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. PTCY CyA+MTX MTX Cyclosporin A TCD ex vivo
CyA + MMF
FK+ Sirolimus
TCD ex vivo
ex vivoCD34 sel / αβ CD19 dep
T CD in vivo (ATG /CAMP)

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
40%
, n=840
20%
12%
>2010, n=914

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

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

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

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

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

13. 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 CyA MTX
UD 8/8 CyA MTX ATG 5
CB (4/6 5/6) CyA MTX ATG 5
HAPLO 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)
Acute GvHD (grade II-IV)
P= 0.003
P= 0.02
UD; 31%
SIBS ; 29%
SIBS ; 31%
UD; 21%
UCB; 19%
UCB; 21%
HAPLO; 14%
HAPLO; 14%
CMV infection
Transplant Related Mortality
UD; 76%
P= 0.007
HAPLO; 75%
UCB; 74%
SIBS; 55%
UCB; 34%
UD; 34%
SIB ; 19%
HAPLO; 17%
P< 0.001
Fig.2

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

20. Cumulative incidence of CMV response
84%
HAPLO and PT-CY, n=67
59%
UD and ATG, n=30
Both HLA mm
Different GvHD proph
Same incidence of CMV
But HAPLO higher CD4

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
AGE Alt Don
< % 32yy 22%
% 42yy 51%
% 52yy 78%
P=0.001

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

29. Non Infection related death and year of transplant
N= 3126 allografted patients
< % % %
P<

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

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

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

33. Nursing team Genova BMT Unit Gemelli BMT Unit ID Unit GE
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