transplant updates on donor and conditioning for aplastic anemia
TRANSCRIPT
SEIJI KOJIMA, MD, PHD
Nagoya, Japan
• Professor, Nagoya University Graduate School of Medicine
• Dr. Seiji Kojima completed his medical degree at the Nagoya
University School of Medicine and went through his training as
well as faculty appointment at the Nagoya University. Dr. Kojima
is also the Chair of the Aplastic Anemia Working Group at the
Asia Pacific Bone Marrow Transplant Committee. He has several
prestigious publications including Somatic mosaicism for
oncogenic NRAS mutations in juvenile myelomonocytic leukemia
(Blood 2012). Dr. Kojima is also the principal investigator for
several clinical trials for Aplastic Anemia.
Aplastic Anemia – Transplant Updates on
Donors and Conditioning
Seiji Kojima MD / PhD Department of Pediatrics
Nagoya University Graduate School of Medicine
Differential diagnosis of AA / MDS in children
AA
MDSCongenital
BM failure
Fanconi anemia
Shwachman-Diamonod syndrome
Dyskeratosis congenita
Congenital amegakaryocytic
thrombocytopenia
Autoimmune
Immunodeficiency
Metabolic disease
Mitochondrial deficiency
Vit B12 deficiency
Folate deficiency
Infection
Drug
How we can rule out
congenital bone marrow failure syndromes?
Central Review System in Japan
PB and BM smear
Nagoya University
St. Luke’s Hospital
Pathology
Red Cross
Nagoya 1st Hospital
PNH
Telomere length
Nagoya University
Gene analysis
Nagoya University
Patient No. (2009.2 – 2013.10) 1,000
Age, median (range) 6 (0-39)
Male / Female 536 / 464
Classification
AA / RCC / CBMF 575
Advanced MDS / AML 92
MPD 116
Anemia 68
Thrombocytopenia 51
Neutropenia 26
Others 72
AA/RCC/CBMF57%
Advanced MDS/AML
9%
MPD12%
Anemia7%
Thrombocytopenia
5%
Neutropenia3%
Others7%
Results of the Central Review
AA RCMDRCC
AA 137
RCC 236
RCMD 103
Hepatitis related 38
PNH 3
CBMF 58
Fanconi anemia 21
Shwachman syndrome 12
Dyskeratosis congenita 8
CBMF suspected 17
AA24%
RCC40%
RCMD18%
Hepatitis7%
PNH1%
CBMF10%
AA / RCC /CBMF (n = 575)
Whole exome capture/sequencing
biotinylated ‘bait’ cRNA
Recovery
Sequencing
gDNA
Non-targets
targets
Avidin-coated magnet beads
Bind target sequences
PNGS Clinical Dx Exome results Allele 1 Allele 2 Mol Dx Memo
240 FA FANCA com hetero c.G2870A:p.W957X c.T2725C:p.S909P A
241 FA FANCP hetero c.G2629A:p.A877T s/o P not yet validated
242 FA FANCG com hetero c.C1066T:p.Q356X c.307+1G>C G
243 FA FANCG hetero c.1386delC:p.A462fs s/o G
244 FA FANCA homo c.C1303T:p.R435C c.C1303T:p.R435C A
245 FA FANCG homo c.C1066T:p.Q356X c.C1066T:p.Q356X G
246 FA FANCA com hetero c.A2170C:p.T724P c.G505T:p.E169X A
263 FA FANCG homo c.307+1G>C c.307+1G>C G
264 FA FANCI hetero c.3346_3347insT:p.L111fs s/o I
266 FA FANCA com hetero c.2602-2A>T c.C4198T:p.R1400C A
267 FA FANCA com hetero c.2602-2A>T c.C4198T:p.R1400C A
268 FA FANCG com hetero c.907_908del:p.303_303del c.307+1G>C G
270 FA No candidate RepliG sample, low coverage
271 FA FANCG homo c.307+1G>C c.307+1G>C G
291 FA No candidate Novel?, normal MLPA, no D2-Ub
292 s/o FA BRCA2 hetero c.5967_5968del:p.1989_1990del s/o D1
293 s/o FA No candidate DKC?
294 s/o FA FANCA com hetero c.3919_3920insT:p.Q1307fs c.2546delC:p.S849fs A reversion?
