Yüksek Riskli Hematolojik Hastalarda Profilaktik Posakanazol Kullanımının Fungal Enfeksiyon Gelişimi Üzerine Etkisi: Türkiye'de Tek Merkez Deneyimi

Yıl 2021, Cilt: 2 Sayı: 3, 178 - 184, 17.11.2021

Mustafa Karagülle

Öz

Giriş: İnvaziv fungal enfeksiyonlar (IFI), remisyon-indüksiyon tedavisi alan ve allojenik kök hücre nakli yapılan akut myeloid lösemi ve myelodisplastik sendromlu hastalarda en önemli morbidite ve mortalite nedenidir. Tanı koymadaki güçlükler ve tanı koymadaki gecikmeler mortaliteyi artırmaktadır. Bu komplikasyonları azaltmak için birçok klinisyen ve uluslararası kılavuzlar tarafından antifungal profilaksi yapılması önerilmektedir. Posakanazol, yeni jenerasyon, geniş spektrumlu oral azol olup yapılan 2 randomize çalışma ile IFI gelişme riskini ve mortaliteyi de azalttığı gösterilmiştir. Bu çalışmada, posakonazol proflaksisinin, remisyon-indüksiyon tedavisi ( antrasiklin bazlı tedaviler ) alan akut myeloid lösemi ve myelodisplastik sendromlu ve allojenik kök hücre nakli yapılan hastalarda invaziv mantar enfeksiyonu önlemede etkinlik, güvenlilik ve tolere edilebilirliğinin değerlendirilmesi amaçlandı. Yöntemler: Retrospektif çalışmaya 2007-2020 yılları arasında takip edilen 117 hasta çalışmaya alındı. Hastalar posakanazol ve kontrol grubu olarak iki gruba ayrıldı. Posakanazol grubuna remisyon-indüksiyon tedavisi alan 39 AML ve allojenik kök hücre nakli yapılan 10 AML-MDS hasta alındı, gruptaki tüm hastalar posakanazol ile tedavi edildi. Kontrol grubuna ise remisyon-indüksiyon tedavisi esnasında profilaksi almayan 58 AML tanılı hasta ve flukanazol profilaksi alan 10 AML-MDS hasta alındı. Posakanazol kullanan ve kontrol grubundaki hastalarda fungal enfeksiyon tanısında ve şüphesinde EORTC/MSG (Avrupa Kanser Araştırma ve Tedavi Organizasyonu/ (Mikoz Çalışma Grubu) tanı kriterleri kullanıldı. Tanıya yönelik HRCT (Yüksek Rezolusyonlu Akciğer Tomografisi) gibi görüntüleme tekniklerinin yanı sıra galaktomannan gibi biyokimyasal tetkiklerde incelendi. Bulgular: Bu çalışmada allojenik kök hücre nakli yapılan MDS ve AML hasta grubunda posakanazol profilaksisi kullanılanlarda fungal enfeksiyon gelişme riskinin ve antifungal kullanım ihtiyacının diğer gruba oranla daha düşük olduğu saptandı (P<0,001). Kontrol grubunda (profilakside flukanazol kullanılan hasta grubu) olası veya şüpheli fungal enfeksiyonu gösteren HRCT bulguları daha yüksek oranda tespit edildi (P=0,001). Yaş, cinsiyet gibi sosyodemografik özelliklerinin yanı sıra galaktomannan düzeyi, mikrobiyolojik incelemeler, remisyon durumu ve risk faktörleri açısından her iki grup arasında bir anlamlı farklılık yoktu (P>0,05). Tedavi esnasında yan etki gelişimi açısından iki grup arasında herhangi bir fark yoktu(P>0,05). Sonuç: Bu çalışmada literatür ile uyumlu olarak remisyon-indüksiyon tedavisi alan hastalarda invaziv fungal enfeksiyon gelişimini önlemede profilaktik posakanazol kullanımının etkin ve güvenli olduğu, allojenik kök hücre nakli yapılan hastalarda ise profilaktik posakanazol kullanımının flukanazol kullanımına göre daha üstün olduğu gösterilmiştir

Anahtar Kelimeler

profilaksi, posakanazol, fungal enefeksiyon, mortalite

The Effect of Posaconazole Prophylaxes on the Course of Fungal Infection in the High Risk Patients of Hematology: A Single-Center Experience in Turkey

