Transcript First Line BMT vs IST

Is allo-SCT first line option for
AA if sibling donor available?
Surapol Issaragrisil
Division of Hematology, Department of Medicine
Siriraj Hospital, Mahidol University
Bangkok, Thailand
Incidence and Etiologic Fraction of
Aplastic Anemia
No. of
Cases
Rate/106
yr
Etiologic
Fraction
Drugs
Other
factors
IAAAS
208
2.0*
45%
27%
18%
Thailand
374
4.1†
20-30%
3%
15-29%
“The Beggar” of Hematology
1888 - First described by Paul Ehrlich
1904 - Vagues and Aubertin – used term
“Aplastic anemia”
Outline of The Talk
• Guideline for management of AA
• HSCT vs IST
• Improvement of MSD HSCT outcome
UK Guideline For Management of
Severe Aplastic Anemia
Marsh JC et all. Br J Haematol. 2009;147:43-70.
UK Guideline For Management of
Non Severe Aplastic Anemia
Marsh JC et all. Br J Haematol. 2009;147:43-70.
Is allo-SCT first line option for AA
if sibling donor available?
First Line BMT vs IST
• N = 2,479
• Better 10 year survival in BMT group vs IST
• Favorable predictors :
– Younger age
- Transplant after 1996
– Matched sibling donor
- Short diagnosis-transplant interval
– No irradiation
SAA-WP, BMT. Haematologica. 2007; 92:11-18
First Line BMT vs IST
• Meta analysis; N= 26 Non-RCT; N=7,955 ; 1970-2001
• Heterogeneity of non RCT studies did not justify a pooled estimate
Peinemann F et al. Plos One. 2011;6(4):e18572.
First-line Treatment Strategy
IST
HSCT
• Results of MSD HSCT have improved overtime
• Results of IST seem to be unchanged during the past decade
EBMT Database. 2009.
BMT vs IST
Quality Adjusted Analysis in Aplastic Anemia
BMT
IST
• BMT (n=52) or IST (n=155)
• Survival, event-free survival, and QTWiST (Time without symptom and toxic
ity) are similar
• BMT-treated patients had longer periods
free from symptoms, while IST-treated
patients needed closer medical care,
transfusion support, and medications
BMT
IST
Viollier R, et al. Ann Hematol. 2005 Jan;8 4(1):47-55.
BMT vs IST
Quality Adjusted Analysis in Aplastic Anemia
•
•
•
•
•
TOX = treatment-related toxicity
TRANS = transfusion dependency
PR = partial remission
CLON = secondary clonal disorder
GVHD = extensive chronic graft-versus-host disease (GvHD)
Viollier R, et al. Ann Hematol. 2005 Jan;8 4(1):47-55.
Can We Improve
The Result of MSD HSCT?
Factors Predicting HSCT Outcome
•
•
•
•
•
Age
Interval from diagnosis to transplantation
Conditioning
Bone marrow cell dose
Stem cell source
Allogeneic HSCT in SAA
<20 vs 21-30
21-30 vs 31-40
31-40 vs 41-50
41-50 vs >50
• Improved outcomes were seen
overtime
• Less so, in the last decade with
OS rates close 80%
p<0.0001
p=0.1
p=0.3
p=0.005
• Young patients less than 20 years
have best outcome
• Those over 50 years do poorest
• Those with 21-50 years have
intermediate outcome
HLA-identical Sibling HSCT in
age > 40 years
OS 65%
• Retrospective; n=23; median age = 49 (40-68)
• High dose Cy + horse ATG; BMSC = 21, PBSC = 2; CSA+MTX
• Acute GVHD 30%; Chronic GVHD 26%
• Risk of early TRM: documented infection within 1 mo
• Median FU 9.1 yr (0.9-19.2)
Seattle, Sangiolo D et al. Biol Blood Marrow Transplant. 2010 Oct;16(10):14
Impact of Age on Outcomes After BMT
Acute GVHD
Chronic GVHD
Overall Survival
• N = 1,307
Toronto, Gupta V et al. Haematologica. 2010;95(12):2119-25.
