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Experience of Hematopoietic Stem Cell Transplantation in
NTUH, 1983-2012
唐季祿 醫師 台大醫院 , 內科部血液科 , 骨髓移植病
房 台灣大學台成幹細胞治療中心
1983-1991First 100 BMTs in single room
1992-20093D1, 6 HEPA-rooms
2009 July5PW, 8 HEPA-rooms
2010 Mar SCTC, 6 HEPA-rooms
HSCT Center Advancement in NTUH
2
Largest HSCT center in Taiwan, 14 beds, >100 cases/year
*HEPA: high-efficient particle absorbing
Cumulative numbers of HSCT, 1983-2011
N 1 7 5 10 11 11 11 9 13 33 28 47 49 57 53 56 63 64 81 79 72 77 70 77 74 83 104 151 151
Allo-BMT 501 -PBSCT 611 -BM+PB 4 -PB+UCB 1Auto-PBSCT 360 -BMT 36 -BM+PB 10CBT 24Total 1547
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
0
200
400
600
800
1000
1200
1400
1600
1800
1547
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110
20
40
60
80
100
120
140
160
unrelated
Related
Auto
Annual Numbers of HSCT, 1983-2011
N=1547
Types of Donor, 1983-2011
26%
50%
18%2% 2% 1%
Auto
Matched sibling
Unrelated
Parental/Filial
Partial mismatched related donor
True haplo-identical
N=1547
Anteroom
6
Pressure / HumidityCentral monitor
5PW BMT wardClean and safe environments
HEPA-class 10,000 roomToilet- dry/wet separated
7
Friendly and comfortable patient support
HEPA-room (class 10,000)
Pressure-releasing facilities
Toilet- dry/wet separated
8
Anti-mold paintingFamily communication window
Autologous Stem Cell Sources by Recipient Age, 1983-2011
1983-1999 2000-20110
10
20
30
40
50
60
70
80
90
100 BM
PB
BM+PB
CD34+ selection
1983-1999 2000-2011
Age 20 yrs≦ Age >20 yrs
Allogeneic Stem Cell Sources by Recipient Age, 1983-2011
Age 20 yrs≦ Age >20 yrs
1983-1999 2000-20110
10
20
30
40
50
60
70
80
90
100 BM PB BM+PB
CD34+ selection PB+UCB UCB
Mulitple UCB
1983-1999 2000-2011
Trends in Transplantation by Recipient Age, 1983-
2011
1983-1999 2000-20110
10
20
30
40
50
60
70
80
90
100
Autologous Allogeneic
1983-1999 2000-2011
%N=322N=84 N=761N=380
> 50 y
< 50 y
8%
32%12%
Allogeneic transplantations by conditioning regimen intensity and age, 2000-2011
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110
20
40
60
80
100
120
140
160 RIST,≧50
RIST,<50
Myeloablative
69 y, AML, CR2, s/p MUD-RIST, D+17, 轉出隔離病房 ,D+24 出院
Transplant outcome for age older than 55 years of AML or high-risk MDS at NTUH (median age 58 y, 55 - 69)
2006 – 2012, unpublished
3-yr overall survival
56.9%
Unrelated Donor Stem Cell Sources by Recipient Age, 1994-2011
Age 20 yrs≦ Age >20 yrs
1983-1999 2000-20110
10
20
30
40
50
60
70
80
90
100 BM PB UCB Mulitple UCB
1983-1999 2000-2011
Indications of HSCT, 1983-2011
N=1547
CLL
JMML/JCML
Acute leukemia
Unknown
Thalassemia
Others
HL
Solid tumor
MDS/MPD
MM
Anemia
CML
NHL
ALL
AML
0 5 10 15 20 25 30 35
0.4
0.4
0.5
0.700000000000002
2.6
2.6
3
3.3
4.3
6.5
7.1
8.8
14.3
15.8
29.9 %
Reasons to do HSCT twice or more, 1983-2011
N=11335 remains alive
New malignancy
Others
Declining chimerism