407 FA FANCM hetero c.G601A:p.G201R s/o M normal MLPA
408 FA FANCA homo c.2546delC:p.S849fs Exon 1-28 deletion A MLPA positive
224 FA FANCA com hetero c.2546delC:p.S849fsExon 1-5 deletion (copy number
analysis)A
225 FA FANCB homo c.G516A:p.W172X - B single allele on X chrom
226 FA FANCA homo c.2546delC:p.S849fs c.2546delC:p.S849fs A
231 FA FANCA com hetero c.4015_4017del:p.1339_1339del c.3638_3639del:p.1213_1213del A
232 FA FANCA hetero c.978_979del:p.326_327del s/o A
234 FA No candidate Brother of 233, normal D2-Ub
230 FA No candidate low quality of DNA
233 FA No candidate Brother of 234, normal D2-Ub
Fanconi Gene Mutations by Exome Analysis
Target gene list total ~180 genes
[Aplastic anemia] DKC1 EPB42 BCORL1 PHF6 GP1BA
PRF1 NHP2 G6PD BRAF PRPF8 GP9
TERF1 NOP10 GCLC BRCC3 RAD21 ITGA2B
TERF2 RTEL1 GPI CDH23 RB1 ITGB3
[Congenital amegakaryocytic thrombocytopenia] TERC GPX1 CEBPA RIT1 MYH9
MPL TERT GSR CREBBP RUNX1 TUBB1
[Congenital dyserythropoietic anemia] TINF2 GSS CSMD1 SF3B1 VWF
CDAN1 WRAP53 HBA1 CTCF SH2B3 [Paroxysmal nocturnal hematouria]
KLF1 POT1 HBB CUX1 SMC1A PIGA
SEC23B TERF2IP HK1 DAXX SMC3 [Congenital sideroblastic anemia]
[Chromosome fragile syndromes] [Fanconi anemia] NT5C3 DCAF7 SRP72 ABCB7
ATM BRCA2 PFKM Dido1 SRSF2 ALAS2
BLM BRIP1 PGD DIS3 STAG2 GLRX5
DCLRE1C FANCA PGK1 DNMT3A STAT3 HFE
LIG4 FANCB PIEZO1 EED SUZ12 PUS1
NBN FANCC PKLR ETNK1 TET2 SLC19A2
RAD50 FANCD2 SLC4A1 ETV6 TP53 SLC25A38
[Diamond-Blackfan anemia] FANCE SPTA1 EZH2 U2AF1 YARS2
GATA1 FANCF SPTB FBXW7 U2AF2 [Congenital neutropenia]
RPL11 FANCG TPI1 GNAS UMODL1 CSF3R
RPL26 FANCI [Juvenile myelomonocytic leukemia] GPRC5A WT1 ELANE
RPL31 FANCL ASXL1 IDH1 ZRSR2 G6PC3
RPL35A FANCM CBL IDH2 ZSWIM4 GFI1
RPL5 PALB2 FLT3 IRF1 [MonoMAC sydrome] HAX1
RPS10 RAD51C JAK3 JAK1 GATA2 VPS45
RPS14 SLX4 KRAS JARID2 [Myeloproliferative disorder] [Shwachman-Bodian-Diamond syndrome]
RPS17 [Hemolytic anemia] NF1 KANSL1 JAK2 SBDS
RPS19 ADA NRAS KDM6A [Neuronal ceroid lipofuscinosis type 2] [Wiskott-Aldrich syndrome]
RPS24 ADD1 PTPN11 KIT TPP1 WAS
RPS26 AK1 SETBP1 LAMB4 [Pancytopenia] [WHIM syndrome]
RPS29 ALDOA [Hematological malignancy] LUC7L2 AK2 CXCR4
RPS7 ANK1 AEBP2 MAP3K4 IKZF1 [X-linked lymphoproliferative disorder]
[Dyskeratosis congenita] ENO1 ATRX NCOR2 [Congenital thrombocytopenia] SH2D1A
C16orf57 EPB41 B2M NPM1 ACTN1 XIAP
CTC1 BCOR FLI1
[Fanconi anemia]
BRCA2
BRIP1
FANCA
FANCB
FANCC
FANCD2
FANCE
FANCF
FANCG
FANCI
FANCL
FANCM
PALB2
RAD51C
SLX4
[Dyskeratosis congenita]
C16orf57
CTC1
DKC1
NHP2
NOP10
RTEL1
TERC
TERT
TINF2
WRAP53
POT1
TERF2IP
Result of target sequencing
Clinical Dx nwith Genetic
Dx
Rate of Genetic
DxIdentified gene mutations (n)
Total cohort 99 43%
Anemia 13 3 23% ALAS2 (1), SLC25A38 (1), KLF1 (1)
DBA 14 4 29% RPL5 (2), RPS19 (2)
DC 12 6 50%TINF2 (2), DKC1 (2), TERT (1), SBDS
(1)
FA 18 15 83% FANCA (11), FANCF (1), FANCG (3)
HLH 3 1 33% XIAP (1)
Immunodeficiency 4 2 50% ATM (1), WAS (1)
MPD / MDS 6 2 33% PTPN11 (1), NF1 + SETBP1 (1)
Neutropenia 5 2 40% VWF (1), HBB (1)
Other BMFs 2 0 0%
SDS 6 4 67% SBDS (4)
SCN 7 2 29% ELANE (1), HAX1 (1)
Thrombocytopenia 9 2 22% RUNX1 (2)
How we can predict the response to IST?
