Is allo-SCT first line option for AA if sibling donor available?

Is allo-SCT first line option for AA if sibling donor available?

Surapol IssaragrisilDivision of Hematology, Department of Medicine

Siriraj Hospital, Mahidol UniversityBangkok, Thailand

Incidence and Etiologic Fraction of Aplastic Anemia

No. of Cases

Rate/106 yr

Etiologic Fraction

Drugs Other factors

IAAAS 208 2.0* 45% 27% 18%

Thailand 374 4.1† 20-30% 3% 15-29%

“The Beggar” of Hematology 1888 - First described by Paul Ehrlich 1904 - Vagues and Aubertin – used term “Aplastic anemia”

Outline of The Talk

• Guideline for management of AA• HSCT vs IST• Improvement of MSD HSCT outcome

UK Guideline For Management of Severe Aplastic Anemia

Marsh JC et all. Br J Haematol. 2009;147:43-70.

UK Guideline For Management of Non Severe Aplastic Anemia

Marsh JC et all. Br J Haematol. 2009;147:43-70.

Is allo-SCT first line option for AA if sibling donor available?

First Line BMT vs IST

• N = 2,479• Better 10 year survival in BMT group vs IST • Favorable predictors :

– Younger age - Transplant after 1996– Matched sibling donor - Short diagnosis-transplant interval– No irradiation

SAA-WP, BMT. Haematologica. 2007; 92:11-18

First Line BMT vs IST

• Meta analysis; N= 26 Non-RCT; N=7,955 ; 1970-2001 • Heterogeneity of non RCT studies did not justify a pooled estimate

Peinemann F et al. Plos One. 2011;6(4):e18572.

First-line Treatment Strategy

• Results of MSD HSCT have improved overtime• Results of IST seem to be unchanged during the past decade

IST HSCT

EBMT Database. 2009.

BMT vs ISTQuality Adjusted Analysis in Aplastic Anemia

• BMT (n=52) or IST (n=155) • Survival, event-free survival, and Q-TWiST

(Time without symptom and toxic ity) are similar

• BMT-treated patients had longer periods free from symptoms, while IST-treated patients needed closer medical care, transfusion support, and medications

Viollier R, et al. Ann Hematol. 2005 Jan;8 4(1):47-55.

BMT

ISTISTBMT

• TOX = treatment-related toxicity • TRANS = transfusion dependency • PR = partial remission• CLON = secondary clonal disorder• GVHD = extensive chronic graft-versus-host disease (GvHD)

Viollier R, et al. Ann Hematol. 2005 Jan;8 4(1):47-55.

BMT vs ISTQuality Adjusted Analysis in Aplastic Anemia

Can We Improve The Result of MSD HSCT?

Factors Predicting HSCT Outcome

• Age• Interval from diagnosis to transplantation• Conditioning• Bone marrow cell dose• Stem cell source

Allogeneic HSCT in SAA

• Improved outcomes were seen overtime

• Less so, in the last decade with OS rates close 80%

• Young patients less than 20 years have best outcome

• Those over 50 years do poorest• Those with 21-50 years have

intermediate outcome

<20 vs 21-30 p<0.000121-30 vs 31-40 p=0.131-40 vs 41-50 p=0.341-50 vs >50 p=0.005

HLA-identical Sibling HSCT in age > 40 years

• Retrospective; n=23; median age = 49 (40-68)• High dose Cy + horse ATG; BMSC = 21, PBSC = 2; CSA+MTX• Acute GVHD 30%; Chronic GVHD 26%• Risk of early TRM: documented infection within 1 mo • Median FU 9.1 yr (0.9-19.2)

Seattle, Sangiolo D et al. Biol Blood Marrow Transplant. 2010 Oct;16(10):1411-8.

OS 65%

Impact of Age on Outcomes After BMT

Toronto, Gupta V et al. Haematologica. 2010;95(12):2119-25.

