Optimal Prophylaxis: Case for Fluconazole/ Itraconazole Pranatharthi H. Chandrasekar, MD Wayne State University School of Medicine Karmanos Cancer Institute

Outline Itraconazole : Safety/Efficacy What has changed? Fluconazole : Safety/Efficacy Itraconazole : Safety/Efficacy What has changed? Treatment Practices Epidemiology of Cand./Asp Antifungal Resist.: Aspergillus Problems with ‘newer’ azoles Summary : Fluconazole remains a useful drug for prophylaxis Cancer pts & stem cell recipients

Fungal Infection Prevention — Practices Avoidance of potted plants/contact with soil Hand Washing, ?? Masks Water: Drinking/Showering Vascular access care HEPA filtration Reduced duration of neutropenia Reduced immunosuppression CHEMOPROPHYLAXIS

Infection- related mortality Fluconazole Prophylaxis in Hematopoietic Stem Cell Transplant Recipients Fluconazole Placebo Goodman et al: 52% Allografts/ 48% Auto, Fluc (400 mg/d) vs Placebo  Engraftment Slavin et al: 88% Allografts/ 12% Auto, Fluc (400 mg/d) vs Placebo Day 75 Slide 44 Goodman in 1992, and Slavin in 1995, conducted randomized, double-blind, placebo-controlled trials to evaluate fluconazole as antifungal prophylaxis for HSCT recipients. Goodman and colleagues studied 356 autologous and allogeneic HSCT recipients from multiple centers, using large doses of fluconazole (400 mg/day) from the start of the conditioning period for a maximum of 10 weeks; 2.8% of fluconazole patients experienced systemic fungal infection versus 15.8% of placebo patients. Fewer infection-related deaths occurred in the fluconazole arm of the study. However, fluconazole did not significantly alter overall mortality. In the second study, Slavin and co-workers sought to determine if a longer course of prophylaxis with fluconazole would improve survival or lower the incidence of infections. They administered fluconazole (400 mg/day for 75 days) to a primarily allograft-recipient population. The rate of infection in the fluconazole arm during prophylaxis was 10 of 152 patients (or 7%) versus 26 of 148 patients (or 18%) in the placebo arm (P=.004). The rate of fungal infection-related deaths by day 110 after transplant was 13% in the fluconazole arm and 21% in the placebo arm (P=.005). In contrast to the Goodman study, at day 110 the probability of overall survival was improved among fluconazole recipients (20% vs 35%, P=.004). * Patients (%) Patients (%) * * * * Infection Infection- related mortality Overall mortality Infection Infection- related mortality Overall mortality *Statistical significance between fluconazole and placebo. Goodman JL, et al. N Engl J Med. 1992;326:845-851. Slavin MA, et al. J Infect Dis. 1995;171:1545-1552. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:845-851. Marr KA. Antifungal prophylaxis in hematopoietic stem cell transplant recipients. Curr Opin Infect Dis. 2001;14:423-426. 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;171:1545-1552.

Fluconazole Prophylaxis : Acute Leukemia Placebo Overall fungal fungal infection 9% 21% P=.02 Syst fungal infection 4% 8% P=NS Mortality ≡ Flu (400 mg/d) Def/Probable IFI 9 32 P=.0001 Deaths from IFI 1/15 6/15 P=.04 Benefit in: AML/induction therapy with cytarabine +anthracycline-based regimen Winston DJ et al, Ann Intern Med 1993;118:495 Rotstein C et al, Clin Infect Dis 1999; 28:331

Fluconazole : Survival Independent predictor of overall survival/multivar analysis (matched, unrelated donor transplant) Meta analysis: ↓ IFI / ↓ fungus-related death (neutropenic patients : 16 trials) [if inf rate > 15%] ? Optimal dose/duration ? All leukemic patients ? Non-myeloablative stem cell tx ? Allogeneic recip with Graft-versus-Host-Disease Hansen JA et al, N Engl J Med 1998; 338:962 Kanda Y et al, Cancer 2000; 89:1611

ITRACONAZOLE : Prophylaxis in Hematopoietic Stem Cell Transplant Recipients Patients I : 200 mg q 12h x 2d IV; 200 mg sol q 12 (d + 1 to d + 100) F: 400 mg IV/PO q 24h 180d Post SCT I (%) F (%) P Proven IFI 9 25 .01 Fungal-death 18 .13 Inv. Asperg. 4 12 .12 Mort NS GI Intolerance 24 .02 Winston DJ, Ann Intern Med 138: 705, 2003. 304 Patients I : 7.5 mg/kg/d sol with condition regimen Inv. Fungal Inf Intent to Treat I ≡ F On Treatment I < F (P .03) Inv. Mold Inv. Cand Hepatotoxicity / GI Intolerance I : 36% ; F : 16% Marr KA, Blood 103: 1527, 2004.

