Does antithymocyte globulin have a place in reduced-
intensity conditioning for allogeneic hematopoietic stem cell
transplantation?
Tanya Siddiqi1and Didier Blai2
1Department of Hematology/Hematopoietic Cell Transplantation,City of Hope National Medical Center,
Duarte,CA;and2Institut Paoli Calmettes,Departement d’Hematologie Programme de Transplantation
et de Therapie Cellulaire,Marilles,France
A63-year-old male patient without siblings is treated for acute myeloid leukemia with poor prognostic cytogenetics. Despite achieving afirst complete remission,he relapd within thefirst year of diagnosis.He then achieved a cond complete remission.A arch for an HLA-identical unrelated donor identified a10/10possible match.The patient has veral comorbidities(hematopoietic stem cell comorbidity indexϭ3)and it is recommended that he undergo a reduced-intensity conditioning regimen for allogeneic peripheral blood stem cell transplantation.The patient is well-read on allogeneic stem cell
transplantation and asks you the merits of antithymocyte globulin that you propo to include in the conditioning regimen.
Introduction
Reduced-intensity conditioning(RIC)regimens have led to a dramatic reduction of early transplantation mortality after alloge-neic hematopoietic stem cell transplantation(allo-HSCT),thereby allowing patients who are otherwi ineligible for myeloablative conditioning to undergo allo-HSCT.The concept of RIC is to deliver adequate immunosuppression so that there is successful engraftment of donor hematopoietic cells,with manageable graft-versus-host dia(GVHD)and the eventual development of a potent graft-versus-tumor effect.1With this goal in mind,many immunosuppressive strategies have been incorporated into various RIC regimens and studied,but no particular RIC regimen has emerged as the optimal one.Generally,most RIC regimens combine fludarabine with low-do total body irradiation or intermediate dos of alkylating agents.In addition,antithymocyte globulin (ATG)is regularly incorporated to minimize the risk of GVHD. The main mechanism of action of ATG is in vivo T-cell depletion in blood and lymphoid tissues,2,3but it also has other important immunomodulatory effects and is thought to be important in limiting the incidence and verity of GVHD in allo-HSCT while hastening engraftment.However,the effects ca
n potentially lead to rious infections such as CMV and EBV and dia relap.4-6 Indeed in the late1980s,ex vivo or in vivo T-cell depletion of donor graft after myeloablative conditioning led to lower acute GVHD (aGVHD)but higher relap rates compared with T-cell replete transplantations.7Given the various combinations of immunosup-pressive agents ud in RIC regimens,it is unclear whether ATG itlf is responsible for the undesirable effects.At prent,the type,do,and schedule of ATG treatment still need to be more precily defined,and for all of the reasons,the u of ATG in allo-HSCT remains controversial.The scope of this chapter is to review the current place and role of ATG in RIC regimens. Methods
A comprehensive PubMed arch was performed using the terms “ATG”AND“reduced intensity conditioning”as well as“anti-thymocyte globulin”AND“reduced intensity conditioning”and “thymoglobulin”AND“reduced intensity conditioning.“All refer-ences of relevant articles were further scanned to identify studies that should be included in this mini-review.Pediatric and non-human studies have been excluded.Studies pertaining to myelo-ablative conditioning were also excluded.
Results
To date,only a few randomized trials have been reported using ATG in the myeloablative conditioning
tting.8-11The trials showed that ATG-containing regimens lowered the risk of GVHD significantly compared with no ATG,but there was no improve-ment in transplant-related mortality or survival,possibly due to the incread risk of infections or decread dia control.In the RIC tting,however,there are no adequate pha3randomized controlled trials to address the preci role of ATG,which is an authentic weakness.Indeed,to date,a single comparative study of 139patients has partially addresd this question by prospectively comparing2commonly ud RIC regimens with or without ATG.12 Thefirst regimen consisted offludarabine(30mg/m2/d for5days), oral busulfan(4mg/kg/d for2days),and low-do rabbit ATG (rATG;2.5mg/kg on dayϪ1).Cyclosporine alone was adminis-tered for postgraft immunosuppression.The cond regimen in-cludedfludarabine(30mg/m2/d for3days)and2Gy of total body irradiation on day0.Cyclosporine and mycophenolate mofetil were administered for postgraft immunosuppression.In addition to ATG,each strategy obviously differed from the other in terms of myeloablation(intermediate do busulfan vs low-do total body irradiation)and postgraft immunosuppression(cyclosporine alone vs cyclosporine and mycophenolate mofetil).With a median follow-up of5years,overall survival is similar in both arms.The u of low-do of ATG administered on dayϪ1was not associated with higher relap or infectious death rates for either myeloid or lymphoid malignancies.
