Aplastic Anemia
순천향대학교
김 경 하
• Introduction
• Initial therapy for severe aplastic anemia (SAA)
– HSCT
– Immunosuppressive therapy (IST)
• Salvage therapies for SAA
• Evolving concepts in SAA Contents
Aplastic Anemia
Natural history of severe aplastic anemia
Aplastic Anemia
BM Camitta. Blood. 1979 53: 504-514
Survival of 6m : 35%
Androgen in SAA
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)
• 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
Initial therapy for SAA
-HSCT
• Donor
• Stem cell source
• Transplantation protocol
-Immunosuppressive therapy (IST)
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
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
문제
1.
Aplastic Anemia
• 가장 적절한 초 치료는?
1)Unrelated donor HSCT
2)Immune suppressive treatment
(IST)
Phillip Scheinberg. Blood. 2012;120(6):1185
Aplastic Anemia
Algorithm for initial management of SAA
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
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
Aplastic Anemia
HSCT(1) : Donor- Unrelated donor (IBMTR)
Passweg J. Bone Marrow Transplantation. 2006; 37:641
1988-99, 112 centers in 29 countries
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%
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
• 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
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)
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
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
Schrezenmeier H. Blood. 2007;110:1397
HSCT(2) : Stem cell source
Aplastic Anemia
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
HSCT(2) : Stem cell source
Aplastic Anemia
No benefit from GVHD →
bone marrow is preferred !!
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)
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
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
Phillip Scheinberg. Blood. 2012;120(6):1185
Aplastic Anemia
Algorithm for initial management of SAA
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
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
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)
IST(1) : ATG
Aplastic Anemia
Gökbuget N. N Engl J Med 2011;365:430
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
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
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%)
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
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
IST(3) : Other agents
Aplastic Anemia
Tichelli A. Blood 2011;117:4434
•Other immunosuppressants (eg,
mycophenolate mofetil or sirolimus)
•Growth factor
ATG +
Salvage therapies for SAA -Refractory SAA
-Relapsed SAA
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
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
Phillip Scheinberg. Blood. 2012;120(6):1185
Aplastic Anemia
Algorithm for initial management of SAA
1
3
2
Refractory SAA: 1. Older patients with MSD
Aplastic Anemia
Severe pancytopenia at 6 months after
horse ATG → consider related HSCT
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%
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%
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%)
Salvage therapies for SAA -Refractory SAA
-Relapsed SAA
Phillip Scheinberg. Blood. 2012;120(6):1185
Aplastic Anemia
Long term follow up after immunosuppression
Evolving concepts
( Nontransplantation modalities)
- Eltrombopag
• 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
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
Results of Eltrombopag in SAA
Aplastic Anemia
Ollnes MJ. N Engl J Med .2012;367:11
PLT increases after eltrombopag
Aplastic Anemia
Ollnes MJ. N Engl J Med .2012;367:11
Neutrophil increases after eltrombopag
Aplastic Anemia
Ollnes MJ. N Engl J Med .2012;367:11
Neutrophil increases after eltrombopag
Aplastic Anemia
Ollnes MJ. N Engl J Med .2012;367:11
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