Haematologica, 2014
All patients (N=264)Age, years, median (range) 9.0 (0.8-17.4)
Gender, n (%)Male 155 (59)Female 109 (41)
Etiology, n (%)Idiopathic 227 (86)Hepatitis-associated 37 (14)
Severity, n (%)Moderate 81 (31)Severe 75 (28)Very severe 108 (41)
Type of ATG, n (%)Horse 198 (75)Rabbit 66 (25)
Positive minor PNH clone, n (%) 114 (43)Delta relative TL (SD), median (range) -1.12 (-4.01-+3.01)*
Patient characteristics* n=119
Response rates of IST after 3 and 6 months
37%48%
43%
69%
p = 2.1 × 10-5
p = 0.078
PNH-
(n = 150)PNH+
(n = 114)
100%
0%
80%
60%
40%
20%
3 months 6 months
23%
61%
35%
74%
Shorter TLs(n = 62)
Longer TLs(n = 57)
p = 3.2 × 10-5
p = 4.3 × 10-5
100%
0%
80%
60%
40%
20%
Univariate and multivariate analysis for unfavourable response to IST
CovariatesUnivariate analysis Multivariate analysis
HR (95% CI) p value HR (95% CI) p value
Gender
Male 1 - 1 -
Female 2.01 (1.22-3.31) 0.005 2.70 (1.09-6.70) 0.032
Interval from diagnosis to treatment
<30days 1 - - -
≥30days 2.67 (1.56-4.56) <0.001 - -
WBC count
<2.0 1 - 1 -
≥2.0 1.69 (1.03-2.77) 0.038 2.69 (1.10-6.58) 0.030
Positive minor PNH clone
yes 1 - 1 -
no 3.03 (1.82-5.07) <0.001 5.58 (2.20-14.20) <0.001
Relative TL
≥-1.0SD 1 - 1 -
<-1.0SD 5.09 (2.32-11.20) <0.001 5.32 (2.18-13.00) <0.001
Response rates of IST after 3 and 6 months
19.0%
53.2%
23.8%
70.1%
PNH– and shorter TL(n = 42)
Others(n = 77)
100%
0%
80%
60%
40%
20%
p = 2.3 × 10-6
p = 3.9 × 10-2
3 months
6 months
Prognosis after IST
Ove
rall
surv
ival
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
Months from diagnosis
p = 0.785
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
Failu
re-f
ree
su
rviv
al
Months from diagnosis
p = 0.002
PNH– and shorter TL (n=42)
Others (n=77)
骨髄採取1
0 2000 4000 6000 8000
0.0
0.2
0.4
0.6
0.8
1.0
Days
Ove
rall
su
rviv
al
7/8 Matched-RD (n = 55)8/8 Matched-RD (n = 399)
7/8 Matched-UD (n = 98)
8/8 Matched-UD (n = 99)
Muramatsu H, et al. JSH. 2014.
651 children (0-19 y) with AA
Received BMT between 1986-2009
Registered to The Japan Society for Hematopoietic Cell Transplantation
Allogeneic SCT from HLA-mismatched related/unrelated donors in children with AA
Standard conditioning regimens for children with acquired BMF
AA/RCC
Matched related donor:CY (200 mg/kg) + ATG ± low dose TBI
Alternative donor:FLU + CY (100 mg/kg) + ATG ± low dose TBI
→ Is everything all right?