Champlin et al compared cyclophosphamide alone with cyclophos-phamide plus equine ATG conditioning in a randomized controlled trial and did notfind a difference in outcomes.13However,the study
H EMATOPOIETIC S TEM C ELL T RANSPLANTATION II:T OWARD S AFER A LLOGENEIC T RANSPLANTATION
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246American Society of Hematology
T a b l e 1.S t u d i e s r e p o r t i n g o n A T G i n R I C f o r a l l o -H S C T
S t u d y S t u d y t y p e D i s e a s e t y p e
D i s e a s e s t a t u s a t H S C T A T G s c h e d u l e
N D o n o r t y p e a G V H D c G V H D O u t c o m e s
承德小布达拉宫B l a i s e e t a l 12
R a n d o m i z e d p r o s p e c t i v e p h a s e 2
H e m a t o l o g i c m a l i g n a n c i e s
A r m 1:38%C R /c h r o n i c p h a s e ,50%P R /S D ,12%r e f r a c t o r y d i s e a s e ;a r m 2:36%C R /c h r o n i c p h a s e ,57%P R /S D ,7%r e f r a c t o r y d i s e a s e
r A T G 2.5m g /k g o n d Ϫ3i n a r m 1(F l u /B u /A T G )v s n o A T G i n a r m 2(F l u /T B I )139:69i n a r m 1,70i n a r m 2M a t c h e d r e l a t e d 47%v s 27%(g r a d e I I -I V ,P ϭ.01)47%v s 38%(e c G V H D a t 1y e a r ,P ϭ.155)65%v s 46%o b j e c t i v e r e s p o n s e r a t e (P ϭ.05);27%v s 54%r e l a p s e r a t e (P Ͻ.01);38%v s 22%N R M (P ϭ.027);41%v s 29%5-y O S (n o t s i g n i fic a n t )L o w s k y e t a l 14;H o l b r o o k e t a l 15
P r o s p e c t i v e
M a l i g n a n t l y m p h o i d (n ϭ64)o r m y e l o i d d i s e a s e (n ϭ47)
L y m p h o i d :26.6%C R ,59.4%P R ,14.1%S D o r P D ;m y e l o i d :55.3%C R 1,21.3%C R 2,23.4%ՆC R 2/P R /S D /P D
r A T G ;1.5m g /k g /d o n d Ϫ11t o Ϫ711155%r e l a t e d (98.4%m a t c h e d ,1.6%1-a l l e l e m i s m a t c h e d )a n d 45%u n r e l a t e d (90%m a t c h e d ,10%1-a l l e l e m i s m a t c h e d 2%(r e l
a t e d ),10%(u n r e l a t e d )a t 100d 27%(e c G V H D )a t 3y
4%N R M a t 1y ;60%O S a n d 40%E F S a t 3y ;r e l a p s e 60%a n d d i s e a s e p r o g r e s s i o n 53%a t 4y
S o r m a n i e t a l 17
R e t r o s p e c t i v e ;a b s t r a c t
Ͼ65%p a t i e n t s h a d a d v a n c e d -p h a s e l e u k e m i a
D a t a n o t p r o v i d e d
r A T G ;t o t a l d o s e s ϭ0,7.5,11.25,o r 15m g /k g ;6g r o u p s ϭn o A T G o r l a s t A T G d o s e o n d Ϫ3,Ϫ2,Ϫ1,ϩ1,ϩ7257
U n r e l a t e d o r r e l a t e d m i s m a t c h e d (d i s t r i b u t i o n n o t d e s c r i b e d )
G r a d e I I I -I V a G V H D i n t h e 6g r o u p s r e s p e c t i v e l y ϭ32%,23%,13%,6%,5%,a n d 0%(P Ͻ.00001);o v e r a l l r i s k o f g r a d e I I -I V a G V H D i n A T G p a t i e n t s 0.23(P ϭ.001)I
n t h e 6g r o u p s :61%,46%,25%,29%,23%,a n d 19%,r e s p e c t i v e l y (P ϭ.0005)N o t r e p o r t e d i n a b s t r a c t
B a s h i r e t a l 16
B a y e s i a n a d a p t i v e l y r a n d o m i z e d p r o s p e c t i v e
A M L o r M D S
50%i n C R ,r e s t n o t i n C R r A T G 4.5m g /k g t o t a l d o s e v s 7.5m g /k g t o t a l d o s e e a c h d i v i d e d o v e r d Ϫ3t o Ϫ120:15p a t i e n t s o n l o w -d o s e a r m v s 5p a t i e n t s o n h i g h e r -d o s e a r m U n r e l a t e d (75%m a t c h e d ,25%m i s m a t c h e d )
