Immunosuppressive Strategies and Infectious Risk in Hematopoietic Stem Cell Transplantation

This presentation discusses various immunosuppressive strategies and their impact on infectious risks in hematopoietic stem cell transplantation, presented by Andrea Bacigalupo from Fondazione Policlinico Universitario Gemelli. Topics covered include cyclosporin A, methotrexate, post-transplant cyclophosphamide, acute GvHD rates over different transplant years, GvHD prophylaxis approaches, and instances of bloodstream infections pre-engraftment. The slides examine tolerance mechanisms, patient outcomes, and prophylactic measures implemented from 2000 to 2018.

• Immunosuppression
• Hematopoietic stem cell transplantation
• Infectious risk
• GvHD prophylaxis
• Tolerance mechanisms

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1. Immunosuppressive strategies and infectious risk in hematopoietic stem cell transplantation Andrea Bacigalupo Istituto di Ematologia Fondazione Policlinico Universitario Gemelli IRCCS Universita Cattolica del Sacro Cuore Roma Varese, 23 maggio 2019

2. Cyclosporin A MTX PTCY CyA+MTX CyA + MMF FK+ Sirolimus TCD ex vivo ex vivoCD34 sel / CD19 dep T CD in vivo (ATG /CAMP) 1970 1980 1990 2000 2010 2017

3. Post-transplant CY: Three distinct and sequential mechanisms for induction and maintenance of tolerance 3 Intrathymic clonal deletion of donor-derived anti host T cells 1 1 anti-host and anti-donor T cells are destroyed in the periphery 2 development of peripheral tolerance Luznik, 2012

4. All patients and year of transplant: acute GvHD II P<0.000001 <2000, n=1062 40% 2001-2010, n=840 20% 12% >2010, n=914

5. All patients and year of transplant: acute GvHD III-IV P<0.000001 <2000, n=1238 13% 2001-2010, n=927 >2010, n=961 5% 4%

6. GvHD prophylaxis 2000-2018 HLA id.sibs UD 8/8 CB (4/6 5/6) HAPLO CyA MTX CyA MTX ATG 5 CyA MTX ATG 5 CyA MMF PT-CY

10. Pre-engr BSI G+ 19% 15% G- F N=166 (30%) at least 1 BSI Median int from SCT 8 days Year 2010-2012 =29% Year 2013-2016 =31% 18% 14% 20% 16% HLA id SIB UD CB HAPLO 7% 7% 26% 11% 26% 19% 4% 16%

11. Pre-engr BSI: 7 and 30 day mortality 7d 30d N=166 at least 1 BSI G+ G- Coli (4) Klebsiella (6) Pseudomonas (3) Multiple only G+ (8) G+G- (19) 5% 0% 6% 2% 33% 50% 33% 67% 8% 1% 11% 4% 0% 21% 26% 1%

12. Pre-engr BSI: Factors predicting IR mortal NRM D 60 BSI Etiology Engraftm Year YES G- no >2012 (2.5%) G-

13. 1. Pre-engraftment infections # predicted by donor type HLA mismatch and/or GvHD proph ? # negative impact on 60-day NRM # caused mainly by carbapenem resistant Gram- pathogens, # particular attention should be given to appropriate empiric therapy and management of patients at high risk for Gram-negative BSI.

15. Post engraftment infections CMV EBV Aspergillus Bacteria

16. GvHD prophylaxis HLA id.sibs UD 8/8 CB (4/6 5/6) HAPLO CyA MTX CyA MTX ATG 5 CyA MTX ATG 5 CyA MMF PT-CY

17. CD4 recovery after HSCT median counts CsA+MTX CsA+MMF+PTCY CsA+MTX+ATG CsA+MTX+ATG

18. Chronic GvHD (moderate-severe) P= 0.02 Acute GvHD (grade II-IV) P= 0.003 SIBS ; 29% UD; 31% SIBS ; 31% UD; 21% UCB; 21% UCB; 19% HAPLO; 14% HAPLO; 14% 1,000 CMV infection Transplant Related Mortality P= 0.007 UD; 76% HAPLO; 75% 0,750 Cumulative Incidence UCB; 74% SIBS; 55% 0,500 UCB; 34% UD; 34% SIB ; 19% 0,250 HAPLO; 17% P< 0.001 0,000 Fig.2 0,0 300,0 600,0 900,0 1200,0 days from transplant

19. CMV infection after engraftment # higher risk with HLA mm donors And treatment?

20. Cumulative incidence of CMV response P=0.01 84% HAPLO and PT-CY, n=67 59% UD and ATG, n=30

21. Actuarial survival HAPLO and PT-CY, n=67 71% 51% UD and ATG, n=30 P=0.02

25. Rituximab 200 mg fixed dose Day +5

26. Infections: donor type/ diagnosis / ATG/ HLA mm / GvHD prophylaxis/ CD4 recovery Complex interplay

27. Infections related death and year of transplant N= 3126 allografted patients 10% 12% 7% AGE 32yy 42yy 52yy Alt Don 22% 51% 78% <2000 2000-2010 2011-2018 P=0.001

28. Infections related death and year of transplant N= 3126 allografted patients 10% 12% 7% AGE 32yy 42yy 52yy Alt Don 22% 51% 78% (PTCY 65%) <2000 2000-2010 2011-2018 P=0.001

29. Non Infection related death and year of transplant N= 3126 allografted patients <2000 2000-2010 2011-2018 44% 45% 38% P<0.00001

30. Non Infection related death and year of transplant N= 3126 allografted patients (ge-gem) <2000 2000-2010 (n=927) 2011-2018 (n=963) (n=1236) 45% 42% 54% P<0.00001

31. Conclusions # Better GvHD prophylaxis # Better CD4 recovery with PT-CY as compared to ATG # Improved survival What now?

32. GvHD proplylaxis 2019 CyA MMF PT-CY CyA MMF PT-CY CyA MMF PT-CY CyA MMF PT-CY <=2018 CyA MTX CyA MTX ATG 5 CyA MTX ATG 5 CyA MMF PT-CY HLA id.sibs UD 8/8 CB (4/6 5/6) HAPLO

33. Genova BMT Unit E Angelucci AM Raiola, F Gualandi, A Dominietto, R Varaldo, M T Van Lint , S Bregante, C di Grazia T Lamparelli Gemelli BMT Unit S Sica, L Laurenti, P Chiusolo, F sora , S Giammarco, E Metafuni, I Innocenti, F Autore A DiGiovanni E Alma ID Unit GE C Viscoli M Mikulska V del Bono Gemelli ID Unit R Cauda M Tumbarello Microbiology M Sanguinetti Commissione Infezioni Corrado Girmenia Data Manager R Oneto G Conti M Daneri Nursing team