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(1)

Aplastic Anemia

순천향대학교

김 경 하

(2)

• Introduction

• Initial therapy for severe aplastic anemia (SAA)

– HSCT

– Immunosuppressive therapy (IST)

• Salvage therapies for SAA

• Evolving concepts in SAA Contents

Aplastic Anemia

(3)

Natural history of severe aplastic anemia

Aplastic Anemia

BM Camitta. Blood. 1979 53: 504-514

Survival of 6m : 35%

Androgen in SAA

(4)

Improved survival over time

Aplastic Anemia

Valdez JM. Clin Infect Dis. 2011;52(6):726

(2002–2008)

(1996-2002)

(1989-1996)

(1989-1996) (1996-2002) (2002–2008)

(5)

• Severe aplastic anemia (SAA) ( Camitta et al, 1976) – BM cellularity <25% or 25-50% with <30% residual

haemopoietic cells

– Two of the three of the following:

• Neutrophils <500/µ L

• Platelets <20,000/µ L

• corrected reticulocyte count <1% (or absolute reticulocyte count <60,000/µ L).

• Very-severe AA (Bacigalupo et al, 1988)

– Same as for SAA but neutrophils < 200/µ L

• Non-severe AA

Assessment of Disease Severity

Aplastic Anemia

(6)

Initial therapy for SAA

-HSCT

Donor

• Stem cell source

• Transplantation protocol

-Immunosuppressive therapy (IST)

(7)

HSCT

Aplastic Anemia

Gupta V. Haematologica 2010;95:2119

• Factors for decision for HSCT

• Age

• Presence of a histocmpatible donor

• Comorbidities

OS according to age Acute GVHD according to age

1307 SAA patients –

CIBMTR retrospective

study

(8)

문제

1.

Aplastic Anemia

• 30/F, 다리에 멍이 들어서 내원

• 혈액 검사: WBC 1,300/mm

3

(neutrophil 25%,

lymphocyte 70%, monocyte 5%), Hb 7.0 g/dL, PLT 15,000/mm

3

, reticulocyte 0.8%

• 골수검사:

• 형제 없음

• full matched unrelated donor 있음

(9)

문제

1.

Aplastic Anemia

• 가장 적절한 초 치료는?

1)Unrelated donor HSCT

2)Immune suppressive treatment

(IST)

(10)

Phillip Scheinberg. Blood. 2012;120(6):1185

Aplastic Anemia

Algorithm for initial management of SAA

(11)

Young NS. Blood. 2006;108(8):2509

Aplastic Anemia

HSCT(1) : Donor- Matched sibling donor

Institution

/study Years of

study N Age, y (median

in y)

Graft rejection/

failure, %

Acute

GVHD,% Chronic GVHD, %

Actuarial survival,

%

IBMTR 1988-1992 471 20 (1-51) 16 19 32 66 at 5 y

Vienna 1982-1996 20 25 (17-37) 0 26 53 95 at 15 y

EBMT 1991-1998 71 19 (4-46) 3 30 35 86 at 5 y

Seoul 1990-1999 22 22 (14-43) 5 10 33 95 at 5 y

Seoul 1990-2001 64 28 (14-43) 18 31 19 79 at 6 y

Hamburg 1990-2001 21 25 (7-43) 5 5 5 86 at 5 y

Paris 1994-2001 33 20 (8-42) 6 0 42 94 at 5 y

Sao Paulo 1993-2001 81 24 (3-53) 22 37 39 56 at 6 y

Taipei 1985-2001 79 22 (4-43) 8 7 35 74 at 5 y

Tunis 1998-2001 31 19 (4-39) 16 11 3 86 at 2 y

Seoul 1995-2001 113 28 (16-50) 15 11 12 89 at 6 y

London 1989-2003 33 17 (4-46) 24 14 4 81 at 5 y

Seattle 1988-2004 94 26 (2-59) 4 24 26 88 at 6 y

Mexico City 2000-2005 23 25 (4-65) 26 17 26 88 at 4 y

(12)

Aplastic Anemia

HSCT(1) : Donor- Alternative donor studies

Study Year of

pub. N Donor source

N Conditioning Age, y, median (range)