27%v s 0%r e s p e c t i v e l y (g r a d e I I -I V ;P ϭ.53)
55%v s 50%,r e s p e c t i v e l y (P ϭ.999)
20%v s 60%T R M ,r e s p e c t i v e l y ,a t d 100(P ϭ.131);n o d i f f e r e n c e i n O S (P ϭ.607)o r R F S (P ϭ.607);4r e l a p s e s ,a l l i n l o w -d o s e a r m M i c h a l l e t e t a l 18
P r o s p e c t i v e p h a s e 2H e m a t o l o g i c m a l i g n a n c i e s
A M L :13C R 1,16C R 2;m u l t i p l e m y e l o m a :9P R ;M D S :1C R 1,2P R 2,3S D ,2r e l a p s e d ;C L L :C R ,4P R ;A L L :C R 1,2C R 2;C M L :1C R a f t e r b l a s t c r i s i s r A T G 2.5m g /k g /d o n d Ϫ2a n d Ϫ156M a t c h e d u n r e l a t e d 31%a t 3m o n t h s 34%(l i m i t e d )a n d 8%(e c G V H D )a t 18m o
3-y m e d i a n O S 52%;3-y r e l a p s e 25%;1-a n d 2-y T R M 20%a n d 23%,r e s p e c t i v e l y
L e e e t a l 19P r o s p e c t i v e A M L ,A L L ,M D S
74%s t a n d a r d r i s k (C R 1a c u t e l e u k e m i a s a n d l o w -r i s k M D S ),26%h i g h r i s k
r A T G 3m g /k g /d o n d Ϫ4t o Ϫ2i n 117p a t i e n t s ;h o r s e A T G l y m p h o g l o b u l i n 15m g /k g /d o n s a m e d i n 8p a t i e n t s ;h o r s e A T G (A t g a m )30m g /k g /d o n s a m e d i n 3p a t i e n t s 128
这个冬季U n r e l a t e d (74%m a t c h e d a t a n t i g e n i c l e v e l ,26%m i s m a t c h e d ;b y a l l e l i c m a t c h i n g ,w h i c h w a s n o t a v a i l a b l e f o r 8p a t i e n t -d o n o r p a i r s ,38%w e r e f u l l y m a t c h e d a n d 60%w e r e m i s m a t c h e d )7%33%1-y T R M 14%
Hematology 2012
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T a b l e 1.S t u d i e s r e p o r t i n g o n A T G i n R I C f o r a l l o -H S C T (c o n t i n u e d )
S t u d y S t u d y t y p e D i s e a s e t y p e
D i s e a s e s t a t u s a t H S C T A T G s c h e d u l e
N D o n o r t y p e a G V H D c G V H D O u t c o m e s
B l a i s e e t a l 20R e t r o s p e c t i v e
H e m a t o l o g i c m a l i g n a n c i e s
35%C R 1,9%C R 2,42%S D ,14%p r o g r e s s i o n
r A T G 2.5m g /k g o n d Ϫ3100M a t c h e d r e l a t e d 43%81%N R M 15%a t 1y a n d 25%a t 5y ;r e l a p s e 22%;O S 60%a n d P F S 54%a t 5y M i c h a l l e t e t a l 21R e t r o s p e c t i v e
H e m a t o l o g i c m a l i g n a n c i e s
40%C R ,30%P R ,10%S D ,20%P D r A T G 2.5-12.5m g /k g t o t a l d o s e s d i v i d e d o v e r 1-5d (a c t u a l s c h e d u l e s n o t a v a i l a b l e )1108R I C p a t i e n t s w i t h 465g e t t i n g A T G 84%m a t c h e d r e l a t e d ,9%m a t c h e d u n r e l a t e d ,7%m i s m a t c h e d u n r e l a t e d 38.4%i n l o w -d o s e a r m (2.5m g /k g t o t a l d o s e )v s 15%i n h i g h e r -d o s e a r m (Ͼ5m g /k g t o t a l d o s e )a t 100d (P ϭ.001)60.6%a n d 21%,r e s p e c t i v e l y ,a t 3y (P Ͻ.001)
13.5%T R M a t 1y a n d 15%a t 2y ;42%O S a n d 30%E F S a t 3y ;s u r v i v a l s i g n i fic a n t l y w o r s e w i t h Ͼ10m g /k g A T G a n d b e s t w i t h 5m g /k g d o s e H a m a d a n i e t a l 22R e t r o s p e c t i v e
