Therapy of Hematologic Malignancies Period at high risk of IFI Neutrophils (/mm 3 ) 5 Chemotherapy Conditioning Regimen HSCT Engraftment GVHD + Immunosuppressive Treatment Cutaneous and mucositis : - Direct inoculation (Central catheter) - ingestion or translocation (alimentation, intestinal flora) - Inhalation, Fungal colonisation of GI tractus, mucositis High Incidence of IFI in HSCT recipients : 35 % in case of acute GVHD (grades III-IV) 39 % in case of chronic GVHD chronique (*) * Increase incidence because of RIC, PBSC and Cord blood cell using Jantunen E et al,. Bone Marrow Transplant 1997;19 : 81-8
1st Case : The Story of de Mrs H Female, 35 years AML 1 : Diagnosis in october 26 During Induction Therapy - We precribed Posaconazole PO 2 mg TID - She achieved a complete remission (CR1) 2
Posaconazole Prophylaxis in Neutropenic Patients Study Overview Posaconazole (n = 34) N = 62 Chemotherapy & prophylaxis Chemotherapy & prophylaxis (if needed) Day 1 postrandomization Fluconazole Itraconazole or (n = 298) Primary end point time period Secondary end point time period Treatment phase (on-treatment period): From randomization up to 7 days after last dose (primary end point time period). 1-day period after randomization (fixed time period): 1 days after randomization (secondary end point time period). Cornely OA et al. N Engl J Med. 27;356:348-359. Additional information available in Study Report P1899, p 3,4. SPRI, Kenilworth, NJ, USA; November 25.
Posaconazole Prophylaxis in Neutropenic Patients Results Proven/Probable IFI Number of IFIs 35 3 25 2 15 1 5 P <.1 7 2% All IFIs 25 8% Treatment Phase 1* P <.1 2 7% 2 1% Aspergillosis P =.3 14 5% IFI indicates invasive fungal infection. 1. Noxafil [summary of product characteristics]. Brussels, Belgium; SP Europe; 26. 2. Cornely OA et al. N Engl J Med. 27;356:348-359. 3. Study report P1899, p 16,18,19. SPRI, Kenilworth, NJ, USA; November 25. All IFIs Posaconazole (n = 34) Standard azoles (n = 298) 33 11% 4 P <.1 1% 26 9% Aspergillosis 1-day Period After Randomization 1-3 *On-treatment period. Fixed-time period.
Posaconazole Prophylaxis in Neutropenic Patients Results Time to Invasive Fungal Infection Probability of Invasive Fungal Infection.15.1.5 Posaconazole Fluconazole or Itraconazole P =.3*. 2 4 6 8 1 Days After Randomization *Estimated using log-rank statistics. Censoring time is the minimum of the last contact date and day 1. Cornely OA et al. N Engl J Med. 27;356:348-359.
Posaconazole Prophylaxis in Neutropenic Patients Results Death From Any Cause.3 Posaconazole Probability of Death.25.2.15.1.5 Fluconazole or Itraconazole P =.4*. 2 4 6 8 1 Days After Randomization *Estimated using log-rank statistics. Censoring time is the minimum of the last contact date and day 1. Cornely OA et al. N Engl J Med. 27;356:348-359.
