transplant updates on donor and conditioning for aplastic anemia

48
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.

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Page 1: Transplant Updates on donor and conditioning for Aplastic Anemia

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.

Page 2: Transplant Updates on donor and conditioning for Aplastic Anemia

Aplastic Anemia – Transplant Updates on

Donors and Conditioning

Seiji Kojima MD / PhD Department of Pediatrics

Nagoya University Graduate School of Medicine

Page 3: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 4: Transplant Updates on donor and conditioning for Aplastic Anemia

How we can rule out

congenital bone marrow failure syndromes?

Page 5: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 6: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 7: Transplant Updates on donor and conditioning for Aplastic Anemia

AA RCMDRCC

Page 8: Transplant Updates on donor and conditioning for Aplastic Anemia

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)

Page 9: Transplant Updates on donor and conditioning for Aplastic Anemia

Whole exome capture/sequencing

biotinylated ‘bait’ cRNA

Recovery

Sequencing

gDNA

Non-targets

targets

Avidin-coated magnet beads

Bind target sequences

Page 10: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 11: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 12: Transplant Updates on donor and conditioning for Aplastic Anemia

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)

Page 13: Transplant Updates on donor and conditioning for Aplastic Anemia

How we can predict the response to IST?

Page 14: Transplant Updates on donor and conditioning for Aplastic Anemia

Haematologica, 2014

Page 15: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 16: Transplant Updates on donor and conditioning for Aplastic Anemia

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%

Page 17: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 18: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 19: Transplant Updates on donor and conditioning for Aplastic Anemia

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)

Page 20: Transplant Updates on donor and conditioning for Aplastic Anemia

骨髄採取1

Page 21: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 22: Transplant Updates on donor and conditioning for Aplastic Anemia

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?

Page 23: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 24: Transplant Updates on donor and conditioning for Aplastic Anemia

WBC1200, Neutro 0

Day 1360

Page 25: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 26: Transplant Updates on donor and conditioning for Aplastic Anemia

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%)

Page 27: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 28: Transplant Updates on donor and conditioning for Aplastic Anemia

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)

Page 29: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 30: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 31: Transplant Updates on donor and conditioning for Aplastic Anemia

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”

Page 32: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 33: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 34: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 35: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 36: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 37: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 38: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 39: Transplant Updates on donor and conditioning for Aplastic Anemia

Haplo transplantation is feasible for AA?

Page 40: Transplant Updates on donor and conditioning for Aplastic Anemia

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 (+)

Page 41: Transplant Updates on donor and conditioning for Aplastic Anemia

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)

Page 42: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 43: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 44: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 45: Transplant Updates on donor and conditioning for Aplastic Anemia

Haploidentical HSCT for SAA

Page 46: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 47: Transplant Updates on donor and conditioning for Aplastic Anemia

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

Page 48: Transplant Updates on donor and conditioning for Aplastic Anemia

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