H e m a t o l o g i c m a l i g n a n c i e s
N o t r e p o r t e d
r A T G 2m g /k g /d o n d Ϫ4t o Ϫ2(l o w -d o s e )v s 2.5m g /k g /d o n t h e s a m e d (h i g h -d o s e )72
L o w -d o s e a r m :9.1%r e l a t e d ,90%/0%u n r e l a t e d ,87%8/8m a t c h ,75%10/10m a t c h ;h i g h -d o s e a r m :12.8%r e l a t e d ,87.2%u n r e l a t e d ,79%8/8m a t c h ,74%10/10m a t c h
27%v s 32%r e s p e c t i v e l y (g r a d e I I -I V ,P ϭ.73)
61%v s 44%,r e s p e c t i v e l y ,a t d 400(P ϭ.09)
C M V r e a c t i v a t i o n 30%v s 64%,r e s p e c t i v e l y (P ϭ.005);b a c t e r i a l i n f e c t i o n s 18%v s 56%,r e s p e c t i v e l y (P ϭ.001);1-y N R M 3%v s 18%,r e s p e c t i v e l y (P ϭ.03);1-y O S 84%v s 64%,r e s p e c t i v e l y (P ϭ.07)
D e v i l l i e r e t a l 23R e t r o s p e c t i v e A M L ,M D S
A M L :80%C R 1,12%C R 2,8%n o C R ;M D S :25%C R ,75%n o C R .r A T G 2.5m g /k g o n d Ϫ3v s 2.5m g /k g /d o n d Ϫ3a n d Ϫ287M a t c h e d r e l a t e d 30.2%v s 8.8%r e s p e c t i v e l y (g r a d e I I -I V ,P ϭ.038)60.4%v s 12%,r e s p e c t i v e l y (e c G V H D ,P Ͻ.001)
1-y N R M 17%v s 19.6%(P ϭ.56);2-y r e l a p s e 18.9%v s 28.5%(P ϭ.64);2-y O S 65.8%v s 59.2%(P ϭ.55);2-y P F S 64.2%v s 47.4%(P ϭ.386)M a l a r d e t a l 24R e t r o s p e c t i v e
L y m p h o i d m a l i g n a n c i e s
36.8%C R ,45.6%P R ,17.6%r e l a p s e /P D r A T G 5m g /k g d i v i d e d o v e r 2d v s n o A T G 6
857%m a t c h e d r e l a t e d ,38%m a t c h e d u n r e l a t e d ,4%m i s m a t c h e d r e l a t e d o r u n r e l a t e d
15%v s 44%(g r a d e I I I -I V ,P ϭ.006)12%v s 58%(e c G V H D ,P ϭ.0003)
2-y T R M 22%v s 41%(P ϭ.09);2-y O S 71%v s 60%(P ϭ.20);2-y P F S 63%v s 52%(P ϭ.18)S o i f f e r e t a l 25
R e t r o s p e c t i v e (C e n t e r f o r I n t e r n a t i o n a l B l o o d a n d M a r r o w T r a n s p l a n t R e s e a r c h )
H e m a t o l o g i c m a l i g n a n c i e s 1/3o f p a t i e n t s i n a l l t r e a t m e n t g r o u p s w e r e i n C R 1
r A T G a t m e d i a n d o s e o f 7m g /k g i n 70%;h o r s e A T G a t m e d i a n d o s e o f 40m g /k g i n 27%;A T G t y p e n o t d o c u m e n t e d i n 3%1676(584g o t A T G )M a t c h e d r e l a t e d ,m a t c h e d o r s i n g l e -l o c u s m i s m a t c h e d u n r e l a t e d
少儿围棋入门
L o w e r i n p a t i e n t s r e c e i v i n g A T G c o m p a r e d w i t h T -c e l l –r e p l e t e r e g i m e n s (P ϭ.03f o r g r a d e I I -I V a G V H D )L o w e r i n p a t i e n t s r e c e i v i n g A T G (40%,P Ͻ.0
01)
3-y N R M (26%)a n d r e l a p s e (49%)h i g h e r (P ϭ.003a n d P Ͻ.0001,r e s p e c t i v e l y )i n p a t i e n t s r e c e i v i n g A T G ;o v e r a l l m o r t a l i t y h i g h e r w i t h A T G (P Ͻ.0001)
C R i n d i c a t e s c o m p l e t e r e m i s s i o n ;P R ,p a r t i a l r e m i s s i o n ;S