Acute GVHD Chronic GVHD

Overall Survival

• N = 1,307

The Interval From Diagnosis to Transplant and Pretransplant IST

>1998≤ 1998

≤ 1998 >1998

Cyclophosphamide Alone as Conditioning

≤1998 >1998

Seattle and EBMT 2009.

• In non-RCT, Cy + ATG is well tolerated and effective in heavily pretreated aplastic anemia patients • Lower incidence of chronic GVHD• Overall survival 88% with long term follow-up

Cy/ATG as Conditioning

Kahl et al. Br J Haematol. 2005 Sep;130(5):747-51.Storb R et al. Biol Blood Marrow Transplant. 2001;7(1):39-44.

Year after HSCT

ATG in Conditioning Regimen

• ATG is a favorable predictor of outcome both for BM and PB; especially for patients >20 years

• ATG reduces chronic GvHD (and its consequence , BOS)• ATG improves survival

ATG in Conditioning Regimen

Bacigalupo A et al.Biol Blood Marrow Transplant. 2006;12: 560-5.

• A randomized controlled study• No difference in graft failure, GVHD and survival• The addition of ATG to conditioning regimen did not significant

improve outcome

Cy vs Cy/ATG as Conditioning

Champlin RE et al. Blood. 2007;109: 4582-4585.

P = 0.44

Cy/ATG as Conditioning: Long Term Follow Up

• n=61; median age 21 years (4-43)• Median duration of the disease before HSCT 93 days• Cyclophosphamide 200mg/kg + antithymocyte globulin 2.5 mg/kg/day x 5

days HLA matched sibling HSCT CsA and MTX (days 1,3,6 11) • BMSC 97%; Primary graft failure 3%• acute grade II-IV GvHD 23%; chronic GvHD 32% associated with higher

number of infused CD3 cells (p=0.017)

6yr OS 87%

Paris, Konopacki J, et al. Haematologica. 2011 Dec 29.

Cy/ATG as Conditioning: Long Term Follow Up

• Long term complication:– AVN 21%– Endocrine dysfunction 19% (3 had diabetes, 4 hypothyroidism, 4 dyslipidemia, 1 Cushing’s syndrome and 1 hypogonadism)– EBV associated HL 1%

Konopacki J, et al. Haematologica. 2011 Dec 29.

61%

8%

25%

Risk Factors for AVN

Fludarabine Based as Conditioning in Patients over 30 years

• Retrospective; n = 30; median 46 (31-66)

• BMSC = 20, PBSC = 10• Reduced incidence of graft failure (0

vs 11 %, p = 0.09)• No difference in GVHD• Higher probability of overall survival

when adjusting for recipient’s age

Maury S et al. EBMT-SAAWP. Haematologica. 2009;94:1312-1315.

Fludarabine Based as Conditioning

• Prospective study; n = 38, median age = 20 yr (14-36); median FU = 43 mo• Flu/Cy CSA + MTX; Unmanipulated BM stem cell• aGVHD grade ≥ II 11%; extensive cGVHD 25%• Graft rejection 3% ; D+100 TRM 16%

Al-Zahrani H et al. Biol Blood Marrow Transplant. 2011;17: 717-722.

OS 79% 83%

71%

Alemtuzumab Based as Conditioning

• Fludarabine 30 mg/m2 x 4 days, cyclophosphamide 300 mg/m2 x 4 days, and alemtuzumab median total dose of 60 mg

• Cumulative incidence of graft failure was 9.5%

• Acute GVHD 13.5% and chronic GVHD 4%

• Low incidence of viral infection

Marsh JC et al. Blood2011 ;118(8):2351-7.

Factors influencing OS 2-year OS P value

HSCT comorbidity index

0-1 vs ≥2 92% vs 42% < .001

Age (years)

<50 vs ≥50 92% vs 71% < .001

2 yr OS 95% vs 83%

Bone Marrow Cell Dose, Chronic GVHD and Survival

BM cell dose (×108/kg)

Hazard Ratio P-value

2.3

1

2.4–3.3

3.8 0.06

3.4 7.7 0.004

Quartiles

Variable n Mean S.D. Min .25 Median .75 Max

No chronic GVHD

Cell dose 57 3.02 1.88 0.94 1.90 2.51 3.50 10.75

Chronic GVHD

Cell dose 20 3.72 1.49 2.19 2.52 3.20 4.77 8.07

Deeg HJ. Unpublished data.