Planned second HSCT
No hematopoietic recovery
Unknown
Persistent primary disease
Partial hematopoietic recovery
Graft failure/rejection
Recurrent primary disease
0 5 10 15 20 25 30 35 40 45
1.5
1.5
1.5
2.3
5.3
5.3
6.8
7.5
29.3
39.1
CLL
AML
NHL
MDS
Solid tumor
PTLD
0 5 10 15 20 25 30 35 40 45
1.8
5.3
7
12.3
31.6
42.1
Numbers of 2nd Malignancy
N=57
20 remains alive
Overall Survival,1983-2011 Disease free survival, 1983-2011
692 dead, 719 alive, 242 remains alive more than 10 years
Overall survival, by transplant eras, 1983-2011
Relapse49.7%
New malignancy3.3%
Unknown4.5%
Cardiac toxicity
0.4%
GVHD8.8%
Infection22.8%
rejection2.5%
Hem-or-
rhage0.6%
IP3.9%
Pulmonary toxicity0.4%
VOD0.7%
Others2.3%
Main cause of death
N=692
Relapse; 46.7
New malignancy; 3.3Unknown; 4.4
Infec-tion; 22.4
GVHD; 11.2IP; 4.6
rejec-tion; 1.6
others; 4.4 VOD; 1.4
Main cause of death – by Donor type
Matched sibling donor
Autologous
Unrelated donor
Relapse; 38.6
New ma-lignancy;
5.5
Unknown; 1.6Infection; 30.7
GVHD; 12.6IP; 3.1rejection; 3.9 others; 3.9 Relapse; 68
New ma-lignancy;
2
Unknown; 8.5
Infection; 16.3
IP; 2 rejection; 0.7 others; 2.6
Overall survival after HLA-matched sibling donor transplantation for AML, by risk group and cell sources,
1984-2011
Overall survival after HLA-matched sibling donor transplantation for ALL, by risk group and cell sources,
1984-2011
Overall survival after HLA-matched sibling transplantation for CML, by risk group and transplant year, 1984-2011
Overall survival after autologous transplantation for Lymphoma, by risk group, 1983-2011
Overall survival for Lymphoma, by transplant type, 1983-2011
Overall survival after allogeneic transplantation for MDS/MPD, 1986-2011
Overall survival after allogeneic transplantation for Anemia, by age group, 1984-2011
Results of Stem Cell Yields in Allo-HSCT(Median and 95% C.I.)
BMT PBSCT (n= 55) (n- 34)
18
15
12
9
6
3
0
Total cells
108 / kg BW
p < 0.001
18
15
12
9
6
3
0
CD 34+ cells
106 / kg BW
BMT PBSCT (n= 55) (n- 34)
p = 0.01
Probability of Acute GVHD grade 2-4 in HLA-matched Allo-HSCT NTUH 1993-2008.07
Time (Days)
Pro
bab
ilit
y
PBSCT 27% (n =174)
P = 0.020
1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80 100 120
Allo-BMT 14% (n =180)
Probability of chronic cGVHD in HLA-Identical Allo-HSCT NTUH 1993-2008.07
0 6 12 18 24
1.0
0.8
0.6
0.4
0.2
0
months
BMT 10% (n =162)
PBSCT 48% (n =142)
P < 0.0001P
rob
abili
ty
Extensive cGVHD
BMT 25% (n =162)
PBSCT 70% (n =142)
P < 0.0001
0 6 12 18 24 months
All type cGVHD
GVHD can improve 5-year Leukemia-free survival
GVHD (+) 78%
No GVHD 61%
P =0.006
19M Stem Cell Donors Worldwide
SUM-WW11_11.ppt
Allogeneic Transplants for Age > 20yrs,Registered with the CIBMTR
1992-2009- by Donor Type and Graft Source -
Slide 11
Num
ber
of
Transp
lants
*
* Data incomplete
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
10,000
11,000