D ,s t a b l e d i s e a s e ;P D ,p r o g r e s s i v e d i s e a s e ;F l u ,flu d a r a b i n e ;B u ,b u s u l f a n ;T B I ,t o t a l b o d y i r r a d i a t i o n ;N R M ,n o n r e l a p s e m o r t a l i t y ;O S ,o v e r a l l s u r v i v a l ;P F S ,p r o g r e s s i o n -f r e e s u r v i v a l ;T R M ,t r a n s p l a n t a t i o n -r e l a t e d m o r t a l i t y ;R F S ,r e l a p s e -f r e e s u r v i v a l ;A M L ,a c u t e m y e l o g e n o u s l e u k e m i a ;M D S ,m y e l o d y s p l a s t i c s y n d r o m e ;C L L ,c h r o n i c l y m p h o c y t i c l e u k e m i a ;C M L ,c h r o n i c m y e l o i d l e u k e m i a ;A L L ,a c u t e l y m p h o b l a s t i c l e u k e m i a ;e c G V H D ,e x t e n s i v e c h r o n i c G V H D ;a n d d ,d a y s .
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was clod early and was not adequately powered to detect significant differences between the2trea
tment groups.The remain-ing data evaluating the do,schedule,and outcomes of ATG in RIC come from small pha2or retrospective studies14-25(Table1). With respect to do,the data em to favor an intermediate do of ATG as offering a balance between GVHD prevention and relap incidence in the situation of RIC regimens.For example,Devillier et al23showed in a recent retrospective study that5mg/kg of rATG significantly decread grade II-IV aGVHD and extensive chronic GVHD compared with the2.5mg/kg do.Malard et al,24also in a retrospective study,showed that5mg/kg of rATG significantly reduced grade III-IV aGVHD and extensive chronic GVHD.In another retrospective study,Hamadani et al22showed that6mg/kg of rATG was more effective in decreasing infectious complications and improving nonrelap mortality compared with the7.5mg/kg do,with no difference in GVHD incidence.
Where schedule is concerned,Lowsky et al14in a nonmyelo-ablative conditioning tting using total lymphoid irradiation and rATG,started rATG1.5mg/kg/d11days before graft infusion and continued it for5days.They reported very low aGVHD(2of 37patients)for patients with myeloid and lymphoid malignancies. The results of this study were updated in200915and are shown in Table1.The investigators concluded that it was unlikely that the low incidence of aGVHD could be explained by the persistence of ATG causing in vivo depletion of donor T cells.Biologically active ATG was not det
ectable in the system after dayϩ7of trans-plantation.The more important effect of ATG was thought to be depletion of recipient T cells without depletion of regulatory T cells.Sormani et al17prented an abstract in2007describing 257patients undergoing allo-HSCT.The do of ATG varied from7.5mg/kg(nϭ62),11.25mg/kg(nϭ44),and15mg/kg (nϭ83).Sixty-eight patients received no ATG,17received the last do of ATG on dayϪ3,90patients on dayϪ2,32patients on dayϪ1,19patients on dayϩ1,and31patients on dayϩ7.In the 6groups,grade III-IV aGVHD occurred in32%,23%,13%,6%, 5%,and0%of patients,respectively.Chronic GVHD(cGVHD) occurred in61%,46%,25%,29%,23%,and19%respectively. Patients receiving ATG had a significantly lower risk of developing aGVHD(Pϭ.001).Timing and do of ATG were significant predictors of GVHD,and the investigators concluded that it may be uful to u small dos of ATG clo to transplantation. Most studies have indeed ud ATG in the immediate vicinity of graft infusion.