Acute GVHD

%

Chronic GVHD

%

Survival,

% Nagoya 2001 15 MUD: 11

MMUD: 4 Cy/ATG/TBI 11 (3-19) 33 13 100 at 4 y Great

Britain 2001 8 MUD: 7

MMUD: 1 Cy/CP/TBI 7 (0-10) 25 0 100 at 3 y Japan

Marrow Donor Program

2002 154 MUD: 79 MMUD: 75 Cy ± TBI or LFI;

Cy/ATG ± TBI or LFI 17 (1-46) 29 30 56 at 5 y

Memphis 2004 9 MUD: 4 MMUD: 5

High CD34+ cell dose, TCD, Cy/ATG/TLI or TBI

± thiotepa 11 (6-16) 0 0 89 at 4 y Gyeonggi-

do 2004 5 MUD Cy/Flu/ATG 13 (7-18) 0 0 80 at 2 y Guangzhou 2004 6 UCB Cy/ATG 26 (22-37) 0 33 66 at 2 y

Genoa 2005 38 MUD: 33

MMRD: 5 Cy/Flu/ATG 14 (3-37) 11 24 73 at 2 y Philadelphia 2005 12 MUD: 4;

MMUD: 8

Partial TCD, TBI + Cy/Ara-C or Cy/TT or

ATG 9 (1-20) 33 25 75 at 4 y Seoul 2005 13 MUD: 12

MMUD: 1 Cy/ATG 22 (15-34) 31 62 75 at 3 y IBMTR 2006 318 MUD: 181

MMRD: 86

MMUD: 51 Various 16 (1-55) 48 for MUD 29 for

MUD 39 at 5 y for MUD Seattle 2006 87 MUD: 62

MMUD: 25 Cy/ATG/TBI 19 (1-53) 70 for MUD 52 for

MUD 61 at 5 y for MUD

Young NS. Blood. 2006;108(8):2509

(13)

Aplastic Anemia

HSCT(1) : Donor- Unrelated donor (IBMTR)

Passweg J. Bone Marrow Transplantation. 2006; 37:641

1988-99, 112 centers in 29 countries

(14)

Aplastic Anemia

HSCT(1) : Donor- Unrelated donor (French)

Maury S. Haematologica 2007;92:589

Graft failure: 10%

aGVHD III-IV: 22%

cGVHD: 26%

Survival:50%

(15)

Study

(year) N Design Conditioning Graft failure

%

Median age y

aGVHD grade 2-4, %

cGVHD

% Survival

% Kim

(2007) 40 Prospective Cy/TBI 5 27 30 38 75 (3 y)

Maury

(2007) 89 Retrospective Various 14 17 50 28 42 (5 y)

Viollier

(2008) 349 Retrospective Various 11 18 28 22 57 (5 y) Kosaka

(2008) 31 Prospective Cy/ATG/TBI;

Flu/Cy/ATG/TBI 16 8 13 13 93 (3 y)

Perez- Albuerne

(2008) 195 Retrospective Various 15 10 43 35 51 (5 y) Bacigalupo

(2010) 100 Retrospective Flu/Cy/ATG;

Flu/Cy/ATG-TBI 17 20 18

27 (no TBI) (TBI) 50

75 (5 y)

Kang

(2010) 28 Prospective Flu/Cy/ATG 0 13 46 35 68 (3 y)

Lee (2010) 50 Prospective Cy/TBI 0 28 46 50 88 (5 y)

Marsh

(2011) 29 Retrospective Flu/Cy/Alem 15 35 14 4 83 (2y)

Aplastic Anemia

HSCT(1) : Donor- Unrelated donor studies

Phillip Scheinberg. Blood. 2012;120(6):1185

(16)

• Horse ATG/CsA → excellent

• Optimal conditioning for UD HSCT ?

• Graft rejection and GVHD !!

• Chronic immunosuppression for GVHD !!

• More generalizable data from larger cohorts → long-term survival :50% to 60%

• Late effects of low dose total body irradiation and alkylating agents ?