12,000
13,000
1992-93 1994-95 1996-97 1998-99 2000-01 2002-03 2004-05 2006-07 2008-09
Related BM/PBUnrelated BMUnrelated PBUnrelated CB
First Taiwan UD-BMT Outcome Report (Shaw CK et al, BMT 23:727,
1999 )• 1994~1997 Total 48 Taiwan patients
analyzed
Engraftment rate
83.3%
Acute GVHD 80%
≧ grade 2
67.5%
grade 3-4
37.5%
Similar to NMDP data but higher than that from JMDP, Japan
Time (Days)
Allo-PBSCT (n =34)
P = 0.051.0
0.8
0.6
0.4
0.2
00 60 120
Allo-BMT (n =55)
HLA-Matched sibling donor
1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80 100
Grade 2-4 acute GVHD
CsA + MTX 84% (18/22)
FK-506 + MTX 36% (4/17)
ATG + MMF/MTX 47% (14/35)
P < 0.0001
Post-HSCT days
Impact of GVHD Prophylaxis on Acute GVHD after URD-HSCT, NTUH 1994-2005
1.0
0.8
0.6
0.4
0.2
0
0 20 40 60 80 100
Grade 3-4 acute GVHD
CsA + MTX 73% (12/22)
FK-506 + MTX +Steroid 0% (0/17)
ATG + MMF/MTX 5% (1/35)
P < 0.0001
Post-HSCT days
Improving 3y-OS after URD-HSCT in leukemia
since 2004 in NTUH (n=254)
2004-2012 52% (n=102)
1994-2003 24% (n=41)
P < 0.001
2004-2012 50% (n=39)
1994-2003 8% (n=12)P < 0.001
SR + IR HR
D-8 D-7 D-6 D-5 D-4 D-3 D-2 D-1 D 0 D+1 D+2 D+3 D+4
F F F F FFludarabine 30 mg/m2/d x 5d
PBSCT
GVHD prophylaxis : CsA 3 mg/Kg/d, D-1~D+30 then taper Methotrexate
A A A (rabbit)
ATG 2.5 mg/Kg/d x 3d
Fractional TBItotal 1200 cGy
C CCyclophosphamide 60 mg/Kg/d x 2d
Donor : G-CSF 10 ug/Kg/d x 5d
Protocol for Allo-HSCT with PMRD
Busulfan 16 mg/Kgor
42
• All engrafted with 100% donor chimerism (FISH or STR)• Acute GVHD: 9% (1/11, grade 1)• Chronic GVHD: 100% (5/5, 2 extensive)• CMV infection: 73% (8/11), EBV-PTLD: 18% (2/11)
Haploidentical HSCT ─ Results
Parental donor vs. URD HSCTNTUH 2001-2011
AML: significant advancement in the past decades
APL: ATRA, AS2O3 •10-20% 80-90%
High-dose Ara-C based consolidation •10-20% 30-40%
BMT in CR1/2 •10-30% 40-70%
Cytogenetic and gene mutation study •Risk stratification
Intensity of Consolidation correlated with adult AML Survival (NTUH, 1985-1999)
BMT (n=41)BMT (n=41)
Standard C/T (n=182)
Low-dose or no C/T (n=36)
Standard C/T (n=139)
Low-dose or no C/T (n=24)
All patients (n=259) Patients age 50 years or less (n=204)
HSCT for AML (NTUH, 1984-2011)
• 425 HSCT, 54 received twice, total 479
• Auto-HSCT 33 (8%), allo-HSCT 392 (92%)
• Sex (M: F) 213 : 212
• Median age (range) 32 y/o (1-69)
• Disease status at HSCT– CR1 (SR) 176 (42%)
– CR2 (IR) 143 (34%)
– Relapsed/refractory (HR) 103 (24%)
Overall Survival Relapse risk
At 5 years, 33% vs. 29%, p=0.770At 5 years, 62% vs. 64%, p=0.602
Allo-HSCT (n=155)
Allo-HSCT (n=155)
Auto-HSCT (n=21) Auto-HSCT (n=21)
Comparable outcome of Auto- vs Allo-HSCT for AML in CR1
Poor outcome after auto-HSCT in AML >CR1
Overall Survival Relapse risk
100% vs. 54%, p=0.003At 5 years, 0% vs. 30%, p=0.196
Auto: 8 at CR2, 1 at CR3, all died, 8 relapse, 1 TRM
Allo-HSCT (n=237)Allo-HSCT (n=237)