Öz

Introduction: Invasive fungal infections (IFIs) are the most important cause of morbidity and mortality in the patients treated with remission-induction therapy and allogeneic stem cell transplantation (ASCT) and suffering from acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Difficulties and delays in diagnosis of the disease increase the mortality rate. Many clinicians and qualified international guidelines recommend the use of antifungal prophylaxis to reduce complications of the AML. Posaconazole is a new generation of broad spectrum oral azole and recent studies have shown that it is effective in curtailing risk of developing IFIs and mortality as well. In the present study, we aimed to assess the effectiveness of posaconazole prophylaxis on preventing development of IFIs, its reliability, and its tolerability in the patients treated with remission-induction therapy and ASCT and suffering from AML and MDS. Methods: Overall, 117 patients were enrolled to the present retrospective study covering the patients followed between the years 2007 and 2020. The patients were divided into two groups as posaconazole group and control group. The posaconazole group contained 39 AML patients put on remission induction chemotherapy and 10 AML-MDS patients that received allogeneic stem cell transplantation, and all the patients in the posaconazole group were treated with posaconazole. The control group comprised 58 AML patients receiving no prophylactic antifungal treatment during the remission induction chemotherapy and 10 AML-MDS patients treated with fluconazole. Diagnoses and suspicions of fungal infections in posaconazole group and control groups were verified using the criteria set by EORTC/MSG. In addition, imaging techniques such as high-HRCT and biochemical tests, i.e., galactomannan were also utilized for diagnoses purposes. Results: In the present study, we noted that the risk for the development of fungal infections and the need for antifungal use in the MDS and AML patients who received ASCT were markedly reduced in the patients administered with posaconazole prophylaxis in comparison to other group (P<0.001). The frequency of HRCT (High- Resolution Computed Tomography) findings implying potential or suspected development of fungal infections was determined to be greater in the control group (the patients treated with fluconazole prophylaxis) (P=0.001). In addition, there were no discernible differences between the groups for the socio-demographic characteristics such as age and gender in addition to the level of galactomannan, microbiological analysis, remission status and risk factors (P> 0.05). Finally, no significant difference was noticed on the development of side effects during the treatment between the groups (P> 0.05). Conclusion: The results of the present study were consistent with the literature and indicated that the use of posaconazole for prophylactic purposes was more effective and reliable than fluconazole in preventing development and spread of invasive fungal infections in the patient receiving remission induction chemotherapy and ASCT.