Itraconazole vs Candida, no advantage over Fluconazole Vs Aspergillus ↓ low-risk patients in studies Different formulations of Itraconazole Inadequate # enrolled in studies Meta analysis (Itra, Flucon, Ampho B) Itra: ↓ invasive fungal infection 48% reduction in IA (with Itra sol.) Oren I et al, Bone Marrow Transplant 2006; 38:127 Vardakas KZ et al, Br J Hematol 2005:131:22 Glassmacher A et al, J Clin Oncol 2003:21:4615

Itraconazole : Drawbacks Suboptimal Bioavailability Inter patient variability Poor tolerability Capsule : Erratic bioavailability Drug interactions/CYP450 eg. Cyclophosphamide, Vincristine anthracyclines ? Greater toxicity Cardiotoxicity (negative inotropic effect) ↓ drug levels: clin failures/↓ fungal-free survival Marr K et al, Blood 2004;103:1527 Maertins J et al, J Antimicrob Chemother 2005;56:33 De Beule KL, Int J Antimicrob Agents Chemother 1996:6:175 Winston DJ et al, Ann Intern Med 2003;138:705

IDSA Guidelines: Prophylaxis Candidiasis Chemo-induced Neutropenia Flucon, Itracon, Posacon (A-I) Caspof (B-II) Stem Cell Transpl (Neutropenia) Flucon, Posacon, Micaf (A-I) Solid Organ Transpl (Hi-risk Liver, Pancrease, Sm Bowel Flucon ICU Hi-risk units with ↑ freq. candidiasis Pappas PG et al, Clin Inf Dis 2009;48:509

What is Changed/Known Now? Treatment Practices Epidemiology of IFI/heme Ca, SCT Resistance in Aspergillus

Frequency of IFI : Influencing Factors Cancer/Stem Cell Recipient Population Ac leukemia/status Salvage for relapse/refr Highest Risk Induction for newly diagnosed High Risk Consolidation Low Risk Duration of Neutropenia Periph blood vs bone marrow Non-myeloablative vs myeloablative Mucositis – Non-myeloablative regimen GVHD & its therapy Antifungal Prophylaxis

Impact of Flucon Prophy : Stem Cell Population ‘80-’86 vs. ‘94-’97 (585 pts) Comm. Colonizer : C. alb. C. alb.: Flu Res. 5% Mort : 39% → 20% □ 1980-1986 ■ 1994-1997 Marr KA et al J Infect Dis  2000;181:309.

Candidemia : 2004 – 2008 (N. America) Prospective Antifungal Therapy (PATH) Alliance (Registry) Non albicans cand 54% C. albicans 46% Distribution of NAC: C. glab.* > C. parap. > C. trop. > C. krusei* (*Prior Flucon use.) Overall mort (12-wk) 35% with C. krusei 53% Risks for C.krusei : Prior Af use; Heme Ca/SCT; Steroids; Neutropenia Horn et al, Clin Infect Dis 2009; 48:1695

Candidemia : Karmanos Cancer Institute 6/05 → 6/09 Prior to Flucon Prophylaxis ~ 15/year Fluconazole Prophy. Since 1994 Ac myelog leukemia (Neutropenia) Stem Cell recip (Pre-engraftment) # Pts with Candidemia 19 C. albicans 9 Non alb Cand C. glab 5 C. parap 3 C. trop 1 C. krusei

Survival with IA > Survival with Cand/other Invasive Fungal Infections/Stem Cell Recipients: 2004-2007 PATH Registry (16 N Am Centers) 234 Adult SCT / 250 IFI Inv Asp 59% Inv Can 25% Mortality (6 wk), IA 22% Survival with IA > Survival with Cand/other *Candida remains a significant pathogen Neofytos D et al, Clin Infect Dis 2009; 48:265

Aspergillus : Azole Resistance Global Antifungal Surveillance Program (‘01-’06) 771 Asp: A. fum 553, A. fl 76, A. niger 59, A. terr 35 A. versicolor 24 MIC Vori./Posa. > 2 mg/L : < 1% isolates MICs of Vori/Ravu & Posa/Itra correlated in A.fum, A.fl Pfaller MA et al, J Clin Microbiol 2008, 46:2568

Azole Resistance : Aspergillus fumigatus 1992 – 2008 (611 isol.) Azole R ‘92-’97 5% (20/400) ’08 11% (5/63) Mechanisms of Resistance Multiple Harrison E et al. ICAAC 2009, (#M-1720) Regional Mycology Lab, Manchester, UK (519 isol, 1992 – 2007) Resist to Itra 34 (5%) Cross Resist to Vori 65% Posa 74% Patient Data (14) Prior Azole Aspergilloma + CCPA ABPA/bronchitis Acute Invasive Dis Cerebr Asperg 13 9 3 1 Novel Mutations in CYP51A target enzyme Howard SJ et al, Emerg Infect Dis 2009;15:1068