BM vs PB Stem Cell Source

Schrezenmeier H et al. Blood 2007;110: 1397-1400.

Chronic GVHD Overall survival

• N = 692 (134 PBPC, 558 BM); HLA-matched siblings • Similar rates of hematopoietic recovery and grades 2 to 4 chronic GVHD• Higher chronic GVHD (RR 2.82; P = .002) and overall mortality (RR 2.04;

P = .024) in patient < 20 years who received PBPC • BM grafts are preferred to PBPC grafts in young patients

BM vs PB Stem Cell Source

Bacigalupo A. Haematologica. 2012. Feb 7.

BMSC Gives Survival Advantage in All Age Group

Bacigalupo A. Haematologica. 2012. Feb 7.

G-CSF stimulated BMSC vs BMSC vs PBSC

• N = ( 78 G-BM, 547 BM, 134 PBPC) • No difference in neutrophil and platelet recovery rate• aGVHD and cGVHD were significantly higher in PBPC

group• aGVHD and cGVHD were similar after G-BM and BM• Mortality risks were lower after transplantation of BM

compared to G-BM (RR = 0.63, P = .05)• No advantage to using G-BM • BM is the preferred graft for HLA-matched sibling

transplants for SAA

Chu R et al. Biol Blood Marrow Transplant. 2011 Jul;17(7):1018-24.

Negative Predictors for HLA identical HSCT in SAA Patients

Bacigalupo A. Haematologica. 2012. Feb 7.

Negative Predictors for HLA identical HSCT in SAA Patients

• Interval ≥114 days

• Age ≥20 years

• Conditioning other than Cy 200

• No ATG in conditioning

Bacigalupo A. Haematologica. 2012. Feb 7.

CSA/MTX vs CSA alone as GVHD Prophylaxis• RCT; N = 71; median age 19 years (4-46) • HLA-identical BMT; Cy 200 mg/kg• Faster median time for neutrophil engraftment

in CSA alone group (12 vs 17 days, p = 0.01)• Better 1 year TRM (3% vs 15%, p = 0.07) and 5

year survival (94% vs 78 %, p = 0.05) in CSA/MTX

Locatelli F et al. Blood 2000; 96: 1690-1697.

Effect of Serial Chimerism in SAA

McCann S et al. Bone Marrow Transplantation (2007) 39, 109–114

• N = 45 (72% Complete donor chimerism, 11% stable mixed chimerism, 17% progressive mixed chimerism)

• The overall 5-year survival probability was 82% with a significant survival advantage (P = 0.0009) in CDC or SMC compared to those with PMC

• Chronic GvHD was more frequent in CDC; no patient with SMC developed cGvHD • Graft failure occurred in 50% of the PMC

Post-Transplantation Cyclophosphamide for GVHD Prophylaxis in SAA

Dezern AE et al. Bone Marrow Transplant. 2011 Jul;46(7):1012-3.

• 2 cases; age 54 and 55 years old• Myeloablative regimen in older, heavily pretreated and transfusion

dependent• Successful engraftment, transfusion independent and no GVHD• Follow up time 12 months

Post-Transplantation Cyclophosphamide for GVHD Prophylaxis in SAA - Thailand

• 25-year-old female; median transfusion 30 unit; Positive for allo Ab• ANC engraftment = 15 days; Platelet engraftment = 24 days• CMV reactivation at D+33• Post HSCT 1 mo = full donor chimerism• Acute skin GVHD gr I well response to steroid• Follow up time 6 months

ATG 2.5 mg/kg/day Cy 50 mg/day

Cy 60 mg/day Unmanipulated BMSC

Issaragrisil S. Unpublished data. 2012

Second HLA-Matched Sibling Transplantion

• N = 166 ( Primary graft failure 16%, secondary graft failure 84%)• Second HLA matched sibling HSCT with 88% use the same donor• BMSC 84%• non-engraftment 43% early 100 day mortality rate 30%• Acute GVHD 9%, Chronic GVHD 16%

Horan JT et al. Biol Blood Marrow Transplant. 2009 ;15(5):626-31.

