Antifungal Prophylaxis During Induction Therapy for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome
Kathryn Maples, PharmD
PGY-2 Oncology Pharmacy Resident
Virginia Commonwealth University Health System
Richmond, VA
Invasive fungal infections (IFIs) have a significant impact on morbidity and mortality in patients with hematologic malignancies and occur most often in those with acute myeloid leukemia (AML) who are undergoing chemotherapy or hematopoietic cell transplantation.1 Currently, Candida species (spp) and Aspergillus are the most common causes of IFIs; however, the incidence of non-albicans Candida spp and resistant Aspergillus spp is increasing.2,3 In addition to direct IFI-related mortality, these complications often cause delays in antileukemia treatment, which can affect cure rates for the underlying disease process.4 Primary prevention of fungal infections has continually been shown to reduce the incidence of IFIs, infection-associated mortality, and overall mortality.5 Antifungal prophylaxis has therefore become a standard of care for AML and high-risk myelodysplastic syndrome (MDS) patients undergoing traditional chemotherapy induction with cytarabine and an anthracycline.6 Unfortunately, prophylactic therapy introduces additional risks, including drug toxicities, drug-drug interactions, selection for resistant pathogens, and high costs. Because of the need for balancing the various risks and benefits, the choice of an antifungal prophylaxis agent remains controversial.
Both the National Comprehensive Cancer Network (NCCN) Guidelines and the Infectious Diseases Society of America Clinical Practice Guidelines recommend prophylaxis with posaconazole for AML and MDS patients undergoing intensive chemotherapy until resolution of neutropenia, defined as an absolute neutrophil count greater than 500/microL.6,7 This recommendation is based upon the landmark randomized multicenter study in which AML/MDS patients undergoing standard induction treatment were randomized in a 1:1 ratio to posaconazole or to either fluconazole or itraconazole.8 Prophylaxis was administered with each remission-inducing chemotherapy cycle for newly diagnosed AML, first-relapse AML, and MDS requiring induction. Prophylaxis started either 24 hours after the last dose of anthracycline or on day 1 of chemotherapy in patients not receiving an anthracycline. Antifungal prophylaxis was continued until recovery of neutropenia and complete remission, occurrence of IFI, or for up to 12 weeks from randomization, whichever came first. Fifty-seven percent of patients in the posaconazole group received only one chemotherapy cycle, while the remaining 43% were treated with two or more successive cycles of chemotherapy during the study. Similarly, in the control group, 61% received one cycle, and 39% were treated with two or more cycles of chemotherapy. The authors did not report which chemotherapy regimens were used. Patients who received posaconazole 200 mg oral suspension three times daily (n = 304) compared to fluconazole 400 mg oral suspension once daily (n = 240) or itraconazole 200 mg oral solution twice daily (n = 58) were found to have significantly lower proven or probable IFIs (total IFIs: 2% vs. 8%, p < .001) and significantly fewer invasive aspergillosis infections (1% vs. 7%, p < .001). In addition, the 100-day overall mortality rate was significantly lower in the posaconazole group than in the fluconazole/itraconazole group (14% vs. 21%; p = .04). However, serious adverse events possibly or probably related to treatment were significantly higher in the posaconazole group compared with the fluconazole/itraconazole group (6% vs. 2%, p = .01). The adverse events more commonly associated with posaconazole were increased hepatic enzymes, hyperbilirubinemia, QTc prolongation, and syncope. The authors concluded that for AML and MDS patients undergoing chemotherapy, posaconazole improved overall survival and was superior to fluconazole or itraconazole in preventing IFIs.8
Despite the effectiveness of posaconazole, the oral suspension has several practical limitations, including the need for three daily administrations, variable bioavailability, and the need for administration with a high-fat meal. These restrictions are of utmost concern for AML/MDS patients, who have several factors (e.g., mucositis, nausea, vomiting, and diarrhea) that may affect absorption of posaconazole, and subtherapeutic drug levels have been associated with increased risk of breakthrough IFIs in AML patients.9 This limitation has been largely overcome by the recent introduction of the delayed-release tablet and intravenous (IV) formulations, which were approved by the U.S. Food and Drug Administration on the basis of pharmacokinetic studies.10 Unlike the oral suspension, the delayed-release tablet is administered with a loading dose of 300 mg twice daily on day 1, followed by 300 mg once daily without regard to meals, because its absorption is minimally affected by food, mucositis, and gastrointestinal pH.11 In addition, the therapeutic drug-monitoring recommendation pertains only to use with the oral-suspension formulation. It is important to note that although the clinical success with the suspension formulation was simply extrapolated to the tablet formulation, small studies have confirmed an increase in serum drug levels in AML patients taking the tablet formulation.10-12
Further, although current guidelines recommend standard prophylaxis with posaconazole, a potential argument against the use of this agent for primary prophylaxis is the concern of resistance in the setting of breakthrough fungal infections. Posaconazole is one of the broadest antifungal agents available, with activity against resistant Candida spp, Aspergillus, Cryptococcus, Coccidioides, Blastomyces, Histoplasma, and Zygomycetes.4 Prophylaxis with such a highly active and broad-spectrum antifungal agent could favor the emergence and growth of resistant fungal strains. A cohort study of AML patients (N = 250) receiving intensive chemotherapy revealed that 24% of patients experienced a breakthrough IFI (17.6% possible IFI and 6.4% probable or proven). All patients with a breakthrough IFI had received posaconazole prophylaxis, and 35% of these patients were switched to liposomal amphotericin B for treatment.13 For the treatment of resistant fungal infections, echinocandins have a limited role outside of resistant Candida spp. Amphotericin B is the remaining broad-spectrum antifungal agent with a different mechanism of action that can treat fungal strains resistant to azoles. Liposomal amphotericin B is available only as an IV solution, and administration of this medication requires extensive support, which may not be feasible over a long term. Therefore, some providers may prefer to start with a narrower-spectrum agent and reserve posaconazole for patients who have a breakthrough IFI later in treatment.