Thus Since Risk for Cand/Asp infections in Ac Leukemia/Stem Cell Recipients is widely varied Candida remains a significant pathogen Mortality from non-albicans (‘Flu- resistant’) candida infections remains low Frequency of azole-resistance in Aspergillus is low Fluconazole (?itraconazole) remain as useful prophylactic drugs in the majority of patients

Problems with ‘Newer’ Azoles

Azole-Mediated Cytochrome P450 Drug-Drug Interactions Pharmacology_R1 3/25/2017 9:57 AM Azole-Mediated Cytochrome P450 Drug-Drug Interactions Drug Mechanism Flu Itr Pos Vor Inhibitor 2C19 + +++ 2C9 ++ 3A4 Substrate Dodds Ashley ES, Clin Infect Dis 2006;43 (Suppl 1):43

Voriconazole Prophylaxis : Allogeneic SCT (’03-’06) Prospective, Randomized, Double Blind Trial (600 pts) [Vori vs Flu] Duration d 0  d + 100/+180 Serum GM twice wkly x 60d, 1-2 wkly until d +100 IFI : Proven/Prob/Presumptive IFI : Similar in 2 arms Fungal Free Survival (6 mos) : Similar Event free / Overall Survival : Similar Concl : Efficacies of V and F are similar with close monitoring and early therapy Wingard JR, Am Soc Hem 2007 (#163)

Posaconazole Prophylaxis (vs Flucon/Itra) Acute Leuk/MDS (602 Pts) P (%) F/I (%) Prov/Prob IFI (During Rx) 2 8 IA 1 7 All IFI (100 d) 5 11 Time to death P=.035 (within 100 d) Overall mortality ↓ with Posa Ullman AJ et al, N Engl J Med 2007;356:335 Cornely OA et al, N Engl J Med 2007;356:348 Stem Cell Transplt/GVHD (600 Pts) P (%) F (%) Prov/Prob IFI (During Rx) 2 8 I A 3 17 All IFI (16 wks) 5 9 Death 2° IFI 1 4 Overall mortality ≡

Therapeutic Drug Monitoring : Posaconazole Interpatient Variability Stem Cell recip/GVHD Cmax (ng/mL) Cavg (ng/mL) IFI (n=5) 635 611 No IFI (n=241) 1360 922 Krishna G et al Pharmacotherapy 2007; 27:1627

Posaconazole Prophylaxis : Limitations Oral Bioavailability – Ability eat fatty meal Ac leukemia trial Most ‘probable’ cases : Dx by Asp. Galactomannan only; if removed, Ø advant. with Posa. GVHD Trial Posa : Baseline GM (+) : 21 (7%); IFI 2 (10%) Flu : Baseline GM (+) : 30 (10%); IFI 7 (23%) ? Pre emptive rather than prophylactic trial Overall Mortality not reduced Cornely OA, New Engl J Med 356: 348, 2007. Ullmann AJ, New Engl J Med 356: 335, 2007.

IDSA Guidelines: Prophylaxis Aspergillosis Stem Cell Transpl/with Graft Versus Host Disease (GVHD) Acute myelogenous Leukemia/myelodysplastic syndrome Posaconazole A-I Itraconazole B-II * “Because of the heterogeneity of risk for IA (in the above 2 populations), further study needed to identify which patients may benefit the most….” Walsh TJ et al Clin Infect Dis 2008;46:327

Fluconazole Prophylaxis: ? Pre Emptive Approach Heme Ca/Neutropenia/Monitor with Serum Asp. GM Thrice wkly Routine Fluconazole Prophylaxis Neutropenic Fever Episodes (117) Antifungal use if Asp GM x consecutive 2 positive CT abnorm & BAL (+) Aspergillus Compared to emp. Approach, antifungal use reduced by 78% Survival with IFI, 64% Maertens J et al, Clin Infect Dis 2005;41:1242

Summary Fluconazole : Markedly diminished frequency of candidiasis in stem cell recipients and pts with acute myelogenous leukemia Itraconazole : Effective, usefulness mainly limited by drug intolerance Non-albicans candida have emerged as pathogens; mortality rate remains stable Frequency of aspergillosis: Wide variability in stem cell and leukemia populations; zygomycosis and others: Low frequency Better delineation of hi-risk subgroups for IFI needed

Summary Long-term use of Voricon/Posacon: Drug interaction/toxicities/resistance/cost Polyenes/Echinocandins : parenteral drugs, not suited for prophylaxis Thus, Fluconazole is a useful drug; with surveillance tools (fungal antigens, pcr, CT), the drug remains useful despite the emergence of molds.