8 yr OS

2nd HSCT within 3 mo

2nd HSCT after 3 mo

Good PS 56% 76%

Poor PS 33% 61%

HLA Matched Sibling Transplatation in SAA: Comparison for Results in Asia

Study Years NMedian

Age (years)

Median transfusion

unitsConditioning Stem

cellGraft

rejection GVHD Relapse Survival

JapanInamoto

2008

1984-2006 33 24 134 Cy/TLI 85% BMSC 4.1% Acute 23%,

chronic 29% No 81% at 7 yrs

ChinaCheng 2009

2000-2008 20 NA NA Cy/ATG

G-BMSC+ G-PBSC

No Acute 16%, Chronic 36% No 82.5% at

1.5 yrs

TaiwanBai 2004

1985-2001

79(MSD 84%)

22 NA Cy/TBI 3.6% Acute 6.8%, Chronic 35% 3.8% 74% at 5

yrs

KoreaKim 2003

1995-2001 113 28 126 Cy/ATG/PCB PBSC+B

MSC 5.6%Acute gr 2-4

10.5%, Chronic 11.9%

11.5% 89% at 6 yrs

KoreaCho 2010

1999-2007 32 39 146

Cy/ATG/PCB 59%,

Cy/ATG/Flu 31%

PBSC + BMSC No Acute 9.4%,

Chronic 18% NA 87.5% at 5 yrs

KoreaAhn 2003

1990-2001 64 NA NA NA NA 12.5

Acute gr 2-4 31.1%, Chronic

18.8%NA 79% at 6

yrs

ThailandIssaragrisil

2011

1988-2010

32 33 39Cy 91%

Cy/ATG 6%Flu/Cy/ATG 3

PBSC 78%

BMSC 22%

6% Acute 12%Chronic 40% 15% 87% at 5

yrs

Overall survival

83%

Study Years NMedian

Age (years)

Response Relapse Clonal Evolution Survival

Japan 1992-1997 119 9 68% 22% 6% 88% at 3 yrs

KoreaAhn 2005 1999-2001 156 46.8% 7.1% NA 69% at 6 yrs

ChinaZheng 2006 1991-2000 47 35 78.7% NA NA 81% at 5 yrs

Japan Teramura 2007

1996-2000 101 5479% vs 76%

(G-CSF vs no)15% vs

42%15 vs 6%

94% vs 88% at 4 yrs

JapanHattori 2008

1989-1999survey

421 55 54% NA NA 80% at 3 yr

ThailandIssaragrisil 2010

1986-2010 95 38 54% NA NA 60% at 5 yrs

KoreaChang MH 2010 1994-2007 62 49 53% NA No 74.9% at 4 yrs

ChinaWang W 2011

2003-2007 9 35 77.8% NA NA 74% at 5 yrs

Overall survival

Immunosuppressive Therapy in SAA:Comparison for Results in Asia

Conclusion (1)

• HSCT in younger patients give better outcome• HSCT may be performed in patients age 41-50 years with

comparable outcome to those age below 40 years• Early transplant improves survival• Previous IST seems to have less effect on survival• Standard conditioning is high dose cyclophosphamide with or

without ATG• Fludarabine based conditioning gives better outcome in

patients age over 30 years

Conclusion (2)

• Marrow cell dose of 2.1-2.5 x108/kg is most appropriate to be transplanted

• BMT is the standard therapy • PBSC should not be performed because of more incidence of

GVHD and having a neagtive impact on survival and quality of life

• Cyclosporin and short course methotrexate is the standard GVHD prophylaxis

Acknowledgements

• Andrea Bacigalupo• HJ Deeg• Simrit Parmar