The Interval From Diagnosis to Transplant
and Pretransplant IST
≤ 1998
>1998
≤ 1998
>1998
Cyclophosphamide Alone as Conditioning
≤1998
>1998
Seattle and EBMT 2009.
Cy/ATG as Conditioning
Year after HSCT
• In non-RCT, Cy + ATG is well tolerated and effective in heavily pretreated
aplastic anemia patients
• Lower incidence of chronic GVHD
• Overall survival 88% with long term follow-up
Storb R et al. Biol Blood Marrow Transplant. 2001;7(1):39-44.
Kahl et al. Br J Haematol. 2005 Sep;130(5):747-51.
ATG in Conditioning Regimen
ATG in Conditioning Regimen
• ATG is a favorable predictor of outcome  both for BM and PB; especially
for patients >20 years
• ATG reduces chronic GvHD (and its consequence , BOS)
• ATG improves survival
Bacigalupo A et al.Biol Blood Marrow Transplant. 2006;12: 560-5.
Cy vs Cy/ATG as Conditioning
P = 0.44
• A randomized controlled study
• No difference in graft failure, GVHD and survival
• The addition of ATG to conditioning regimen did not
significant improve outcome
Champlin RE et al. Blood. 2007;109: 4582-4585.
Cy/ATG as Conditioning:
Long Term Follow Up
6yr OS 87%
• n=61; median age 21 years (4-43)
• Median duration of the disease before HSCT 93 days
• Cyclophosphamide 200mg/kg + antithymocyte globulin 2.5 mg/kg/day x 5
days  HLA matched sibling HSCT  CsA and MTX (days 1,3,6 11)
• BMSC 97%; Primary graft failure 3%
• acute grade II-IV GvHD 23%; chronic GvHD 32%  associated with higher
number of infused CD3 cells (p=0.017)
Paris, Konopacki J, et al. Haematologica. 2011 Dec 29.
Cy/ATG as Conditioning:
Long Term Follow Up
Risk Factors for AVN
61%
25%
8%
• Long term complication:
– AVN 21%
– Endocrine dysfunction 19% (3 had diabetes, 4 hypothyroidism,
4 dyslipidemia, 1 Cushing’s syndrome and 1 hypogonadism)
– EBV associated HL 1%
Konopacki J, et al. Haematologica. 2011 Dec 29.
Fludarabine Based as Conditioning in
Patients over 30 years
• Retrospective; n = 30; median 46 (3166)
• BMSC = 20, PBSC = 10
• Reduced incidence of graft failure (0
vs 11 %, p = 0.09)
• No difference in GVHD
• Higher probability of overall survival
when adjusting for recipient’s age
Maury S et al. EBMT-SAAWP. Haematologica. 2009;94:1312-1315.
Fludarabine Based as Conditioning
OS 79%
83%
71%
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•
•
•
Prospective study; n = 38, median age = 20 yr (14-36); median FU = 43 mo
Flu/Cy  CSA + MTX; Unmanipulated BM stem cell
aGVHD grade ≥ II 11%; extensive cGVHD 25%
Graft rejection 3% ; D+100 TRM 16%
Al-Zahrani H et al. Biol Blood Marrow Transplant. 2011;17: 717-722.
Alemtuzumab Based as Conditioning
2 yr OS 95% vs 83%
Factors influencing OS
2-year OS
P value
92% vs 42%
< .001
92% vs 71%
< .001
• Fludarabine 30 mg/m2 x 4
days, cyclophosphamide 300
mg/m2 x 4 days, and
alemtuzumab median total
dose of 60 mg
• Cumulative incidence of graft
failure was 9.5%
• Acute GVHD 13.5% and
chronic GVHD 4%
• Low incidence of viral infection
HSCT comorbidity index
0-1 vs ≥2
Age (years)
<50 vs ≥50
Marsh JC et al. Blood2011 ;118(8):2351-7.
Bone Marrow Cell Dose, Chronic GVHD
and Survival
BM cell dose Hazard Ratio
(×108/kg)
P-value
2.3
1
2.4–3.3
3.8
0.06
3.4
7.7
0.004
Quartiles
Variable
n
Mean
S.D.