Auto-HSCT (n=9)
Auto-HSCT (n=9)
VariablesHazard ratio 95% CI p value
Non allo-HSCT patients (n=225)
Age > 45 2.08 1.44~3.00 <0.001Unfavorable karyotype 2.36 1.43~3.90 0.001WBC > 50 x 109/L 1.69 1.18~2.42 0.004LDH > 460 U/L 1.54 0.89~2.67 0.122CEBPA 0.56 0.33~0.96 0.036NPM1mut/FLT3-ITDneg 0.39 0.20~0.77 0.006FLT3-ITD 1.50 1.01~2.23 0.047AML1/RUNX1 1.80 1.09~2.95 0.021
Allo-HSCT patients(n=100)Disease status in HSCT 3.01 1.78~5.09 <0.001Unfavorable karyotype 2.05 1.05~4.01 0.035
Independent risk factors for OS in 325 AML
Multivariate Cox regression analysis for OS
50
CEBPA double mutation
Post-HSCT 5 year RFS
CEBPA double mutation 88% (n=9)
Other genotypes 46% (n=91)
P=0.045
Post-HSCT 5 year OS
CEBPA double mutation 78% (n=9)
Other genotypes 38% (n=91) P=0.04
5
CEBPA double mutation had better OS and RFS
Post-HSCT 5 year RFS
P=0.307
NPM1+/FLT3-ITD- 71% (n=7)
Other genotypes 48% (n=93)
Post-HSCT 5 year OS
P=0.096
NPM1+/FLT3-ITD- 71% (n=7)
Other genotypes 39% (n=93)
NPM1+/FLT3-ITD- genotype had trend for better OS and RFS
Allo-HSCT (n=100)Non allo-HSCT (n=225)
Time (Months) Time (Months)
FLT3-ITDmut n=54OS=10.5
FLT3-ITDneg n=171OS=26
FLT3-ITDneg n=75OS=64
FLT3-ITDmut n=25OS=29
P<0.001
P=0.568
Adverse impact of FLT3-ITD reversed after HSCT
53
Non-HSCT group
AML1/RUNX1 mutation
AML1/RUNX1 wild-type
AML1/RUNX1 mutation
AML1/RUNX1 wild-type
From Blood 2009; 114:5352
Allo-HSCT group
P=0.064
Allo-HSCT group
P=0.053
AML1/RUNX1 mutation 83% (n=12)
Other genotypes 44% (n=88)
AML1/RUNX1 mutation 63% (n=12)
Other genotypes 38% (n=88)
✓8 RUNX1 mutated patients received HSCT at CR1/2
--> No relapse, 3 died of TRM (HBV, lung, infection)
✓4 RUNX1 mutated received HSCT at induction failure or
relapse
--> 2 relapse, 1 died of relapse
Allo-HSCT can overcome the AML1/RUNX1 effect on OS/RFS
OS
RFS
Impact of flow RD on HSCT outcome: preliminary data
• Jan 2010 ~ Dec 2011, 64 consecutive patients • AML: 44 (69%), ALL: 20• Age: 20 - 69, median: 40• Conditioning myeloablative: 37; reduced-intensity: 27• Donors HLA-matched siblings: 21, alternative: 43
(67%)• Disease status at SCT CHR: 38 (60%), no CHR: 26
OS according to pre- & post-SCT RD status
Pre-SCT RD-/post-SCT RD-, n = 35, median OS: not reached
P < 0.001
Pre-SCT RD+/post-SCT RD-, n = 23, median OS: not reached
Pre-SCT RD+/post-SCT RD+, n = 6, median OS: 2 M
1-yr cumulative relapse rate
Pre-SCT RD+/post-SCT RD+, n = 6, 100%
Pre-SCT RD+/post-SCT RD-, n = 23, 100%
Pre-SCT RD-/post-SCT RD-, n = 35, 14.3%
P < 0.01
Overall survival rate
FCM-/CHR, n = 30, median OS: not reached
FCM+/No CHR, n = 21, median OS: 4 M
FCM-/No CHR, n = 5, median OS: not reached
FCM+/CHR, n = 8, median OS: 7 M
P = 0.002
Slide preparation and delivery: Four-Step Process.
Pre-emptive DLI can improve survival in high-risk AML after HSCT
Blood 2008;112:4371-4383
Slide preparation and delivery: Four-Step Process.