Prophylaxis in Neutropenic Patients Serious Treatment-related AEs* Event Event possibly or probably related to treatment Total Bilirubinemia Increased hepatic enzymes Increased alanine aminotransferase Hepatic failure Hepatitis Hepatocellular damage Jaundice Diarrhea Atrial fibrillation Syncope Decreased ejection fraction QT or QTc prolongation Torsades de pointes Diplopia POS (n = 34) 19 (6) 5 (2) 3 (1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 1 (<1) 2 (1) 1 (<1) 1 (<1) 1 (<1) FLU/ITZ (n = 298) 6 (2) 3 (1) 1 (<1) 1 (<1) 1 (<1) Patients, n (%) Standard Azoles FLU (n = 24) 4 (2) 2 (1) 1 (<1) 1 (<1) ITZ (n = 58) * Events are listed for the period from randomization until 3 days after the last dose of the study drug had been administered. Numbers for subentries may not sum to the total numbers because patients could have more than 1 event. QTc denotes the QT interval corrected for heart rate. Prolongation was defined as a period of more than 45 msec for men and more than 47 msec for women. Cornely OA et al. N Engl J Med. 27;356:348-359. 2 (3) 1 (2) 1 (2)
The Story of de Mrs H In January 27 : She underwent an Allogeneic HSCT from an HLA Identical Unrelated Donor (1/1) after a myeloablative conditioning regimen combining Cyclophosphamide 12 mg/kg and TBI at 12Gy She received a gut decontamination and an antiviral prophylaxis from D-9 to D1
Do you prescribe an Antifungal Prophylaxis? 1) No Prophylaxis 2) Yes : - Fluconazole PO Voriconazole PO Ambisome IV Caspofungine IV Posaconazole PO
The story of de Mrs H We decided to give : Fluconazole PO 4 mg qd 1
Antifungal Prophylaxis Hematologic Malignancies and Allogeneic HSCT 3 Fluconazole Micafungine Itraconazole Caspofungine 26.6 p =,3 25 IFI Incidence (%) Placebo p <,1 * proven proven and probable proven probable, possible FU of 4 weeks 2 p =,4 p = NS 2 18 16 15.8 13 15 p = NS 1 7 6 5 6 2.5 Goodman et al (1)* N = 356 Slavin et al (2)* N = 3 Marr et al (3) N = 34 van Burik et al (4) N = 882 Mattiuzzi et al (5)* N = 2 1. Goodman JL et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:845-51. 2. Slavin MA 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. 3. Marr KA et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 24;13:1527-33. 4. van Burik JA et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 24; 39: 147-16. 5. Mattiuzzi GN et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother. 26; 5:143-47.
The story of de Mrs H She well engrafted without any immediate complication and she discharged on D28 with: - Neoral PO (3 mg/kg/day day) - Fluconazole PO 4mg qd - Oracilline, Valaciclovir and Bactrim At Day 36 she developped an acute GVHD of Grade III that we treated with Methylprednisolone (2 mg/kg/day) with maintenance of Neoral 12
Antifungal Prophylaxis Do you maintain Fluconazole? Do you switch? For which molecule?
The story of de Mrs H We decided to switch to : Posaconazole PO 2mg TID The evolution of the patient was good without any complications and any breakthrough fungal infections.
Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD (Double-blind, randomized trial) Posaconazole 2 mg 3x daily or Fluconazole 4 mg oral capsule 1x daily Posaconazole (n = 31) N = 6 First dose Last dose Last dose + 7 days Day 112 Day 112 +2 months (n = 299) Fluconazole Secondary end point time period Primary end point time period Follow-up - Fixed treatment period (fixed-time period) : study period, 112 days - Exposure period (on-treatment period) : time from first study drug dose to 7 days after last dose Principal Objective : Determine efficacy of posaconazole versus fluconazole in preventing proven or probable IFI from randomization to 112 days after first dose Ullmann AJ et al. N Engl J Med. 27;356:335-347
Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD Characteristics Acute graft-versus-host disease grade I II III IV Chronic graft-versus-host disease Limited Extensive Posaconazole (n = 31) 3 (1) 135 (45) 52 (17) 12 (4) 2 (1) 96 (32) Fluconazole (n = 299) 1 (<1) 136 (45) 54 (18) 6 (2) 1 (<1) 99 (33) Ullmann AJ et al. N Engl J Med. 27;356:335-347
Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD Aspergillus antigen, n (%) Positive (.5 baseline) Negative Missing Immunosuppressive agents, n (%) 1 2 3 None Prior antifungal therapy duration Mean ± SD Median (range) Posaconazole (n = 31) 21 (7) 259 (86) 21 (7) 64 (21) 151 (5) 85 (28) 1 (<1) 26.4 ± 39 16 (-254) Fluconazole (n = 299) 3 (1) 243 (81) 26 (9) 48 (16) 168 (56) 82 (27) 1 (<1) 35.3 ± 82 19 (-12) Ullmann AJ et al. N Engl J Med. 27;356:335-347
Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD Posaconazole (n = 31) Fluconazole (n = 299) Duration of prophylaxis, days Mean ± SD Median (range) 8 ± 43 111 (1-138) 77 ± 43 18 (1-13) Ullmann AJ et al. N Engl J Med. 27;356:335-34
Number of IFIs Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD 16 14 12 1 8 6 4 2 P =.7 27 P =.6 9% 21 16 7% 5% 7 7 2% 2% All IFIs Aspergillosis All IFIs P =.4 22 P =.1 8% 17 6% 3 1% Aspergillosis Fixed Treatment Period* Posaconazole n = 31 Fluconazole n = 299 Exposure Period Posaconazole n = 291 Fluconazole n = 288 Ullmann AJ et al. N Engl J Med. 27;356:335-347.
Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD 2 Probability of Onset of Infection (%) 18 16 14 12 1 8 6 4 2 Mean (days) Fluconazole (88) Posaconazole (12) P =.48 1 2 3 4 5 6 7 8 9 1 * Days From First Dose Ullmann AJ et al. N Engl J Med. 27;356:335-347
Posaconazole Prophylaxis in Allogeneic HSCT Recipients With GVHD Cause of death (Investigator assessment), n (%) Total deaths Adverse event Complications related to invasive fungal infection Progression of underlying disease/graft-versushost disease Other Posaconazole n = 31 76 (25) 39 (13) 4 (1) 31 (1) 2 (1) Fluconazole n = 299 84 (28) 37 (12) 12 (4) 33 (11) 2 (1) No significant difference in time to death (P =.847) between groups P =.1 by Chi-square test. P =.46 by log-rank test. Ullmann AJ et al. N Engl J Med. 27;356:335-347
Prophylaxis in Allogeneic HSCT Recipients With GVHD Body System/Preferred Term Subjects reporting any AE Body as a whole General disorders Anorexia Dizziness Drug level altered Fatigue Headache Weakness Cardiovascular disorders, general Hypertension Central and peripheral nervous system disorders Tremor Disorders of the eye Vision blurred Posaconazole (n = 31) 17 (36) 3 (1) 4 (1) 5 (2) 4 (1) 3 (1) 3 (1) 2 (1) 4 (1) 3 (1) Patients, n (%) Fluconazole (n = 299) 115 (38) 7 (2) 5 (2) 2 (1) 6 (2) 8 (3) 5 (2) 5 (2) 6 (2) 5 (2) Supplementary Appendix to: Ullmann AJ et al. N Engl J Med. 27;356:335-347
Prophylaxis in Allogeneic HSCT With GVHD Body System/Preferred Term Gastrointestinal system disorders Abdominal pain Constipation Diarrhea Dyspepsia Nausea Vomiting Liver and biliary system disorders Bilirubinemia GGT increased Hepatic enzymes increased Aspartate aminotransferase increased Alanine aminotransferase increased Posaconazole (n = 31) 4 (1) 1 (<1) 8 (3) 3 (1) 22 (7) 13 (4) 8 (3) 9 (3) 8 (3) 8 (3) 9 (3) Patients, n (%) Fluconazole (n = 299) 7 (2) 5 (2) 12 (4) 6 (2) 28 (9) 15 (5) 5 (2) 7 (2) 7 (2) 3 (1) 4 (1) Supplementary Appendix to: Ullmann AJ et al. N Engl J Med. 27;356:335-347
ECIL
IDSA
1st case: Conclusion In acute myelogenous leukemia patients with neutropenia due to chemotherapy, posaconazole was Significantly better than pooled standard azoles for prophylaxis for Candida and Aspergillus infections Associated with a decrease in all cause mortality at day 1 In hematopoietic stem cell transplant recipients with graft versus host disease, posaconazole was Significantly better than fluconazole for prophylaxis for Candida and Aspergillus infections during the exposure period* Associated with a reduction in invasive fungal infection-related mortality Posaconazole has a safety profile comparable to fluconazole *On-treatment period.
2nd Case: The story of de Mrs B The similar story in the beginning but patient maintained fluconazole when she developed GVHD At D 7 : she developed a Fever,, a productive cough, a chest pain and she was hospilalized. The leucocyte count showed 118/mm 3 (16 Neutro) GM Antigenemia was positive at a level of 2.9 The Fibrinogen level was 11.7 g/l 27
The story of de Mrs B Chest Xray
The story of de Mrs B Scanner 29
It is a probable Invasive pulmonary Aspergillosis according to the EORTC criteria What do you do? - Complementary exams? - Specific Treatment? 3
The story of de Mrs B We do : A Bronchoalveolar Lavage which showed : - Mycellar filaments at the direct exam and culture showed an Aspergillus Fumigatus - BAL : Ag+ 31
Diagnosis of Proven Pulmonary Apergillosis Choice of Antifungal Treatment - Voriconazole IV then PO? - Voriconazole PO? - Caspofungine IV? - Ambisome IV? - Posaconazole PO? - Amphotericine B? - Combinations?
