Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA Matched Cadaveric Donors (RTB-003)
Phase: PHASE1
Conditions: Primary Immunodeficiency, PID
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
BIL A T E R AL O R T H O T O PI C L U N G T R A N S PL A N T I N T A N D E M WI T H C D 3 + A N D C D 1 9 + C ELL 
D E PL E T E D B O N E M A R R O W T R A N S PL A N T F R O M P A R TI ALL Y HL A -M A T C H E D C A D A V E RI C 
D O N O R S  
P R O T O C O L R T B -0 0 3  
V er si o n 8. 0 /  J a n u ar y 15 , 2 0 2 1  
St u d y S p o n s or( s):  
 
 
 
N ati o n al I n stit ut e of All er g y a n d I nf e cti o u s Di s e as e s 
NI AI D F u n di n g M e c h a nis m:   
 
U 0 1 AI 1 2 5 0 5 0 -0 1  
 
I N D S p o n s or / N u m b er :  
 
 
NI AI D / 1 7 4 9 7  
 
P RI N CI P AL IN V E S TI G A T O R / P R O T O C OL C H AI R   
P a ul Sz a b olcs, M D  
C hi ef, Divisi o n of Bl o o d a n d M arr o w 
Tr a ns pl a nt a n d C ell ul ar T h er a pi es  
C hil dr e n’s H os pit al of Pitts b ur g h of U P M C  
O n e C hil dr e n’s H os pit al Driv e  
4 4 0 1 P e n n Av e n u e,  
R a n g os B uil di n g, 5 t h Fl o or  
Pitts b ur g h, P A  
 
 
 
 
 C O -P RI N CI P AL IN V E S TI G A T O R  
J o h n Mc D y er, M D 
Divisi o n of P ul m o n ar y, All er g y, a n d Critic al 
C ar e M e dici n e  
U niv ersity of Pitts b ur g h M e dic al C e nt er  
C o m pr e h e nsiv e L u n g C e nt er  
3 6 0 1 Fift h Av e n u e, 4 t h Fl o or  
Pitts b ur g h, P A 1 5 2 1 3  
 
 
 
NI AI D  M E DI C AL O F FI C E R   
 
  
 
 
5 6 0 1 Fis h ers L a n e, R o o m 6 B  
R oc kvill e, M D 2 0 8 5 2  
 
 
 
 
B I O S T A TI S TI CI A N 
 
 
U P M C Hill m a n C a nc er C e nt er  
S uit e 3 2 5 St erli n g Pl az a  
2 0 1 N ort h Cr ai g Str e et  
Pitts b ur g h, P A 1 5 2 1 3  
 
 
 
NI AI D  P R OJ E C T M A N A G E R  
 
 
 
5 6 0 1 Fis h ers L a n e, R o o m 6 B 2 7  
R oc kvill e, M D 2 0 8 5 2  
 
 
 
 
 
NI AI D  R E G UL A T O R Y O FFI C E R 
 
 
 
 
5 6 0 1 Fis h ers L a n e  
R oc kvill e, M D 2 0 8 5 2  
 
 
 
C o nfi d e nti ality St at e m e nt  
T h e i nf or m ati o n c o nt ai n e d wit hi n t his d oc u m e nt is n ot t o b e discl os e d i n a n y w ay wit h o ut t h e pri or p er missi o n of t h e Pr ot oc ol C h air, or 
th e  Divisi o n of All er g y, I m m u n ol o g y a n d Tr a ns pl a nt ati o n, N ati o n al I nstit ut e of All er g y a n d I nf ecti o us Dis e as es of t h e N ati o n al I nstit ut es of 
H e alt h.  
  
                                                  