Double edges of a sward— GVL vs. GVHD
Key issues: separate GVL from GVHD and enhance GVL
Slide preparation and delivery: Four-Step Process.Case 1 —DLI for CML relapse after HSCT
Years after BMT
Lo
g
BC
R-A
BL
/AB
L
BMT
DLI, at 13 months
Relapse at 12 months
Molecular remission
0
-1
-2
-3
-4
-50 1 2 5 10
Donor lymphocyte infusion (DLI) can generate powerful GVL effect even stronger than high-dose therapy
GVL effect can have long-term survival or cure in CML after BMT
Case 2
Immunotherapy in a case of highly refractory acute
myeloid leukemia
44 years old male
• 2006/02 Dx: AML, M4
with NPM1 mutation and
FLT3-ITD
• Treatment:
1. I3A7 poor response
2. N3-HD Arac-C (1)
CR1
3. N3-HDAra-C (2)
Relapse
• CR1 duration = 1
month !• 2006/07 received
allo-HSCT using HLA-
mismatched unrelated-
donor in Beijing,
China
• Leukemic relapse
occurred before day
60 !
Slide preparation and delivery: Four-Step Process.Case 2 — Extra-BM relapse after DLI
Soft tissue (thigh)
C7 spine
palate
Clivus
Soft tissue (foot)
020406080
100120140160180200
0 30 60 90 120 150 180 210 240 270 300 330 360
Up to 3000/uL on D344
Days after HSCT
Ab
so
lute
bla
st
co
un
ts (
pe
r u
L) WT1-CTL
D69 DC CsA
D72 aGVHD Gr III
020406080
100120140160180200
0 30 60 90 120 150 180 210 240 270 300 330 360
Up to 3000/uL on D344
Days after HSCT
Ab
so
lute
bla
st
co
un
ts (
pe
r u
L) WT1-CTL
D69 DC CsA
D72 aGVHD Gr III
Up to 3000/uL on D344
Days after HSCT
Ab
so
lute
bla
st
co
un
ts (
pe
r u
L) WT1-CTL
D69 DC CsA
D72 aGVHD Gr III
0
1
2
3
4
5
0 2 4 6 8 10 12
AML-MRD by NPM1-PCR
PB blast count / μL
Slide preparation and delivery: Four-Step Process.
Case 2: preparation of AML immunotherapy
DC-CIKAML tumor lysateAML fusion to DCAntigen-specific CTL with specific peptideWT1Mi-HA: ACC1Cloning of T cell receptor to ACC1
Slide preparation and delivery: Four-Step Process.Immune effector cells
• Mixed effector cells– DC-CIK (dendritic cell-cytokine induced killers)
• Antigen-specific T cells– CD8-CTL (cytotoxic T lymphocyte)– Central memory T cell – Regulatory T cell– Engineering of T cell receptor
• NK or NK-T cell
Slide preparation and delivery: Four-Step Process.
020406080
100120140160180200
0 30 60 90 120 150 180 210 240 270 300 330 360
Up to 3000/uL on D344
Days after HSCT
Abs
olut
e b
last
cou
nts
(per
uL) WT1-CTL
D69 DC CsA
D72 aGVHD Gr III
020406080
100120140160180200
0 30 60 90 120 150 180 210 240 270 300 330 360
Up to 3000/uL on D344
Days after HSCT
Abs
olut
e b
last
cou
nts
(per
uL) WT1-CTL
D69 DC CsA
D72 aGVHD Gr III
Up to 3000/uL on D344
Days after HSCT
Abs
olut
e b
last
cou
nts
(per
uL) WT1-CTL
D69 DC CsA
D72 aGVHD Gr III
Donor lymphocyte infusionAML-CTLs other than ACC-1YACC-1Y CTLAML DC-CIK
0
1
2
3
4
5
0 2 4 6 8 10 12weeks
Clinical course of immunotherapy
Slide preparation and delivery: Four-Step Process.HLA DNA typing after frank AML relapse
Unrelated Donor: Haplotype 1: A0201, B4006, C1502, DR1201, DQ0603Haplotype 2: A2402, B3503, C1203, DR1301, DQ0301
Patient AML blast at relapse:Haplotype 1: A0210, B4006, C0801, DR1201, DQ0301Haplotype 2: A2402, B3503, C1203, DR1301, DQ0301
(very weak)
ACC1-TCR transfer CTL target
MHC-restricted GVHD target?
Slide preparation and delivery: Four-Step Process.