Min
.25
Median
.75
Max
3.02
1.88
0.94
1.90
2.51
3.50
10.75
3.72
1.49
2.19
2.52
3.20
4.77
8.07
No chronic GVHD
Cell dose
57
Chronic GVHD
Cell dose
20
Deeg HJ. Unpublished data.
BM vs PB Stem Cell Source
Chronic GVHD
Overall survival
• N = 692 (134 PBPC, 558 BM); HLA-matched siblings
• Similar rates of hematopoietic recovery and grades 2 to 4 chronic GVHD
• Higher chronic GVHD (RR 2.82; P = .002) and overall mortality (RR 2.04;
P = .024) in patient < 20 years who received PBPC
• BM grafts are preferred to PBPC grafts in young patients
Schrezenmeier H et al. Blood 2007;110: 1397-1400.
BM vs PB Stem Cell Source
Bacigalupo A. Haematologica. 2012. Feb 7.
BMSC Gives Survival Advantage
in All Age Group
Bacigalupo A. Haematologica. 2012. Feb 7.
G-CSF stimulated BMSC vs BMSC vs PBSC
• N = ( 78 G-BM, 547 BM, 134 PBPC)
• No difference in neutrophil and platelet recovery rate
• aGVHD and cGVHD were significantly higher in PBPC
group
• aGVHD and cGVHD were similar after G-BM and BM
• Mortality risks were lower after transplantation of BM
compared to G-BM (RR = 0.63, P = .05)
• No advantage to using G-BM
• BM is the preferred graft for HLA-matched sibling
transplants for SAA
Chu R et al. Biol Blood Marrow Transplant. 2011 Jul;17(7):1018-24.
Negative Predictors for HLA identical HSCT
in SAA Patients
Bacigalupo A. Haematologica. 2012. Feb 7.
Negative Predictors for HLA identical HSCT
in SAA Patients
• Interval ≥114 days
• Age ≥20 years
• Conditioning other
than Cy 200
• No ATG in conditioning
Bacigalupo A. Haematologica. 2012. Feb 7.
CSA/MTX vs CSA alone as GVHD Prophylaxis
• RCT; N = 71; median age 19 years
(4-46)
• HLA-identical BMT; Cy 200 mg/kg
• Faster median time for neutrophil
engraftment in CSA alone group
(12 vs 17 days, p = 0.01)
• Better 1 year TRM (3% vs 15%, p =
0.07) and 5 year survival (94% vs
78 %, p = 0.05) in CSA/MTX
Locatelli F et al. Blood 2000; 96: 1690-1697.
Effect of Serial Chimerism in SAA
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•
•
•
N = 45 (72% Complete donor chimerism, 11% stable mixed chimerism, 17%
progressive mixed chimerism)
The overall 5-year survival probability was 82% with a significant survival
advantage (P = 0.0009) in CDC or SMC compared to those with PMC
Chronic GvHD was more frequent in CDC; no patient with SMC developed cGvHD
Graft failure occurred in 50% of the PMC
McCann S et al. Bone Marrow Transplantation (2007) 39, 109–114
Post-Transplantation Cyclophosphamide
for GVHD Prophylaxis in SAA
• 2 cases; age 54 and 55 years old
• Myeloablative regimen in older, heavily pretreated and transfusion
dependent
• Successful engraftment, transfusion independent and no GVHD
• Follow up time 12 months
Dezern AE et al. Bone Marrow Transplant. 2011 Jul;46(7):1012-3.
Post-Transplantation Cyclophosphamide
for GVHD Prophylaxis in SAA - Thailand
Cy 60 mg/day
Unmanipulated BMSC
ATG 2.5 mg/kg/day
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•
•
•
•
•
Cy 50 mg/day
25-year-old female; median transfusion 30 unit; Positive for allo Ab
ANC engraftment = 15 days; Platelet engraftment = 24 days
CMV reactivation at D+33
Post HSCT 1 mo = full donor chimerism
Acute skin GVHD gr I  well response to steroid
Follow up time 6 months
Issaragrisil S. Unpublished data. 2012
Second HLA-Matched Sibling
Transplantion
8 yr OS
•
•
•
•
•
2nd HSCT
within 3 mo
2nd HSCT
after 3 mo
Good PS
56%
76%
Poor PS
33%
61%
N = 166 ( Primary graft failure 16%, secondary graft failure 84%)
Second HLA matched sibling HSCT with 88% use the same donor
BMSC 84%
non-engraftment 43%  early 100 day mortality rate 30%
Acute GVHD 9%, Chronic GVHD 16%
Horan JT et al. Biol Blood Marrow Transplant. 2009 ;15(5):626-31.
