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！