Loss of patient-specific HLA allele at leukemic relapse after HLA-mismatched HSCT
SNP array-copy number ratio
NEJM 2009; 361:478
43 AML/MDS patients
Haploidentical HSCT
Donor T-cell infusion
17 relapse
Genomic HLA typing, microsatellite mapping, SNP array
5 lost mismatched haplotypes
Timing of CMV Reactivation after HSCTNTUH 2000-2003 (N=160)
200150100500
1.0
.8
.6
.4
.2
0.0
HSCT months
• CMV reactivation occurred 71 cases
• Kaplan-Meier probability before day 100 43.9 ± 4.0 % before day 180 46.3 ± 4.0 %• Median onset: day 36 (4~180)
Inferior Survivor in Patients with CMV Reactivation after HSCT NTUH 2000-2003 (N=160)
4842363024181260
1.0
.8
.6
.4
.2
.0
5 months 56% vs. 83% p < 0.00011-year 40% vs. 70% p < 0.0001
Kaplan-Meier probability of survivor
HSCT months
Interstitial Pneumonitis after HSCTIncidence (NTUH, 1983-1996 n = 233)
(n=88)
15%
1%
10%
0% 10% 20%
Allogeneic
Autologous
Total
Mortality Rate
(n=233)
(n=145)
0% 50% 100%
CMV
Idiopathic
Total
1.0
.8
.6
.4
.2
01801501209060300
MUD, 73%
Sibling, 40%
p < 0.0001
1801501209060300
1.0
.8
.6
.4
.2
0
ATG(+), 79%
ATG(-), 37%
p < 0.0001
1801501209060300
1.0
.8
.6
.4
.2
0
Steroid(+), 84%
Steroid(-), 18%
p < 0.0001
Risk Factors for CMV Reactivation after HSCT NTUH 2000-2003 (N=160)
Use of steroid Use of ATG Unrelated donor
Anti-viral Strategies to Prevent CMV Disease after HSCT
• General prophylaxis-- in all
allogeneic HSCT patients since
engraftment to day 100
• Preemptive therapy – in patients with documented CMV viremia or antigenemia before onset of CMV disease
• Risk-adapted prophylaxis– in high-risk patients at intense immunosuppressed states like GVHD, use of steroid use, T-cell depletion, unrelated donor
CMV Pneumonitis: Early Detection by High-Resolution CT of the Chest (HRCT)
HRCT-chestChest X-ray
•CMV pneumonitis: high mortality if
delayed treatment
•HRCT: very sensitive in detecting
interstitial lung lesion
PTLD Incidence and Risk factors NTUH experience
• PTLD after HSCT:– Incidence at the 1 year: 2.5% 1 (0.45 – 29%)2
– PTLD related mortality: 58.3%1 (64 - 84.6 %)2
1.HA Hou. BMT 2009; 43, 315–3212.Curtis RE. Blood 1999; 94: 2208-2216
3.Van Esser JW. Blood 2002; 99: 4364–4369.
• Risk factors1 : ATG, aGvHD, CMV antigenemia; T-cell depleted graft, unrelated allo-HSCT
Prospective Monitoring of EBV Reactivation by EBV Viral Load in Plasma
Total 587 HSCT patients
222 at-risk patients (total 2945 assay)
EBV- Reactivation: 50 (22%)
• NTUH, 2004-04 to 2010-10
Kaplan-Meier Probability of EBV Reactivation after HSCT (NTUH, 222 HSCT)
Kaplan-Meier Probability of EBV-PTLD after HSCT (NTUH, 222 HSCT)
Risk Factor for EBV ReactivationUse of ATG
Risk Factor for EBV ReactivationMismatched donors
Multi-variate Analysis of EBV ReactivationVariables HR p-valueATG use 5.44 0.001TBI conditioning 3.52 <0.001Fludara-based RIC 3.16 0.01CsA+MMF vs CsA+MTX 2.56 0.051
Non-sibling donor 1.46 0.283
HLA-mismatched donor 1.60 0.156
CMV antigenemia 1.46 0.231
Acute GVHD, grade 2-4 1.16 0.615
Chronic GVHD 1.22 0.511
EBV-PTLD (n=8)Median (ranges)
Onset days Median 45 (26-214)Viral copies at PTLD
Median 35,678 (971-269K)
Peak viral load Median 98,199 (6130-2.7M)
