1. VALDEZ ET AL CLINICAL INFECTIOUS DISEASES 2011;52(6):726–735 R2 Kim Dong Hyun Decreased Infection-Related Mortality & Improved Survival in Severe Aplastic Anemia in the Past Two Decades

2. INTRODUCTION Severe aplastic anemia (SAA)  A half century ago, treatment options limited to androgens, transfusion support, and antibiotics.  Striking improvement in survival because of hematologic recovery.  In the 1970s, introduction of hematopoietic stem cell transplantation (HSCT)  In the 1980s, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA)

3. INTRODUCTION Severe aplastic anemia (SAA)  Since the introduction of ATG + CsA, hematologic response rate has remained steady at 60%–70%  Sizeable population of patients with SAA remain pancytopenic after IST  But infections remain the main cause of death, with invasive fungal infections (IFIs) being the most lethal.  Hematological salvage treatments (Repeat course of IST or HSCT)  To support IST-unresponsive patients through extended periods of pancytopenia to receive salvage hematological interventions is critical to their outcome.

4. PATIENTS AND METHODS Patient Demographic Characteristics  Consecutive patients who fulfilled diagnostic criteria for SAA were enrolled in sequential treatment protocols ( Nov. 1989 ~ Apr. 2008)  Diagnostic criteria for SAA  Bone marrow cellularity of < 30%, and  Severe pancytopenia satisfying at least 2 criteria ANC < 500 cells/uL Absolute reticulocyte count < 60,000 cells/uL platelet count < 20,000 platelets/uL  Response  No longer meeting criteria for SAA at 6 months after ISI

5. METHODS Study Design and SAA Treatment Regimens  Retrospectively reviewed the records of 174 patients with SAA who were unresponsive to initial IST from 1989 through 2008  Three patient cohorts defined by date of implementation of the different immunosuppression protocols  Group 1 : 43 patients, from December 1989 ~ October 1996  Group 2 : 51 patients, from November 1996 ~ October 2002  Group 3 : 80 patients, from November 2002 ~ April 2008

6. RESULTS

7. Patient Characteristics

8. Bacterial Infections RR = 2.14 95% CI, 1.34–3.42 P = 0.003 RR = 0.15 95% CI, 0.03–1.34 P = 0.03 RR = 1.13 95% CI, 0.74–1.70 P = 0.70

9. Blood Isolates in Patients with SAA

10. Susceptibility Profiles of Organisms

11. IFIs 30% to 3% (P < 0.001) 16% to 5% (P < 0.05)

12. Overall Survival - 1 64% to 79% (P < 0.001) No difference in survival

13. Overall Survival - 2 23% to 57% (P < 0.001) 61% to 89% (P < 0.001)

14. 6-Month survival IFI  Commonly diagnosed within the first 6 months after IST  Usage of antifungal agents was distinct  group 1 : Deoxycholate amphotericin B (DAmB)  group 2 : Amphotericin B → Voriconazole  Group 3 : Voriconazole  The improved 6-month survival observed in groups 2 and 3 corresponds to the introduction of liposomal formulations amphotericin B and voriconazole in these groups.

15. Infection-related mortality

16. Probability of Death within 1 Year for Patients Unresponsive to ISI

17. Salvage Therapy 23% to 57% (P < 0.001) 61% to 89% (P < 0.001 ) G1G2G3

18. Discussion Markedly improved survival during the 20 yrs  Conjunction with decreased infection-related mortality & decreased frequency of IFIs  Independent variables associated with survival  Younger age  ANC < 200/uL before IST  Absence of IFI  Use of voriconazole  But not occurrence of bacteremia

19. Discussion Impact of IFIs  The first report describing the independent impact of IFIs in a logistic regression model  Newer antifungal therapy, an independent predictor of improved outcome  Those who received voriconazole had a significantly improved outcome, with approximately 12-fold odds ratio  The role of improved antifungal supportive care is more clearly defined in the first 6 months following IST  The improvement in survival beyond 6 months also benefited from repeat IST and/or HSCT

20. Conclusion During the past 2 decades, a significant decrease in IFIs, infection-related mortality, and overall mortality in patients with SAA unresponsive to initial IST. Improved outcomes have paralleled advances in infectious diseases supportive care, especially antifungal therapy with voriconazole.