The paucity of randomized prospective trials limits the value of all of the data.In fact,they are challenged by the results from a large retrospective Center for International Blood and Marrow Transplant Rearch study by Soiffer et al.25Seventy percent of patients had acute myeloid leukemia,myelodysplastic syndrome, and non-Hodgkin lymphoma.A total of797patients(48%)received anti–T-cell antibodies:584(35%)received ATG,and213(13%) received al
emtuzumab.Eight hundred venty-nine(52%)received no in vivo T-cell depletion.For patients receiving ATG,approxi-mately70%received rATG at a median do of7mg/kg and 27%received hor ATG(hATG)at a median do of40mg/kg. The type of ATG was not reported in3%of patients.Compared with T cell–replete regimens,there were no differences in grades II-IV and III-IV aGVHD with ATG-containing regimens overall,al-though grade II-IV(Pϭ.03)and grade III-IV(Pϭ.01)aGVHD rates were lower in patients receiving rATG compared with tho receiving hATG.The rate of cGVHD was lower with all ATG-containing regimens(PϽ.001).Compared with T cell–replete regimens,3-year nonrelap mortality was higher(Pϭ.003),as was the3-year relap rate(PϽ.0001),with ATG-bad RIC. Nonrelap mortality was lower(Pϭ.004)and relap risk was higher(Pϭ.02)after rATG compared with tho receiving hATG. Dia-free survival was lower in T-cell–depleted patients,and there was no difference in the rATG versus the hATG groups or in the lower-do(Ͻ7mg/kg of rATG orϽ40mg of hATG)versus higher-do(Ն7mg/kg of rATG vsՆ40mg of hATG)ATG groups.The3-year overall survival was lower in ATG-containing regimens compared with the T-cell–replete regimens(38%vs 46%,Pϭ.008).Results appeared to be similar to the above analysis for transplantations performed from HLA-matched siblings or unrelated donors except that ATG emed to be less effective in reducing aGVHD in the unrelated donor tting compared with the related donor tting.Overall,the results suggested that the u of in vivo T-cell depletion with
RIC regimens reduces cGVHD but significantly increas the likelihood of dia relap,which negatively affects dia-free survival after both related and unrelated donor allo-HSCT.Once again,the retrospective nature of the study limits definitive conclusions and emphasizes the need for future prospective evaluations.
Conclusions
Bad on this review,and despite the limitations of existing data,we conclude that ATG may reduce GVHD in patients with hematologi-cal malignancies undergoing RIC for allo-HSCT.The do and timing of ATG em to be important.Low dos(Ͻ3mg/kg) appear not to curb GVHD adequately and high dos(Ͼ7mg/kg) em to be associated with unacceptable incidence of infection and relap,the latter occurring despite(or becau of)a major reduction in GVHD incidence.Intermediate dos of rATG are able to efficiently decrea the incidence of both aGVHD and cGVHD and to limit infectious complications.Bad on the data reviewed herein,we suggest that a do of4.5-6mg/kg of rATG administered on the last few days before transplantation is the best schedule to incorporate ATG into a RIC regimen(grade2C),and this do should be ud in future prospective evaluations to confirm the potential benefit of rATG in RIC regimens for GVHD. Disclosures
Conflict-of-interest disclosure:The authors declare no competing financial interests.Off-label drug u:None disclod. Correspondence
Tanya Siddiqi,Department of Hematology/Hematopoietic Cell Trans-plantation,City of Hope National Medical Center,1500E Duarte Rd, Duarte,CA91010;Phone:626-256-4673;Fax:626-301-8256;e-mail:
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250American Society of Hematology