Anahtar Kelimeler

Prophylaxes, Posaconazole, Fungal Infection, mortality

Kaynakça

• 1. Michallet M, Sobh M, Morisset S, et al. Risk factors for invasive aspergillosis in acute myeloid leukemia patients prophylactically treated with posaconazole. Med Mycol. 2011;49(7):681-7.
• 2. 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.
• 3. Rüping MJ, Vehreschild JJ, Cornely OA. Antifungal treatment strategies in high risk patients. Mycoses 2008;51(Suppl. 2):46–51.
• 4. Hagen EA, Stern H, Porter D, et al. High rateof invasive fungal infections following nonmyeloablative allogeneic transplantation. Clin Infect Dis 2003;36:9–15.
• 5. Torres HA, Hachem RY, Chemaly RF, Kontoyiannis DP, Raad II.Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis 2005;5:775–85.
• 6. Richardson MD. Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother 2005;56(Suppl. 1):i5–11.
• 7. 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. Clin Infect Dis 1999;28:331-40
• 8. Stam WB, O'Sullivan AK, Rijnders B, et al. Economic evaluation of posaconazole vs. standard azole prophylaxis in high risk neutropenic patients in the Netherlands. Eur J Haematol. 2008;81(6):467-74.
• 9. Caggiano V, Weiss RV, Rickert TS, Linde-Zwirble WT. Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer 2005;103:1916–24.
• 10. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk-based, antifungal strategy in neutropenic patients. Br J Haematol 2000;110:273-84.
• 11. von Eiff M, Roos N, Schulten R, Hesse M, Zuhlsdorf M, van de Loo J. Pulmonary aspergillosis: early diagnosis improves survival. Respiration 1995;62:341-7.
• 12. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis.Lancet Infect Dis 2005;5:609-22.
• 13. Lass-Florl C. The changing face of epidemiology of invasive fungal disease in Europe. Mycoses 2009;52:197–205.
• 14. Cuenca-Estrella M, Bernal-Martinez L, Buitrago MJ et al. Update on the epidemiology and diagnosis of invasive fungal infection. Int J Antimicrob Agents 2008;32(Suppl 2):S143–7.
• 15. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001;32:358-66
• 16. Viscoli C, Girmenia C, Marinus A, et al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999;28:1071-9
• 17. Marr KA. Antifungal therapy for febrile neutropenia: issues in clinical trial design. Curr Opin Investig Drugs 2004;5:202–7.
• 18. Wong GC, Abdul Halim NA, Tan BH. Antifungal Prophylaxis With Posaconazole Is Effective in Preventing Invasive Fungal Infections in Acute Myeloid Leukemia Patients During Induction and Salvage Chemotherapy. Clin Infect Dis. 2015;61(8):1351-2.
• 19. Metan G, Türe Z, Pala Ç, et al. A Single Center Experience for Antifungal Prophylaxis in Patients with Acute Myelogenous Leukemia. Indian J Hematol Blood Transfus. 2015;31(3):339-45
• 20. Schrenk KG, Schnetzke U, Stegemann K, von Lilienfeld-Toal M, Hochhaus A, Scholl S. Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia. J Cancer Res Clin Oncol. 2015;141(9):1661-8.
• 21. Devanlay C, Tavernier-Tardy E, Bourmaud A, et al. Impact of fluconazole versus posaconazole prophylaxis on the incidence of fungal infections in patients receiving induction chemotherapy for acute myeloid leukemia. Biomed J. 2015;38(3):235-43.
• 22. Kung HC, Johnson MD, Drew RH, Saha-Chaudhuri P, Perfect JR. Clinical effectiveness of posaconazole versus fluconazole as antifungal prophylaxis in hematology-oncology patients: a retrospective cohort study. Cancer Med. 2014;3(3):667-73.
• 23. Gomes MZ, Jiang Y, Mulanovich VE, Lewis RE, Kontoyiannis DP. Effectiveness of primary anti-Aspergillus prophylaxis during remission induction chemotherapy of acute myeloid leukemia. Antimicrob Agents Chemother. 2014;58(5):2775-80.
• 24. Gerber B, Köppel J, Paul M, et al. Efficacy of anti-fungal but not anti-bacterial prophylaxis in intensive primary AML therapy: a real-world, retrospective comparative single-centre study. Swiss Med Wkly. 2014;144:w13985.
• 25. Aperis G, Mylonakis E. Newer triazole antifungal agents: pharmacology,spectrum, clinical efficacy and limitations. Expert Opin Investig Drugs. 2006;15:579–602.
• 26. Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 1999;29:239–44.
• 27. Groll AH, Walsh TJ. Uncommon opportunistic fungi: new nosocomial threats. Clin Microbiol Infect. 2001;7:8–24.
• 28. Carroll KJ. On the use and utility of the Weibull Model in the analysis of survival data. Control Clin Trials. 2003;24:682–701.
• 29. Groll AH, Walsh TJ. Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005;3:467-87.
• 30. Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother 2006;50:2009-15.
• 31. Greer ND. Posaconazole (Noxafil): a new triazole antifungal agent. Proc (Bayl Univ Med Cent). 2007;20(2):188-96.
• 32. Ullmann AJ, Lipton JH, Vesole DH et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47.
• 33. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-21.
• 34. 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(5):1052-61.
• 35. Sánchez-Ortega I, Patiño B, Arnan M, et al. Clinical efficacy and safety of primary antifungal prophylaxis with posaconazole vs itraconazole in allogeneic blood and marrow transplantation. Bone Marrow Transplant. 2011;46(5):733-9.
• 36. Hahn J, Stifel F, Reichle A, Holler E, Andreesen R. Clinical experience with posaconazole prophylaxis--a retrospective analysis in a haematological unit. Mycoses. 2011;54 Suppl 1:12-6.
• 37. Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation — a prospective, randomized, double-blind study. J Infect Dis. 1995;171:1545-52.
• 38. Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood. 2003;101:3365-72.
• 39. Kanda Y, Yamamoto R, Chizuka A, et al. Prophylactic action of oral fluconazole against fungal infection in neutropenic patients: a meta-analysis of 16 randomized, controlled trials. Cancer 2000;89:1611-25.
• 40. Tormo M, Pérez-Martínez A, Calabuig M, et al. Primary prophylaxis of invasive fungal infections with posaconazole or itraconazole in patients with acute myeloid leukaemia or high-risk myelodysplastic syndromes undergoing intensive cytotoxic chemotherapy: A real-world comparison. Mycoses. 2018;61(3):206-12.
• 41. Glasmacher A, Prentice A, Gorschluter M, et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol. 2003;21:4615-26.
• 42. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 2004;103:1527-33.
• 43. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients: a multicenter, randomized trial. Ann Intern Med. 2003;138:705-13.
• 44. Glasmacher A, Cornely O, Ullmann AJ, et al. An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia. J Antimicrob Chemother. 2006;57:317-25.
• 45. Maertens JA, Girmenia C, Brüggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infection