Download Document

Infections in non-myeloablative
« Reduced intensity conditioning »
stem cell transplant
Catherine CORDONNIER
Hôpital Henri Mondor, Créteil, France
Reduced intensity conditioning SCT
OBJECTIVES:
-> Reduce the early toxicity of allogeneic SCT
-> Keep the Graft-versus-leukemia effect

Mainly proposed to:
- older patients (> 55 y)
- patients with comorbidity

Reduces the duration of neutropenia

Reduces mucosal and liver toxicity

Does not solve the problem of GVHD
2
Example of a RIC / non myelo-ablative regimen
Immunesuppression vs Myelosuppression
TBI 2 Gy
PB SCT
Chimerism Analyses
-4 -3 -2 -1 0
28
56
84
Fludarabine: 30 mg/sq./d
Cyclosporine
Mycophenolate Mofetil
From Niederwieser et al. 2003
3
RIC: Different preparative regimens
from Kassim AA et al. BMT 2005
MyeloAblative
MOderate
intensity
MInimal
intensity
4
RIC reduces the Transplant (non relapse) Related Mortality
after Allogeneic SCT – Results of historical comparisons
Author
Sorror 2004
Diaconescu 2004
RIC vs MA
Disease
TRM 3 mo
TRM 1 y
60 / 74
various
12% vs 18%
20% vs 32%
p=.07
p=.04
3% vs 23%
16% vs 30% p=.04
73 / 73
various
p=.001
Alyea 2004
71 / 81
various
32% vs 50%
P=.01
Kojima 2005
70 / 137
various
7% vs 15%
22% vs 32%
p=.28
Scott 2006
38 / 112
AML/MDS
TRM 3 y : 41% vs 34% p=.94
BUT TRENDS FOR HIGHER RELAPSE RATES IN MANY DISEASES
5
Immune reconstitution after RIC (1)
Neutropenia
After Fluda-TBI 2Gy in AML (Hegenbart JCO 2006):
No neutropenia at all (PMN > 500/µL):
27%
Median nadir of PMN:
216/µL
Median No. Days with PMN<500/µL:
6 days
Other RIC regimens:
Variable
Never as deep and long as in MA regimens
6
Immune reconstitution after RIC (1)
T and B cell Populations

Few comparative data with conventional transplants

CD4: better recovery in RIC vs MA (Jimenez 2005)
slow recovery in RIC (Larosa 2005)

TRECs: better recovery at 6 months in RIC vs MA (Jimenez 2005)

B cells: slower recovery after RIC vs MA (Schulenburg 2005)
7
EBV-specific immune reconstitution is delayed
after RIC
(Chakrabarti et al. Blood 2003)
Recovery of circulating antigen-specific T-cell immunity to EBV
determined by ELIspot assays / controls
After MA SCT
After RIC
3 mo
6 mo
12 mo
3/6
6/9
12/12
-
1/9
7/10
8
Reduced Intensity Conditioning Regimens
and Infections (1)
Many contradictory reports at the beginning
« High rate of secondary viral and bacterial infections in patients
undergoing allogeneic bone-marrow mini-transplantation »
(Mohty et al. BMT 2000)
« Reduced-intensity conditioning reduces the risk of severe infections
after allogeneic peripheral blood stem cell transplantation »
(Martino et al. BMT 2001)
« High rate of invasive fungal infections following nonmyeloablative
allogeneic transplantation » (Hagen et al. CID 2003)
9
Reduced Intensity Conditioning Regimens
and Infections (2)

No prospective study between RIC and standard SCT
sofar published

Only retrospective, case control studies, with bias of
selection:
- Age
- Contraindication for standard conditioning
10
Fungal and Aspergillus infections
Historical comparison between RIC and Conventional SCT
No.
Author
RIC SCT
% with IFI
% with
Asp
No.
Convent
% with IFI
% with
Asp
SCT
Martino 2001
71
11%
5%
123
14%
8%
Junghanss 2002
56
-
15%
112
-
9%
Fukuda 2003
163
19%
14%
1673
-
10%
Kojima 2004
178
-
8.2%
486
-
4.5%
Sorror 2004
60
12%
-
74
14%
11
Comparison of invasive fungal infection after
nonmyeloablative and myeloablative HCT
(1993-1998)
N=163
Aspergillosis
All IFI
N=163
N=1673
ns
Fukuda, T. et al. Blood 2003;102:827-833
12
Risk factors, timing, and mortality of aspergillosis
after RIC vs conventional SCT
Daly 2003, Fukuda 2004, Kojima 2004
Aspergillosis occurs LATER after RIC (d120 vs d90)
RISK FACTORS are comparable:
age > 50 y
acute/chronic GVHD
CMV
Case FATALITY rates are comparable
Aspergillosis is the first cause of non-relapse (or infectious)
mortality ALSO after RIC
13
Should a RIC be prefered in case of previous
severe infection?