Clinical course11yF, RCC, Donor:matched unrelated, Conditioning regimen: FLU+CY+Campath+TBI(3Gy), GVHD prophylaxis:FK506, Cell dose:1.5x108/kg, aGVHD:grade 1, CMV antigenemia (+), EBV-LPD (+), Onset of aplasia after BMT: day110
Days after BMT
CMV
EBV
RBC, Platelet transfusion, G-CSF
Chimerism: 99% donor type
Chimerism: 99% donor type
Plt×104/ul
1800
1600
1400
1200
1000
800
600
400
200
Neu/ul
WBC1200, Neutro 0
Day 1360
Especially in the recent years, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after SCT.
“Donor-type aplasia”
Risk factors for “Donor-type aplasia”
… One of the main causes of treatment failure
after SCT in children with acquired BMF
Risk factors for “Donor-type aplasia”
Risk factors for “Donor-type aplasia”
No. Age atBMT
Sex Dx-BMT (d)
Morphological classification
at BMT
IST before BMT
HLA
disparityRelated /Unrelated
Conditioningregimen
1 4 M 460 RCC _ matched Relate FLU+CY+TLI
2 11 F 576 RCC _ matched Relate FLU+CY+TLI
3 13 M 3164 RCC + matched Unrelated CY+ATG+TBI
4 5 M 584 RCC + matched Unrelated CY+ATG+TBI
5 6 M 373 RCC _ matched Relate FLU+CY+TLI
6 11 M 42 RCC _ matched Relate FLU+CY+TLI
7 9 M 889 RCC + mismatched Unrelated CY+ATG+TBI
8 13 M 3290 RCC _ matched Relate FLU+CY+TBI
9 11 F 268 RCC + matched Unrelated FLU+CY+Campath+TBI
10 5 F 266 RCC + mismatched Relate FLU+CY+Campath+TBI
11 2 M 308 RCC + mismatched Unrelated FLU+CY+ATG+TBI
A Report from Nagoya groupHama A et.al. 2012 JSHCT
Donor-type aplasia: 11/58 (19%)
Risk factors for “Donor-type aplasia”
P < 0.001
RCC: FLU regimen (n=13)
RCC: Non-FLU regimen (n=19)
AA (n=26)
0 5 10
0
.2
.4
.6
.8
1P
rob
abili
ty
Years from transplantation15
Cumulative incidence of donor-type aplasiaHama A et.al. 2012 JSHCT
RCC + FLU regimen High risk for donor-type aplasia
Risk factors for “Donor-type aplasia”
Risk factors for “Donor-type aplasia”A Report from the JSHCT pediatric AAWG (n=660)
Yoshida N et.al. 2012 ASH
• FLU-based regimen• Infused cells ≤ 3x108/kg• IST before BMT• Unrelated donor• Interval Dx-BMT> 9M
The introduction of FLU << the CY dose reduction ?
FLU + CY (100 mg/kg)
Since the 2000s, FLU-based conditioning regimen has been often used for children with acquired BMF. Moreover, when FLU was introduced in the regimen for Japanese children with acquired BMF, the dose of CY was reduced by half, to reduce the toxicity.
CY (200 mg/kg)
CI of donor-type aplasia
0
.2
.4
.6
.8
1
0 5 10
Pro
bab
ility
Years from BMT
CY-full (n=35): 0%
CY-half (n=175): 15%
P=0.048
• CY-full : FLU+CY (200mg/kg)• CY-half: FLU+CY (100mg/kg)
Heart failure due to CY
CY-half (n=175)CY-full (n=35)
94.3%
5.7% 0.6%
99.4%
Heart failure
P=0.07
Impact of CY dose in FLU regimen group
Risk factors for “Donor-type aplasia”
Yoshida N et.al. 2012 ASH
Risk factors for “Donor-type aplasia”
… needs to be reconsidered
CY 100 mg/m2 → Risk for donor-type aplasiaCY 200 mg/m2 → Risk for heart failure
AA/RCC → Risk for donor-type aplasia
Matched related donor:CY (200 mg/kg) + ATG ± low dose TBI
Alternative donor:FLU + CY (100 mg/kg) + ATG ± low dose TBI
Conditioning regimen for acquired BMF
FLU/MEL-based regimen
FLU/CY -based regimen
Optimal conditioning regimen for acquired BMF children with high risk of donor-type aplasia?