HLA Matched Sibling Transplatation
in SAA: Comparison for Results in Asia
Study
Years
N
Median
Age
(years)
Median
transfusion
units
Conditioning
Stem
cell
Graft
rejection
GVHD
Relapse
Survival
Japan
Inamoto
2008
19842006
33
24
134
Cy/TLI 85%
BMSC
4.1%
Acute 23%,
chronic 29%
No
81% at 7
yrs
China
Cheng
2009
20002008
20
NA
NA
Cy/ATG
GBMSC+
G-PBSC
No
Acute 16%,
Chronic 36%
No
82.5% at
1.5 yrs
Taiwan
Bai 2004
19852001
79
(MSD
84%)
22
NA
Cy/TBI
3.8%
74% at 5
yrs
Korea
Kim 2003
19952001
113
28
126
Cy/ATG/PCB
PBSC+
BMSC
5.6%
Acute gr 2-4
10.5%, Chronic
11.9%
11.5%
89% at 6
yrs
Korea
Cho 2010
19992007
32
39
146
Cy/ATG/PCB
59%,
Cy/ATG/Flu
31%
PBSC +
BMSC
No
Acute 9.4%,
Chronic 18%
NA
87.5% at 5
yrs
Korea
Ahn 2003
19902001
64
NA
NA
NA
NA
12.5
Acute gr 2-4
31.1%, Chronic
18.8%
NA
79% at 6
yrs
Thailand
Issaragrisil
2011
19882010
39
Cy 91%
Cy/ATG 6%
Flu/Cy/ATG 3
PBSC
78%
BMSC
22%
6%
15%
87% at 5
yrs
Overall
survival
32
33
3.6%
Acute 6.8%,
Chronic 35%
Acute 12%
Chronic 40%
83%
Immunosuppressive Therapy in SAA:
Comparison for Results in Asia
Study
Years
N
Median
Age
(years)
Response
Relapse
Clonal
Evolution
Japan
1992-1997
119
9
68%
22%
6%
Korea
Ahn 2005
1999-2001
156
46.8%
7.1%
NA
69% at 6 yrs
China
Zheng 2006
1991-2000
47
35
78.7%
NA
NA
81% at 5 yrs
Japan
Teramura 2007
1996-2000
101
54
79% vs 76%
(G-CSF vs no)
15% vs
42%
15 vs 6%
94% vs 88%
at 4 yrs
Japan
Hattori 2008
1989-1999
survey
421
55
54%
NA
NA
80% at 3 yr
Thailand
Issaragrisil 2010
1986-2010
95
38
54%
NA
NA
60% at 5 yrs
Korea
Chang MH 2010
1994-2007
62
49
53%
NA
No
74.9% at 4 yrs
China
Wang W 2011
2003-2007
9
35
77.8%
NA
NA
74% at 5 yrs
Overall survival
Survival
88% at 3 yrs
Conclusion (1)
• HSCT in younger patients give better outcome
• HSCT may be performed in patients age 41-50 years with
comparable outcome to those age below 40 years
• Early transplant improves survival
• Previous IST seems to have less effect on survival
• Standard conditioning is high dose cyclophosphamide with or
without ATG
• Fludarabine based conditioning gives better outcome in
patients age over 30 years
Conclusion (2)
• Marrow cell dose of 2.1-2.5 x108/kg is most appropriate to be
transplanted
• BMT is the standard therapy
• PBSC should not be performed because of more incidence of
GVHD and having a neagtive impact on survival and quality of
life
• Cyclosporin and short course methotrexate is the standard
GVHD prophylaxis
Acknowledgements
• Andrea Bacigalupo
• HJ Deeg
• Simrit Parmar