate of the mean and the outer circles are the 95% CIs for that point estimate.

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References

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Comments

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Combination antifungal therapy for invasive aspergillosis: Is it better than monotherapy and when could it be helpful?
Posted on May 19, 2015
Corrado Girmenia, Federico Pea, Claudio Viscoli
Anatomia Patologica e Medicina Rigenerativa, Azienda Policlinico Umberto I, Sapienza University of Rome, Italy.Istituto di Farmacologia Clinica
Conflict of Interest: None Declared
Dear Editor,
Marr and colleagues recently reported results from a large, randomized trial in which voriconazole plus anidulafungin was compared to voriconazole plus placebo in the treatment of invasive aspergillosis (IA) in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT) (1).
The interpretation of these results is difficult. While no statistically significant difference in all-cause mortality rate at 6 weeks was found in the overall modified intention-to-treat population (primary endpoint), a post hoc analysis in cases in which the diagnosis was based on a positive galactomannan index (GMI) significantly favored combination therapy. The authors concluded that, although combination was of some benefit in subgroups, no definitive conclusions could be drawn in the overall population and further studies are necessary to define the population that might benefit more from combination antifungal therapy.
Identifying patients who might benefit from a more aggressive therapeutic approach is actually the crucial issue. Indeed, nowadays, voriconazole monotherapy is able to control and cure the majority of azole-susceptible aspergilloses (2-3), and failures mainly depend on i) the underlying hematological conditions ; ii) the extension of the fungal disease (fungal burden); iii) the species of Aspergillus involved (A.flavus and A.niger might benefit from combination therapy more than A.fumigatus) (4),); iv) a diagnosis based on a positive serum GMI, since it seems that patients with positive GMI had worse survival than those with a negative serum GMI and higher serum GMI levels correlated with higher patient mortality) (5). An improvement of the outcome related to a potentially more active antifungal therapy might be expected in these high risk populations rather than in the overall group of patients with IA in which voriconazole monotherapy is probably effective enough.
In the study by Marr and colleagues, patients who had a high risk for death based on organ dysfunction and status of HM-variables were excluded from the enrollment, and no effort was made to select for highest risk populations. One would be interested to evaluate the performance of the addition of anidulafungin to voriconazole in a subgroup population with clinical and mycological features potentially able to be influenced by an intensified antifungal treatment such as those with non-focal disease, high GMI serum levels or, non-fumigatus Aspergillus infections.

References
1. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162:81-9. doi: 10.7326/M13-2508. PubMed PMID: 25599346.
2. Cornillet A, Camus C, Nimubona S, Gandemer V, Tattevin P, Belleguic C, et al. Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey. Clin Infect Dis. 2006;43:577-84. PMID: 16886149.
3. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091-100. doi: 10.1086/651263. PubMed PMID: 20218877. PMCID: PMC3915080
4. Zhang M, Su X, Sun WK, Chen F, Xu XY, Shi Y. Efficacy of the combination of voriconazole and caspofungin in experimental pulmonary aspergillosis by different Aspergillus species. Mycopathologia. 2014;177:11-8. doi: 10.1007/s11046-013-9719-z. PMID: 24306184.
5. Fisher CE, Stevens AM, Leisenring W, Pergam SA, Boeckh M, Hohl TM. The serum galactomannan index predicts mortality in hematopoietic stem cell transplant recipients with invasive aspergillosis. Clin Infect Dis. 2013 Oct;57(7):1001-4. doi: 10.1093/cid/cit393. PMID: 23759343; PubMed Central PMCID: PMC3765008.
Inconsistent conclusions about combination antifungal therapy for invasive aspergillosis
Posted on June 9, 2015
Almudena Martín-Peña, Manuela Aguilar-Guisado, Ildefonso espigado, José Miguel Cisneros
Hospital Universitario Virgen del Rocío de Sevilla (Spain); Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015)
Conflict of Interest: None Declared
To the Editor: We read with great interest the article by Marr KA et al. published in Annals of Internal Medicine on January 20, 2015 (1) and would like to make the following comments.
Marr KA et al. conducted a multinational, randomized, double blind trial on 454 hematological patients, comparing voriconazole and anidulafungin vs. voriconazole for primary treatment of invasive aspergillosis (IA). Their main conclusion was that “compared with voriconazole monotherapy, combination therapy with anidulafungin led to a higher survival in subgroups of patients with IA”. We believe that this main conclusion is far too exhortative and inconsistent with the results obtained for the primary endpoint of “all-cause mortality at 6 weeks” in the entire study population. These results did not show differences among the compared treatment groups (P=0.087) and only a post-hoc analysis, when the patients diagnosed with probable IA were exclusively selected, showed differences in the primary endpoint. However, in our opinion it makes no clinical sense to exclude those patients with proven IA and therefore with the highest diagnostic accuracy of severe fungal infection. Also, it is hard to understand how the exclusion of such a low number of patients (three patients with proven IA in the combination therapy group (CTG) and two in the monotherapy group (MTG)) from the analysis of the primary endpoint modifies both the results and the conclusions of the study.
Moreover, the authors hypothesize that the antifungal treatment (AT) is initiated earlier in patients with a diagnosis of probable IA than in patients with proven IA. But this hypothesis is debatable in current clinical practice because the AT is initiated early upon clinical suspicion of IA and the diagnosis work up is continued during the therapy until the final diagnosis is established (2).
Another point of disagreement with the main conclusion is that the global response result showed a more favorable trend in the MTG than in the CTG (43% vs. 32.6%, respectively). Also, almost twice as many patients in the CTG were unable to be evaluated due to missing data than in the MTG (31 vs. 16 respectively).
Another issue was that the choice of CTG did not affect mortality in the analysis of the prognosis factors for mortality. Furthermore, the authors state that their results have a limited statistical power due to a worse IA outcome than expected and that this fact led to a moderate statistical power when comparing different subgroups of patients. They estimated a 6-week mortality of 19% in the MTG and 7.6% in the CTG (a difference of 11.4 percentage points) and the results obtained were 27.8% and 19.5% (a difference of 8.3 percentage points), respectively.
For all these reasons, we think that the manuscript’s main conclusion does not match the results of the study and that these results are not robust enough to demonstrate the superiority of combined therapy vs. monotherapy as a primary indication for IA. The results of this study support our opinion that combination antifungal therapy has not proven more effective than monotherapy and is not justified for primary therapy of IA (3). Nevertheless, this clinical trial has contributed to scientific evidence about the use of combination antifungal therapy and has demonstrated that the toxicity profile of the voriconazole and anidulafungin combination is similar to that of monotherapy with voriconazole.

References:
1. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015 Jan 20;162(2):81–9.
2. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008 Feb 1;46(3):327–60.
3. Martín-Peña A, Aguilar-Guisado M, Espigado I, Cisneros JM. Antifungal combination therapy for invasive aspergillosis. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014 Nov 15;59(10):1437–45.

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