Voriconazole is a broad-spectrum, mold-active azole but notably lacks activity against Zygomycetes. Although voriconazole has been extensively studied for the treatment of invasive aspergillosis in patients with hematologic malignancies, data on voriconazole for prophylaxis are very limited. In a randomized open-label study (N = 127), IV voriconazole was compared with IV itraconazole and found to have no difference in the incidence of IFIs or mortality. However, of note, this study failed to reach its target accrual number.14Additional single-center cohort studies have reported rates of proven or probable IFIs between 4% and 7% in AML/MDS patients undergoing induction chemotherapy with voriconazole prophylaxis at 200 mg orally twice daily.15,16
Isavuconazole is the newest mold-active triazole, with activity against yeast, molds, and dimorphic fungi. It is currently approved for the treatment of invasive aspergillosis and mucormycosis. Although isavuconazole does not extend posaconazole’s spectrum of activity, this agent seems to have more predictable pharmacokinetics in adults and fewer serious adverse effects.17 Early testing of isavuconazole for antifungal prophylaxis in AML and MDS patients has begun, but additional phase-3 trials are warranted to better determine this novel agent’s role.18
Fluconazole is a non-mold-active azole with activity against Candida spp (except C. krusei), Coccidioides, Histoplasma, and Cryptococcus spp. Despite having no mold coverage, fluconazole remains an attractive antifungal prophylaxis agent because it is available in IV and oral formulations, is well tolerated, has fewer significant drug-drug interactions, and has a significantly lower cost. Fluconazole 400 mg orally once daily has been shown to reduce both the incidence and mortality of IFIs when compared with placebo in adult AML patients receiving induction chemotherapy.19 Further, when compared with amphotericin B, fluconazole was found to be as efficacious but better tolerated.20,21 Fluconazole has also been directly compared with itraconazole, which has a wider spectrum of activity that includes Aspergillus. Though itraconazole has been shown to significantly reduce IFIs compared with fluconazole, no difference was detected for IFI-associated or all-cause mortality between the two agents, and itraconazole has poor gastrointestinal tolerability.22,23
With fluconazole, voriconazole, and posaconazole being the three most common azoles currently used for antifungal prophylaxis, cost is an additional factor to be considered. With the average duration of neutropenia being approximately 30 days,8 the average wholesale price for 30-day prophylaxis with fluconazole, voriconazole, and posaconazole is $859.50, $3,014.70, and $6,777.00, respectively. However, drug cost alone is not the sole contributor to a cost-effective strategy. When medication costs and costs to treat IFIs were analyzed together, Monte Carlo simulations showed that posaconazole is more cost effective when compared with fluconazole/itraconazole or when compared with voriconazole for prophylaxis during induction chemotherapy.24,25
The echinocandins (caspofungin, micafungin, and anidulafungin) are exclusively available as IV formulations and have activity against Candida and Aspergillus spp; however, they have no in vitro activity against Zygomycetes and Fusarium spp.4 In an open-label randomized study, patients with AML or MDS undergoing induction chemotherapy were randomized to receive caspofungin (n = 106) or itraconazole (n = 86) for primary prophylaxis. No differences between the two groups were seen in the incidence of IFIs, IFI-associated and all-cause mortality, or adverse effects.26 Although no randomized controlled trials have been conducted with micafungin or anidulafungin in the prophylaxis setting, the echinocandins are often thought to be interchangeable, and the institution-specific formulary agent can be used. The NCCN guidelines recommend micafungin as a category-2B alternative to posaconazole for antifungal prophylaxis.6
In conclusion, fluconazole has been shown to prevent IFIs in AML patients compared with placebo, but it lacks mold coverage. Epidemiological studies reveal that the characteristics of IFIs in leukemia patients have evolved in the last 2 decades because of the implementation of azole prophylaxis in the early 1990s. Candida spp that are fluconazole resistant (C. krusei) or susceptible-dose-dependent (C. glabrata) are estimated to account for more than 80% of candidiasis infections in leukemia patients.27 In addition, it has been estimated that more than half of proven or probable IFIs in AML patients are caused by molds,28 and mortality rates from aspergillosis are reported as high as 50% in neutropenic patients.29 With the high morbidity and mortality associated with an IFI, using an anti-mold agent as primary prevention during induction chemotherapy may outweigh the risks of increases in drug-drug interactions, toxicities, and cost; however, patient-specific characteristics should always be considered.