Treatment:• All received tapering of IS and anti-CD20• 4 patients had R-COP chemotherapy• Response: CR 4, PR 2, PD 2• Outcome: 2 died of PTLD (25)
Hematologic disease / alloBMT at highest risk for IFI
Pfaller et al. CID. 2006;43:S3-14
Study Overview
Retrospective analysis
Time: 2004 Jan to 2009 Dec
Subjects: 507 acute leukemia patients, receiving induction or re-induction chemotherapy
IFI: Diagnosed as EORTC/MSG revised criteria
Incidence rate of fungal infection from 2004 to 2009
%
Possible IFI increased in recent years
Patients in Risk of IFI
Low Risk
• Conventional chemo for leukaemia/lymphoma
• Short period neutropenia
High Risk
Allogeneic BMT Longer, more profound
neutropenia GVHD / unrelated
donor Immunosuppression
(e.g. steroids, cyclosporin A)
THERAPEUTIC STRATEGIES
0
36
37
38
39
40
41
Tem
per
atu
re
Culture + Tissue +Galactomannan+
PCR +
Treatment
Disease likelihoo
d
-7 0 7 14 21 28 35 42 49 56 63-14
0.1
1
10
Days after transplant // chemotherapy
Gra
nu
locy
tes
Empirical
Possible
Prophylaxis
Remote
Specific
Proven
Pre-emptive
Probable disease
NTUH Annual Survey in HSCT Wards
0
5
10
15
2005 2006 2007 2008 2009 2010
Auto-HSCT
Allo-HSCT
Micafungin anti-fungal prophylaxis
New ward (5PW) set up
New ward (3D1) set up
4/41
1/31
1/28
0/20
1/16
0/201/33
6/50
3/57
2/64 2/75
4/114
Incidence
IFI in HSCT– Micafungin is effective in primary prophylaxis
Characteristics MCF group (N=104) FLC group (N=60) P-value
Death before D+30 0 0 NS
Successful prophylaxis 96/104 (92.3%) 48/60 (80.0%) 0.019
Intolerable adverse effects 2 1 NS
Breakthrough IFI 6 11 0.011
Proven IFI 0 0 NS
Probable IFI 1 4 0.037
Candidiasis 0 1
Aspergillosis/Others 1 3
Possible IFI 5 7 NS
Acute GVHD 28/104 17/60 NS
Grade I 8 5
Grade II-IV 20 12 NS
Death before D+90 5 5 NS
MCF: 2007-2010FLC: 2005-2007
NTUH Data
#, comparing FLC and MCF groups; @, comparing AMB and MCF groups
CharacteristicsMCF group
(N=34)
Historical Control
FLC (N=10) P# AMB (N=12) P@
Death before D+30 0 0 0
Successful prophylaxis31/34
(91.2%)6/10
(60.0%)0.018
5/10(50.0%)
0.003
Intolerable adverse effects 1 0 NS 5 <10-3
Breakthrough IFI 2 4 0.012 0 NS
Proven IFI 0 0 NS 0 NS
Probably IFI 1 3 0.008 0 NS
Candidiasis 0 0 0
Aspergillosis 1 3 0
Possible IFI 3 1 NS 0 NS
Acute GVHD 11/34 6/10 NS 4/12 NS
Grade I 4 1 0
Grade II-IV 7 5 NS 4 NS
Death before D+90 2 2 NS 1 NS
MCF: 2007-2010FLC: 2005-2007 NTUH Data
IFI in HSCT– Micafungin is also effective in second prophylaxis
Major determinants for successful anti-fungal prophylaxis:
Variables Relative Risk (95% C.I.) P-value
High- vs standard-Risk disease 2.70 (0.98-7.14) 0.054
MCF vs FLC/AmB prophylaxis 0.20 (0.07-0.62) 0.005
Myeoablative vs RIC conditioning
2.87 (0.77-10.69) 0.116
Sibling vs unrelated donors 0.52 (0.19-1.44) 0.211
BMT vs PBSCT 1.51 (0.479-4.728) 0.484
Previous IFI: yes vs. no 3.45(0.96-12.50) 0.057
Positive culture: yes vs. no 0.84(0.22-3.13) 0.802
NTUH Data
1. Expanding disease
indications
2. Elderly patients
3. Reduced toxicity
4. Cell-based immunotherapy
5. Stem cell therapy in non-
hematological diseases
6. Personalized medicine
Future perspective
93
Thanks for your attention!