To be taken in consideration:
- underlying disease: risk to go to RIC vs MA
- risk of infection relapse

Previous bacterial infection:
- No if cured, without persistent focus

Current bacterial infection:
- Probably Yes is transplant is urgent, and the infectious
situation is uncontrolled

Previous Fungal infection ?
14
Allogeneic SCT and previous Invasive
aspergillosis

Risk of IA relapse estimated at # 30%
(Nosary 1994, Cowie 1994, Martino 1997, Offner 1998, Cornelly 2002, Fukuda 2004)

Probable protective effect of RIC, no TBI, secondary prophylaxis,
> 1 mo of AF therapy, and resolution of imaging before transplant
(Offner 1998, Fukuda 2004)

Parody et al, EBMT 2006: Retrospective survey from 23 centers on
pts transplanted with previous proven or probable IA
129 pts : 57 RIC and 72 MA
15
Progression of IA before Day 30 of an allogeneic
SCT in patients with previous IA
(Parody et al. EBMT 2006)
RISK FACTORS
Conventional vs RIC
Univariate P
Multivariate P
0.02
0.06
HR 2.5 (0.9-3.1)
Time of neutropenia
(every 5 day period)
<0.001
NT
< 6 weeks between
Dg of IA and AlloHSCT
0.04
NT
≥ 2 post-HSCT serum
positive GM ( ≥ .8)
No
Yes
Not done
0.03
2/43 (5%)
11/24(46%)
14/62(23%)
NT
16
Progression of IA BEFORE day 30 in recipients of a
RIC or a conventional myeloablative regimen (CONV)
[n=13 cases]
20
CONV (9 / 72)
P=0.06
15
10
RIC (4 / 57)
5
0
0
10
20
30
Days after transplant
Parody et al. EBMT 2006
17
Progression of IA after Day 30 of an allogeneic SCT in
patients with previous IA (Parody et al. EBMT 2006)
RISK FACTORS
BMT/CBT vs PBSCT
Univariate P
Multivariate P
<0.0001
0.001
HR 98(9-990)
aGVHD ≥ 2 (high-dose
steroids > 7ds &/or ATG)
0.01
0.04
HR 100(3.7-2900)
CMV disease
0.0001
Advanced disease status
0.0008
NT
0.02
NT
< 6 w between IA-SCT
0.06
0.1
Response status of IA at
SCT
0.04
Not included
Duration of neutropenia
0.01
HR 4.2(1.4-17)
(every 5 day)
18
CMV infection and disease
Retrospective comparisons between RIC and
myeloablative transplants
Author
Martino 2001
No. Pts
Mean age
RIC / MA
RIC / MA
71 / 123
54 / 38
Junghanss
2002
34 / 68
Sorror 2004
60 / 74
54 / 46
CMV Inf
CMV disease
21% vs 39%
1% vs 9.5%
p=.03
p=.05
(Ag) 53% vs 69%
(ns)
6% vs 19%
54 / 41
(ns)
45% vs 35%
ns
Norasetthada
ASH 2005
342 / 2154
53 / 40
49% vs 55%
(ns)
« High grade Inf»
12% vs 23%
(ns)
19
CMV infection and disease in R+ patients
Comparison RIC (n = 34) vs MA (n=68)
Junghanss, C. et al. Blood 2002
CMV Ag « tends » to be less frequent in RIC
(53% vs 69%; p = .11)
CMV viremia « tends » to be less frequent
(3% vs 13%; p=.16) and to occur later
(d60 vs d43; p=.40) in RIC
CMV disease « tends » to be less frequent
(6% vs 19%; p=.08) and to occur later
(d85 vs d36;p=.04)
BUT ! Finally at 1 year:
No difference in the incidence of CMV combined
manifestations
20
Infections after RIC transplants
Conclusion
-
No prospective comparative studies sofar, but….
-
A clear trend for less early bacterial infections
-
Comparable incidences of IFI, a trend for less in RIC
-
A likely protective effect of RIC in case of previous IA
-
Comparable incidences of CMV infection and disease
-
Delayed occurrence of fungal and viral infections
-
No data on late infections
21