References
1. Pechlivanoglou P, Le HH, Daenen S, Snowden JA, Postma MJ. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother. 2014;69:1-11.
2. Tacke D, Buchheidt D, Karthaus M, et al. Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Ann Hematol. 2014;93:1449-56.
3. Verweij PE, Ananda-Rajah M, Andes D, et al. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resist Updat. 2015;21-22:30-40.
4. Halpern AB, Lyman GH, Walsh TJ, Kontoyiannis DP, Walter RB. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia. Blood. 2015;126:2790-97.
5. Ethier MC, Science M, Beyene J, Briel M, Lehrnbecher T, Sung L. Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials. Br J Cancer. 2012;106:1626-37.
6. National Comprehensive Cancer Network. Practice guidelines in oncology: prevention and treatment of cancer-related infections. V.2.2017. https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed April 4, 2017.
7. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:427-31.
8. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348-59.
9. Cattaneo C, Panzali A, Passi A, et al. Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections. Mycoses. 2015;58:362-67.
10. Duarte RF, Lopez-Jimenez J, Cornely OA, et al. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014;58:5758-65.
11. Cumpston A, Caddell R, Shillingburg A, et al. Superior serum concentrations with posaconazole delayed-release tablets compared to suspension formulation in hematological malignancies. Antimicrob Agents Chemother. 2015;59:4424-28.
12. Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014;58:6993-95.
13. Biehl LM, Vehreschild JJ, Liss B, et al. A cohort study on breakthrough invasive fungal infections in high-risk patients receiving antifungal prophylaxis. J Antimicrob Chemother. 2016;71:2634-41.
14. Mattiuzzi GN, Cortes J, Alvarado G, et al. Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Support Care Cancer. 2011;19:19-26.
15. Barreto JN, Beach CL, Wolf RC, et al. The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole. Am J Hematol. 2013;88:283-88.
16. Torres A, Serrano J, Rojas R, et al. Voriconazole as primary antifungal prophylaxis in patients with neutropenia after hematopoietic stem cell transplantation or chemotherapy for acute myeloid leukemia. Eur J Haematol. 2010;84:271-73.
17. Miceli MH, Kauffman CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis. 2015;61:1558-65.
18. Cornely OA, Bohme A, Schmitt-Hoffmann A, Ullmann AJ. Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother. 2015;59:2078-85.
19. Rotstein C, Bow EJ, Laverdiere M, Ioannou S, Carr D, Moghaddam N. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group. Clin Infect Dis. 1999;28:331-40.
20. Bodey GP, Anaissie EJ, Elting LS, Estey E, O’Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia: fluconazole versus intravenous amphotericin B. Cancer. 1994;73:2099-106.
21. Mattiuzzi GN, Estey E, Raad I, et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer. 2003;97:450-56.
22. Vardakas KZ, Michalopoulos A, Falagas ME. Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta-analysis of randomised-controlled trials. Br J Haematol. 2005;131:22-28.
23. Wang J, Zhan P, Zhou R, et al. Prophylaxis with itraconazole is more effective than prophylaxis with fluconazole in neutropenic patients with hematological malignancies: a meta-analysis of randomized-controlled trials. Med Oncol. 2010;27:1082-88.
24. Al-Badriyeh D, Slavin M, Liew D, et al. Pharmacoeconomic evaluation of voriconazole versus posaconazole for antifungal prophylaxis in acute myeloid leukaemia. J Antimicrob Chemother. 2010;65:1052-61.
25. Collins CD, Ellis JJ, Kaul DR. Comparative cost-effectiveness of posaconazole versus fluconazole or itraconazole prophylaxis in patients with prolonged neutropenia. Am J Health Syst Pharm. 2008;65:2237-43.
26. Mattiuzzi GN, Alvarado G, Giles FJ, et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother. 2006;50:143-47.
27. Leventakos K, Lewis RE, Kontoyiannis DP. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis. 2010;50:405-15.
28. Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91:1068-75.
29. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32:358-66.