Aplastic Anemia

UD HSCT is not recommend as first therapy

Phillip Scheinberg. Blood. 2012;120(6):1185

(17)

Regis Peffault de Latour. Biol Blood Marrow Transplant. 2011; 17: 78

Aplastic Anemia

HSCT(1) : Donor- higher risk transplantation

Unrelated cord blood transplantation

• 71 patients, retrospective trial

• Single unit (n=57, 79%), double unit (n=14, 19%)

• Engraftment:

• ANC(day 60) : 51% ± 6%

• PLT(day 180) : 37% ± 7%

• GVHD

•Acute (gr 2-4): 20% ± 5%

•Chronic (at 3yr) : 18% ± 5%

•3yr OS: 38% ± 6%

Cause n (%)

Infections 16 (38%)

Bacterial 5 (12%)

Viral 3 (7%)

Fungal 3 (7%)

Unknown 2 (5%)

EBV-associated LPD 3 (7%) Rejection or graft failure 14 (32%)

GVHD 3 (7%)

Hemorrhage 3 (7%)

Multiorgan failure 3 (7%)

Other 3 (7%)

Causes of Death (n = 42)

(18)

문제

2.

Aplastic Anemia

• 30/F, 다리에 멍이 들어서 내원

• 혈액 검사: WBC 1,300/mm

3

(neutrophil 25%,

lymphocyte 70%, monocyte 5%), Hb 7.0 g/dL, PLT 15,000/mm

3

, reticulocyte 0.8%

• 골수검사:

• Matched sibling donor 있음

(19)

문제

2.

Aplastic Anemia

• 이 환자에서 MSD HSCT 를 시행하기로 하였다.

Stem cell source 로 가장 적절한 것은?

1)Bone marrow

2)G-CSF mobilized PBSC

3)둘 중 어느 하나도 상관 없음

(20)

Schrezenmeier H. Blood. 2007;110:1397

HSCT(2) : Stem cell source

Aplastic Anemia

(21)

Schrezenmeier H. Blood. 2007;110:1397

Chu R. Biol Blood Marrow Transplant. 2011;17:1018 Eapen M. Blood.2011;118:2618

Bacigalup A. Haematologica. 2012;97:1142

HSCT(2) : Stem cell source

Aplastic Anemia

Study N Acute GVHD

II-IV Chronic

GVHD Mortality Comment

Schrenzenmeier

(2007) 692 RR 1.42

(p=0.436) RR 2.822

(p=0.002) RR 2.04 (p=0.0024)

Related HSCT ≠ <20

yrs Chu (2011) 759 RR 2.90

(p<0.001) RR 3.26

(p<0.001) RR 1.28 (p=0.212)

Related HSCT ≠ All

ages Eapen

(2011) 296 RR 1.68

(p=0.436) RR 1.39

(p=0.14) RR 1.62

(p=0.04) MUD Bacigalupo

(2012) 1866 17% vs 11%

(p=0.001) 22% vs 11%

(p<0.001) RR 2.1 (p<0.001)

Related HSCT ≠ All

ages

Peripheral blood vs bone marrow HSCT in SAA

(22)

HSCT(2) : Stem cell source

Aplastic Anemia

No benefit from GVHD →

bone marrow is preferred !!

(23)

HSCT(3) : Transplantation protocol

Aplastic Anemia

•Popular regimen

• Cyclophosphamide(Cy)/ATG

• GVHD prophylaxis: cyclosporine(CsA)/MTX

•Changing (UD HSCT↑/ old age HSCT↑)

•Low dose TBI

•Addition of fludarabine (Flu)

•Addition of alemtuzumab (Alem)

(24)

HSCT(3) : Transplantation protocol

Aplastic Anemia

Deeg H J. Blood 2006;108:1485

Conditioining regimens (UD after failure of IST) : Cy/ATG + TBI

low-dose TBI + CY/ ATG

excellent outcome

of unrelated transplants

(25)

HSCT(3) : Transplantation protocol

Aplastic Anemia

Bacigalupo. Bone Marrow Transplantation. 2005; 36: 947

Flu/Cy + ATG for alternative donor transplantaiton

• Addition of fludarabine to Cy/ATG → Overcoming

graft rejection

(26)

Phillip Scheinberg. Blood. 2012;120(6):1185

Aplastic Anemia

Algorithm for initial management of SAA

(27)

문제

3.

Aplastic Anemia

• 50/F, 다리에 멍이 들어서 내원

• 혈액 검사: WBC 1,300/mm

3

(neutrophil 25%,

lymphocyte 70%, monocyte 5%), Hb 7.0 g/dL, PLT 15,000/mm

3

, reticulocyte 0.8%

• 골수검사:

• Matched sibling donor 있음

(28)

문제

3.