The story of de Mrs B - It is a proven IFI (IPA) - We decided to give : Ambisome IV
Treatment of First Line International Recommendations ECIL 27 - Voriconazole : AI - Ambisome : BI - Combinations : not recommended IDSA 28 - Voriconazole : AI - Ambisome : AI - Combinations : not recommended
The story of de Mrs B Ag Evolution of the Scanner over time on Ambisome IV
What do you do in front of IFI worsening? - A new monotherapy : - Caspofungine IV? - Voriconazole IV? - Posaconazole PO? - Other monotherapies? - A combination of antifungal molecules?
The story of de Mrs B We decided to give Posaconazole azole PO 4 mg X 2 / day 37
The story of de Mrs B 1,5 1,5 Ag Asper. 12 14 16 18 2 22 25 3 45 6 Posaconazole
Posaconazole Treatment of Refractory Invasive Fungal Infections Patients (%) 9 8 7 6 5 4 3 2 1 79/17 67/86 Posaconazole (n = 17) External Control (n = 86) 19/17 11/86 9/17 8/86 Pulmonary Extrapulmonary Disseminated. Walsh T et al. Clin Infect Dis. 27;44:2-12
Posaconazole Treatment of Refractory Invasive Fungal Infections 9 8 94/17 68/86 Posaconazole (n = 17) External Control (n = 86) 7 Patients (%) 6 5 4 3 2 1 13/17 18/86 Refractory* Intolerant *Includes subjects who were both refractory and intolerant. Walsh T et al. Clin Infect Dis. 27;44:2-12
Posaconazole Treatment of Refractory Invasive Fungal Infections 9 8 Posaconazole (n = 17) External Control (n = 86) Patients (%) 7 6 5 4 3 7/17 46/86 37/17 4/86 2 1 Proven Probable Study report P2952, p 87. SPRI, Kenilworth, NJ, USA; March 24
PosaconazoPosaconazole Treatment of Refractory Invasive Fungal Infections 45 42 Responders (%) 4 35 3 25 2 15 1 5 P =.6 26 45/17 22/86 Posaconazole (n = 17) External Control (n = 86) Treatment vs control: OR, 4.6 (95% CI, 1.5 11.4). *Primary efficacy analysis (logistic regression). Walsh T et al. Clin Infect Dis. 27;44:2-12
Posaconazole Treatment of Refractory Invasive Fungal Infections Survival Distribution Function 1..75.5.25. Posaconazole External Control P =.3 16% absolute difference 5 1 15 2 25 3 35 4 Survival (all cause mortality, days) Walsh T et al. Clin Infect Dis. 27;44:2-12
Posaconazole Treatment of Refractory Invasive Fungal Infections Clinical evidence demonstrates posaconazole is an effective option for invasive aspergillosis refractory to amphotericin B or itraconazole or in patients intolerant of these agents Response, n/total (%) Overall response All Aspergillus spp A fumigatus A flavus A terreus A niger Posaconazole 45/17 (42) 34/76 (45) 12/29 (41) 1/19 (53) 4/14 (29) 3/5 (6) External Control 22/86 (26)* 19/74 (26) 12/34 (35) 3/16 (19) 2/13 (15) 2/7 (29) Posaconazole therapy conferred a survival benefit *P =.6. Mycologically confirmed Aspergillus species including other less known or unknown species Walsh T et al. Clin Infect Dis. 27;44:2-12
Posaconazole for Zygomycosis Posaconazole resulted in a 6% success rate in patients with zygomycosis Additional 21% of patients had stable disease Successful outcomes were observed in patients regardless of Infection site Predisposing condition Enrollment reason Primary pathogen Posaconazole may offer an alternative oral treatment to amphotericin B for zygomycosis van Burik J-A et al. Clin Infect Dis. 26;42:e61-e65.