Imm
un
osu
pp
ress
ive
Myelosuppressive
FLU/CY/ATG
FLU/CY/low dose TBI
FLU/CY
FLU/MEL/ATG
FLU/MEL/low dose TBI
FLU/MEL
CY/TBI
BU/CY
Risk factors for “Donor-type aplasia”
Outcomes of SCT with FLU/MEL conditioning for children with acquired BMF
- A report from the JSHCT pediatric AA/MDS WG -
Outcomes of SCT with FLU/MEL
The clinical data of 488 patients with acquired BMF (AA, RCC, RCMD) younger than 16 years who received the first SCT from 2000 to 2012 and were registered in the JSHCT Registry was reviewed.
n=488
n=233FLU/CY-based
regimenn=28
FLU/MEL-based regimen
Age at SCT, y, median (range) 8 (1-15)
Gender male / female 13/15
Interval diagnosis-SCT, m, median (range) 15(0-133)
IST before SCT yes/ no 20/8
GVHD prophylaxis
CyA ± MTX 6
FK ± MTX 22
Donor Related / Unrelated 11/17
HLA Match / Mismatch 13/15
Stem cell source BM / PB / CB 19/1/8
ConditioningFLU (100-180 mg/m2) + MEL (70-180 mg/m2)
• 70: n=6• 80: n=2• 120: n=6• 140: n=10• 180: n=4
+ ATG / ALG / Campath n=17+ Low dose TBI / TAI / TLI n=23
Patient and transplantation characteristics (n=28)
Outcomes of SCT with FLU/MEL
Outcomes of SCT with FLU/MEL-based regimen
OS EFS
0 2 4 6 8 0
.2
.4
.6
.8
1
Years from transplantation
5y-OS: 88 (81-95) %
0 2 4 6 8 0
.2
.4
.6
.8
1
Years from transplantation
5y-EFS: 88 (81-95) %
• Engraftment: 27/28 (96%) median 21 (11-36) days
• Secondary GF: 0
• Donor-type aplasia: 0
• aGVHD (II-IV): 4/27 (14%)
• cGVHD (extensive): 2/26 (7%)
Outcomes of SCT with FLU/MEL
OS according to stem cell source
OS according to MEL dose
0
.2
.4
.6
.8
1
0 2 4 6 8 0
.2
.4
.6
.8
1
Years from transplantation
CB(n=8): 70 (52-88)%
BM(n=19): 100 (100-100)%
PB(n=1): 0 (0-0)%
0 2 4 6 8 Years from transplantation
MEL ≥ 120mg/m2(n=20): 100 (100-100)%
MEL<120mg/m2(n=8): 62 (45-80)%
P=0.006
Outcomes of SCT with FLU/MEL-based regimen
Outcomes of SCT with FLU/MEL
Cause of death (n=3)
1 2 3
Age at SCT 15y 2y 1y
Donor Mismatched R-PB Mismatched UR-CB Mismatched UR-CB
MEL dose 80 mg 70 mg 70 mg
ATG etc. Campath ATG ATG
Irradiation TBI (4Gy) none TAI (6Gy)
Engraftment no yes yes
Cause of deathGF, infection
(P.aeruginosa sepsis, Aspergillus)
Infection (zygomycosis)
Second malignancy
Day 55 33 840
Outcomes of SCT with FLU/MEL
0 2 4 6 8 0
.2
.4
.6
.8
1
Years from transplantation
FLU/MEL vs. FLU/CY -Survival after BMT-
OS EFS
0 2 4 6 8 0
.2
.4
.6
.8
1
Years from transplantation
FLU/MEL (n=19): 100 (100-100)% FLU/MEL (n=19): 100 (100-100)%
FLU/CY (n=219): 93 (92-95)% FLU/CY (n=219): 85 (83-88)%
P=NSP=NS
• Engraftment: 214/219 (98%)• Secondary GF: 9 • Donor-type aplasia: 9
… The FLU/MEL-based regimen provided excellent outcomes especially in the setting of BMT.
Outcomes of SCT with FLU/MEL
FLU : 25mg /m2 x 5 days
MEL : 70mg /m2 x 2 days
BMT
ATG : 2.5mg /kg x 2 days
Day -7 -6 -5 -4 -3 -2 -1 0
FLU : 25mg /m2 x 5 days
MEL : 70mg /m2 x 2 days
BMT
ATG : 2.5mg /kg x 2 days
TBI * : 3Gy
Day -7 -6 -5 -4 -3 -2 -1 0
Conditioning regimen and GVHD prophylaxis :
1) Matched related donor:
2) Alternative donor:
GVHD prophylaxis : CyA + sMTX
* with gonadal shielding if possible
GVHD prophylaxis : FK + sMTX
Proposal of prospective study
Haplo transplantation is feasible for AA?