Aplastic Anemia

• 이 환자에서 IST 로 ATG/CsA 치료를

시작하기로 하였다. 만일 rabbit ATG 혹은 horse ATG 모두 선택 가능할 때 더 효과적인 것은 ?

1) Rabbit ATG/CsA

2) Horse ATG/CsA

(29)

IST(1) : ATG

Aplastic Anemia

Gökbuget N. N Engl J Med 2011;365:430

Horse ATG Rabbit ATG P-value

3 months 37/60(62%) 20/60 (33%) 0.002

6 months 41/60(68%) 22/60(37%) <0.001

Hematologic response at 3 and 6 months to horse

ATG and rabbit ATG (+ CsA 10~15mg/day)

(30)

IST(1) : ATG

Aplastic Anemia

Gökbuget N. N Engl J Med 2011;365:430

(31)

Aplastic Anemia

IST(1) : ATG- comparing horse and rabbit ATG

Phillip Scheinberg. Blood. 2012;120(6):1185

Study (year)

Horse ATG N

Rabbit ATG N

Horse ATG

formulation Rabbit ATG formulation

Horse response ATG

%

Rabbit response ATG

%

Design Zheng

(2006) 47 32 Lymphoglobulin Fresenius 79 53 Prospective, randomized

Garg

(2009) — 13 — Thymoglobulin — 92 Prospective

Atta

(2010) 42 29 Lymphoglobulin Thymoglobulin 60 35 Retrospective

Afable

(2011) 67 20 ATGAM Thymoglobulin 58 45 Retrospective

Scheinberg

(2011) 60 60 ATGAM Thymoglobulin 68 37 Prospective,

randomized

(32)

IST(2) : Cyclophosphamide

Aplastic Anemia

Tisdale JF. Lancet 2000; 356: 1554 Cyclophosphamide

(50mg/kg D1-D4) +CSA

ATG+CSA (n=31) R

Study terminated prematurely due to toxicity of cyclophosphamide !!

Response portion for patients

Patients reaching an ANC of 0.5 X10

3

/L

(33)

IST(2) : Cyclophosphamide

Aplastic Anemia

ATG vs cyclophosphamide – 2012 ASH abstract 1259 Year 2000 ATG/CsA

N=16 Cy(200)/CsA N=15

Overall response 13(81%) 8(53%)

CR 10(63%) 6(40%)

Relapse 6(46%) 2(25%)

Cytogenetic evolution 2(14%) 1(8%)

Fungal infection or death

(first 6 mo) 0(0%) 6(40%)

Year 2012 Cy(120)/CsA N=22

Overall response 9(41%)

CR 4(18%)

Cytogenetic evolution 4(18%)

Fungal infection or death (first 6 mo) 5(23%)

(34)

문제

4.

Aplastic Anemia

• 50/F, 다리에 멍이 들어서 내원

• 혈액 검사: WBC 1,300/mm

3

(neutrophil 25%,

lymphocyte 70%, monocyte 5%), Hb 7.0 g/dL, PLT 15,000/mm

3

, reticulocyte 0.8%

• 골수검사:

• Matched sibling donor 있음

(35)

문제

4.

Aplastic Anemia

• 이 환자에서 IST 로 ATG/CsA 치료를 하면서 시행하는 supportive care 중 환자의 생존을 유의하게 증가시킬 수 있는 것은?

1) Mycophenolate mofetil or sirolimus 2) G-CSF

3) GM-CSF

4) Erythropoietin

5) None

(36)

IST(3) : Other agents

Aplastic Anemia

Tichelli A. Blood 2011;117:4434

•Other immunosuppressants (eg,

mycophenolate mofetil or sirolimus)

•Growth factor

ATG +

(37)

Salvage therapies for SAA -Refractory SAA

-Relapsed SAA

(38)

문제

5.

Aplastic Anemia

• 50/F, 다리에 멍이 들어서 내원

• 혈액 검사: WBC 1,300/mm

3

(neutrophil 25%,

lymphocyte 70%, monocyte 5%), Hb 7.0 g/dL, PLT 15,000/mm

3

, reticulocyte 0.8%

• 골수검사:

• Matched sibling donor 없음

• Mathced unrelated donor 없음

• 20대 아들 2명 있음

(39)

문제

5.

