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Upfront Transplant Strategies in Aplastic Anemia
1. Upfront Transplant Strategies in
Aplastic Anemia
Seiji Kojima MD. PhD.
Department of Pediatrics
Nagoya University Graduate School of Medicine
Chairman of the Severe Aplastic Anemia Working Party
Asia-Pacific Blood and Marrow Transplantation Group
3. Today’s Topics
1. Use of rabbit ATG can be justified as a front-line
therapy?
2. Comparable outcome can be expected between
MRD and 1MMD?
3. Second course of ATG + CSA should be indicated if
no alternative donor is available?
4. 1) Long term outcome of AA children treated with
horse ATG or rabbit ATG
1) Rabbit ATG experience in Nagoya University
Experience of rabbit ATG for SAA
12. Horse ATG: 15 mg /kg/day x 5 days
CSA: 6 mg/kg/day adjusted to blood level
G-CSF: Only when ANC < 0.2 x 109
/L
Rabbit ATG: 3.75 mg /kg/day x 5 days
CSA: 6 mg/kg/day adjusted to blood level
G-CSF: Only when ANC < 0.2 x 109
/L
Immunosuppressive Therapy
Japan AA 97
Nagoya Univ in Thymoglobulin era ( 2009 Aug ~ Now )
18. Today’s Topics
1. Use of rabbit ATG can be justified as a front-line
therapy?
2. Comparable outcome can be expected between
MRD and 1MMD?
3. Second course of ATG + CSA should be indicated if
no alternative donor is available?
19. PATIENTS (N = 578)
578 children (0-19 y) with AA
Received BMT between 1990-2009
Available for serological HLA data (A, B, and DR)
Registered to The Japan Society for Hematopoietic Cell Transplantation
Matched unrelated
Donor (MUD) (n=213)
Matched related donor
(MRD) (n=312)
MMRD (n=53)
1MMRD @HLA Class I (n =32)
1MMRD @HLA class II (n=12)
2-3 MMRD (n=9)
Grouped by SEROLOGICAL
HLA typing data (A, B, and DR)
20. PATIENT CHARACTERISTICS
MRD
1MMRD
2-3 MMRD MUD
Class I Class II
n 312 32 12 9 213
Donor, n (%)
Sibling 294 (94%) 22 (69%) 4 (33%) 1 (11%) -
Others Related 18 (6%) 10 (31%) 8 (67%) 8 (89%) -
Unrelated donor - - - - 213 (100%)
Gender, n (%)
Male 176 (56%) 19 (59%) 7 (58%) 3 (33%) 120 (56%)
Female 136 (44%) 13 (41%) 5 (42%) 6 (67%) 93 (44%)
Age, median (range) 11.5 (0 - 19) 9 (1 - 16) 9 (1 - 19) 10 (1 - 17) 11 (1 - 19)
Age, n (%)
< 10 y 106 (34%) 17 (53%) 7 (58%) 4 (44%) 87 (41%)
10y - 19 y 206 (66%) 15 (47%) 5 (42%) 5 (56%) 126 (59%)
25. TREATMENT ALGORISM
FOR CHILDREN WITH AA
Newly
diagnosed
AA
MRD/1MMRD(+)
BMT from MRD/1MMRD
IST
CR/PR
NR
MUD(+)
MUD(-)
BMT from MUD
2nd
IST
or
HAPLO / CBT
MRD/1MMRD(-)
FIRST LINE THERAPY SECOND LINE THERAPY
26. Today’s Topics
1. Use of rabbit ATG can be justified as a front-line
therapy?
2. Comparable outcome can be expected between
MRD and 1MMD?
3. Second course of ATG + CSA should be indicated if
no alternative donor is available?
33. Conclusion
1. Use of rabbit ATG as a front-line therapy is justified
when horse ATG is not available.
2. When 1MMD donor is available, bone marrow
transplantation is the first choice of treatment for
SAA children.
3. Haploidentical transplantation can be indicated if
HLA-mached unrelated donor is not found for non-
responder to immunosuppressive therapy.
34. Acknowledgement
• Asian Pacific Blood and Marrow Transplantation Group :
Childhood Aplastic Anemia Study Group
Dao Chul Jeong, Xiao Fan Zhu
• The Japan Society for Hematopoietic Cell Transplantation
Childhood Aplastic Anemia Working Group
Hideki Muramatsu, Hiromasa Yabe, Akira Kikuchi,
Ryoji Kobayashi
• Japan Childhood Aplastic Anemia Study Group
Nao Yoshida, Yoshiyuki Takahashi, Akira Ohara
Immunosuppressive therapy consisted of horse ATG (Lymphoglobulin from Genzyme) at a dose of 15 mg/kg/day and CSA. In the Japanese study the ATG had been given for 5 days, in the German study for 8 days. G-CSF was administered to patients with less than 200 neutrophils/µl in the Japanese group and less than 500/µL in the German cohort.
To supply a gap of evidence for transplantation from HLA mismatched family donor, We planned and analyzed 578 pediatric AA patients received Bone marrow transplantation between 1990 and 2009, and get registered in the database of the Japan Society for Hematopoietic Cell transplantation. Of course, majority of patients are transplanted from HLA matched related donor or matched unrelated donor, but A substantial number of patients are transplanted from serologically HLA mismatched related donor, MMRD. Among 53 mismatched related transplantation, 32 patients transplanted from donor who is 1locus mismatched in HLA Class I, and 12 patients from 1 locus mismatched in class II. 9 patients are transplanted from 2-3 loci mismatched donor, that is to say, Haploidentical transplantation donor.
This slide shows the patient characteristics. Patients’ gender and age are equally distributed among each group. But, as expected, sibling donor percentage is unsymmetrical.
This slide shows the 5 year overall survival of each patient group. Compared to matched related donor, matched unrelated donor and 2-3 loci mismatched related donor were significantly worse outcomes, while class I and class II 1 locus mismatched donor groups showed perfectly superimposed survival curves to matched related donor group.
In multivariate analysis, age over 10 years, and transplanted before 2000 and 2-3 loci mismatched related donor and unrelated donor are identified independent risk factors for poor survival.
Compared to HLA matched related donor, the incidence of Acute GVHD grade III – IV is significantly higher in 1 locus HLA mismatched related donor and matched unrelated donor. Unexpectedly, none of the patients transplanted from haploidentical donor developed severe acute GVHD, despite patient number is very small, only 9.
This slide shows the cumulative incidence of extensive chronic GVHD. In any donor group, severe chronic GVHD is occurred in very small percentage of patients, and there is no statistical significance.
If the newly diagnosed aplastic anemia patient have matched related donor OR 1 LOCUS MISMATCHED RELATED DONOR, first line therapy would be BMT. And IST indication should be narrowed.
BU (1mg/kg×4/day)×2days day –7 , -6 L-PAM (60mg/m 2 /day)×3days day –5 ~ -3 ATG (2.5mg/kg/day)×2days day –3 , -2 ATG (5mg/kg/day) day +4 TBI (12Gy,4 分割 ) 眼球半遮蔽 day –2 , -1 2/2 BMT 総細胞数: 3.6×10^8/kg CD34(+) 細胞数 0.7% : 2.55×10^6/kg 2/7 PBSCT 1 日目 総細胞数: 1.67×10^9/kg CD34(+)45(+) 細胞数: 5.0×10^6/kg 2/8 PBSCT 2 日目 総細胞数: 6.5×10^8/kg CD34(+)45(+) 細胞数 0.4% : 2.6×10^6/kg