WBC 200/μl, Neutr 0/μl, Hb 9.3g/dl, Ret 0‰, Plt 2000/μl, CRP 26mg/dl
12 years old Female
Blood, Throat, Stool culture : Pseudomonas aeruginosa (+)
FK506
TBI
BMT
day0 10 20 30
0
5
10
50
0
4
8
12
Hb
(mg/dl)
MEPMAMPH
PZFXVCM
PSL
G G G G GG G G G
γ
fever
G G G G G G G
γ γ
PBSCT
BMT:NCC 1.3×108/kg, CD34 4.7×106/kg
PBSCT:NCC 4.1×108/kg, CD34 1.3×106/kg
MMM MMTXGCV
CZOPfever
γ γ
CMV
+
EBV
+
Rituximab
Clinical course
WBC
(x102)
Plt(x104)
Institute SeoulShanghai/
NagoyaTotal
Number of patients 18 15 33
Ex vivo Tcell depletion yes no -
Severity of the disease
SAA/VSAA12/6 9/6 21/12
Age at transplant(yrs)
Median(range)14(4-22) 10(3-16) 12(3-22)
Months from diagnosis to transplant
Median(range)66(0.9-139) 15(0.7-60) 26(0.7-139)
IST prior to transplant
yes/no13/5 14/1 27/6
Donor
mother/father/sibling10/5/3 5/9/1 15/14/4
HLA matching at A,B,DR
3/6 vs. 4/610/8 6/9 16/17
Patient Characteristics
Institute SeoulShanghai/
NagoyaTotal
Conditioning regimens
FLU/CY/ATG/TBI
FLU/CY/ATG
FLU/MEL/ATG/TBI
FLU/MEL/ATG
CY/TBI
11
7
7
6
1
1
18
7
6
1
1
GVHD prophylaxis
CSP/MMF
FK/MMF
FK/MTX
CSP/MTX/MMF
CSP/MTX
4
14
7
6
2
4
14
7
6
2
CD34+ cells in graft (x10⁶/kg)
Median (range) 5.5(3.0-15.2) 4.2(1.3-35.0) 5.3(1.3-35.0)
Conditioning regimen and GVHD prophylaxis
Institute SeoulShanghai/
NagoyaTotal
Neutrophil engraftment (days)
Median(range)10(9-13) 15(11-34) 12(9-34)
Graft failure
Primary graft failure
Graft rejection
1
4
1
0
2
4
Cumulative incidence of GVHD(%)
Acute GVHD
≥Grade Ⅱ≥Grade Ⅲ
Extensive chronic GVHD
38
15
11
57
21
25
48
18
16
Death 1 1 2
Overall survival at 2 years 93.8% 85.6% 90.1%
Median FU of survivors (months) 28.2 33.8 30.5
Clinical Outcome
Haploidentical HSCT for SAA
TREATMENT ALGORISM FOR CHILDREN WITH SAA
Newly diagnosed
SAA
MRD (+)
BMT from MRD
IST
CR/PR
NR
MUD(+)
MUD(-)
BMT from MUD
2nd ISTor
HAPLO / CBT
MRD (-)
FIRST LINE THERAPY SECOND LINE THERAPY
UPDATEDTREATMENT ALGORISM
FOR CHILDREN WITH SAA
Newly diagnosed
SAA
MRD/1MMRD(+)
BMT from MRD/1MMRD
HAPLOEMERGENT CASE
Others IST
BMT from MUDMRD/1MMRD(-)
FIRST LINE THERAPY SECOND LINE THERAPY
PNH⁻ and shorter TL
Acknowledgements
●Nagoya UniversityYoshiyuki TakahashiAsahito HamaHideki Muramatsu
●Asan Medical CenterJong Jin SeoHo Joon Im
●Shanghai Children’s Medical CenterJing Chen
●The JSHCT Pediatric AA/MDS WGHiromasa YabeRyoji KobayashiKen-ichiro WatanabeNao Yoshida
●The Japan Childhood AplasticAnemia Study GroupKazuko KudoHiroshi YagasakiShoichi OhgaAkira Ohara