Aplastic Anemia

• 이 환자에서 IST 로 ATG/CsA 치료를 하였으나 6개월 째 반응이 없었다. 이 환자에서 적절한

salvage treatment 는?

1) 다른 약제로 IST 재 시행

2) Haploidentical allogeneic HSCT 고려

(40)

Phillip Scheinberg. Blood. 2012;120(6):1185

Aplastic Anemia

Algorithm for initial management of SAA

1

3

2

(41)

Refractory SAA: 1. Older patients with MSD

Aplastic Anemia

Severe pancytopenia at 6 months after

horse ATG → consider related HSCT

(42)

Refractory SAA: 2. Younger patients with MUD

Aplastic Anemia

Marsh. Blood. 2011 118: 2351

• Patient number:29pts, meidan age: 35 y

• Conditioing regimen:

-Fludarabine 30 mg/m2 D-7 ~ D-4

-Cyclophosphamide 300 mg/m2 D-7 ~ D-4

-Alemtuzumab 40-100mg between D-7 ~ D-3

• Graft failure :15%

• Acute GVHD (gr 2-4): 14%

• Chronic GVHD: 4%

• Survival at 2yrs: 83%

(43)

Refractory SAA: 3. Patients without

histocompatible donor

Aplastic Anemia

Phillip Scheinberg. Br J Haematol. 2006;133:622 Phillip Scheinberg. Blood. 2012;119:345

Second IST

High risk transplantation

- mismatched unrelated donor - haploidentical donor

- umbilical cord donor

>

Survival at 3yrs Response

Rabbit ATG/CsA 60% 30%-77%

Alemtuzumab 83% 30-40%

(44)

Refractory SAA: 3. Patients without

histocompatible donor

Aplastic Anemia

Phillip Scheinberg. Blood. 2012;119:345

Treatment

arm (N=54) Overall response Rabbit ATG

(n=27) 9 (35%) Alemtuzumab

(n=27) 10 (37%)

(45)

Salvage therapies for SAA -Refractory SAA

-Relapsed SAA

(46)

Phillip Scheinberg. Blood. 2012;120(6):1185

Aplastic Anemia

Long term follow up after immunosuppression

(47)

Evolving concepts

( Nontransplantation modalities)

- Eltrombopag

(48)

• c-mpl is expressed on HSCs and early progenitor cells

• TPO expands HSCs defined phenotypically and functionally in vitro

• c-mpl and TPO knockout mice have reduced HSCs

• CAMT patients (c-mpl loss of function mutations) develop multi-lineage marrow failure

Beyond thrombopoiesis

Aplastic Anemia

Kaushansky K. Blood. 2008;111:981

Zeigler FC. Blood. 1994;84:4045-52

(49)

Results of Eltrombopag in SAA

Aplastic Anemia

26 patients enrolled

25 evaluable patients

1 patient ineligible, not treated

11 responders (44%)

• 9 PLT responses

• 2 Hb responses

- Additional 4 at>16wks

• 4 neutrophil responses - Additional 3 at >16wks

14 non-responders

• 10 stable disease

• 2 died of progression

• 2 clonal evolution to MDS - 1 died

- 1 HSCT

Median f/u 13mos (range 4-28mos)

Ollnes MJ. N Engl J Med. 2012;367:11

(50)

Results of Eltrombopag in SAA

Aplastic Anemia

Ollnes MJ. N Engl J Med .2012;367:11

(51)

PLT increases after eltrombopag

Aplastic Anemia

Ollnes MJ. N Engl J Med .2012;367:11

(52)

Neutrophil increases after eltrombopag

Aplastic Anemia

Ollnes MJ. N Engl J Med .2012;367:11

(53)

Neutrophil increases after eltrombopag

Aplastic Anemia

Ollnes MJ. N Engl J Med .2012;367:11

(54)

Conclusions

Aplastic Anemia

• Patients who non candidates for a MSD HSCT → IST with horse ATG/CsA

• Matched UD HSCT → salvage therapy in younger patients who are unresponsive to initial IST

• Histocompatible UD is not available → second course of IST

•Evidence of higher risk transplantation protocols (eg, haploidentical or UC donors) → limited

(55)

경청해 주셔서 감사합니다.

Aplastic Anemia

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