 
C o nfi d e nti al  
P a g e 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
Pr ot oc ol S y n o psis  
Titl e  
Bil at er al Ort h ot o pic L u n g Tr a ns pl a nt i n T a n d e m wit h C D 3 + a n d C D 1 9 + C ell 
D e pl et e d B o n e M arr o w Tr a ns pl a nt fr o m P arti ally HL A -M atc h e d C a d av eric 
D o n ors  
S h ort Titl e  
B OL T -B M T  
Cli nic al P h as e  
P h as e I /II 
N u m b er of Sit es  
Si n gl e c e nt er st u d y   
I N D S p o ns or/N u m b er  
NI AI D / 1 7 4 9 7  
Pri m ar y O bj ecti v e s 
T h e pri m ar y o bj ectiv e s ar e  t o e v al u at e t h e s af ety a n d effic ac y of 
p erf or mi n g bil at er al ort h ot o pic l u n g tr a ns pl a nt ati o n f oll o w e d b y 
c a d av eric, p arti ally HL A-m atc h e d  (≥2/ 6 HL A -m atc h wit h a n i d e ntic al A B O 
bl o o d ty p e) C D 3 +/ C D 1 9 + d e pl et e d b o n e m arr o w tr a ns pl a nt f or p ati e nts 
wit h pri m ar y i m m u n o d efici e nc y a n d e n d -st a g e l u n g dis e as e. 
S ec o n d ar y O bj ecti v es  
T h e s ec o n d ar y o bj ectiv es ar e t o  e v al u at e t h e f e asi bility a n d l o n g -t er m 
c o m plic ati o ns ass oci at e d wit h c o m bi n e d s oli d or g a n a n d B M T i ncl u di n g 
t h e a bilit y t o i niti at e a n d s ucc essf ully wit h dr a w s u bj ects fr o m 
i m m u n os u p pr essi o n f oll o wi n g B M T a n d t o att ai n i n d e p e n d e nc e fr o m 
tr e at m e nt d os e a nti micr o bi al dr u gs.   
St u d y D esi g n  
T his is a si n gl e c e nt er, P h as e I/II st u d y i n w hic h s u bj ects r ec ei v e a 
c a d av eric, p arti ally HL A-m atc h e d l u n g tr a ns pl a nt f oll o w e d b y a 
C D 3 +/ C D 1 9 + d e pl et e d b o n e m arr o w tr a ns pl a nt fr o m t h e s a m e d o n or.  
Pri m ar y E n d p oi nt s 
S af et y E n d p oi nt  
S af ety will b e d et er mi n e d b y ass essi n g t h e pr es e nc e or a bs e nc e  of  t h e 
f oll o wi n g a d v ers e e v e nts d uri n g t h e st u d y p eri o d ( u p t o 2 y e ars p ost -
B M T) :  
•  
D e at h  
•  
E n gr aft m e nt s y n dr o m e  
•  
E n gr aft m e nt f ail ur e  
•  
Gr a d e 4 or 5 e v e nts p ot e nti ally attri b ut a bl e t o Rit u xi m a b  
Effi c ac y E n d p oi nts (s u bj ects w h o r ec ei v e b ot h B OL T a n d B M T) 
•  
B O S at 1 -y e ar p ost B OL T; s u p pl e m e nt al oxy g e n r e q uir e m e nt a n d/ or 
v e ntil at or y s u p p ort ( n o ni n v asiv e/i n v asiv e) at 1 -y e ar p ost B OL T  
•  
≥ 2 5 % d o n or T -c ell c hi m eris m at 1 2 m o nt hs p ost B M T.  
•  
F or s u bj ects wit h m y el oi d dis or d ers ( e. g. C G D),  att ai ni n g  ≥ 1 0 % 
m y el oi d c hi m eris m at 1 2 m o nt hs  p ost B M T . 
•  
F or s u bj ects wit h B -c ell dis or d ers, att ai ni n g  ≥ 1 0 % B -c ell c hi m eris m at 
1 2 m o nt hs  p ost B M T .  
S ec o n d ar y E n d p oi nt s 
S ec o n d ar y E n d p oi nts  ( all e nr oll e d s u bj ects, as a p plic a bl e) 
T h e f oll o wi n g s ec o n d ar y e n d p oi nts will b e ass ess e d:  

 
C o nfi d e nti al  
P a g e 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
•  
F e asi bility of pr oc e e di n g t o B M T wit hi n 6 m o nt hs f oll o wi n g l u n g 
tr a ns pl a nt ati o n. 
•  
D e v el o p m e nt of t ol er a nc e t o b ot h t h e h ost a n d p ul m o n ar y gr aft.  
•  
Lo n g -t er m c o m plic ati o ns of c o m bi n e d s oli d or g a n a n d B M T . 
•  
Inci d e nc e of ac ut e c ell ul ar r ej ecti o n a n d gr aft f ail ur e p ost B M T.  
•  
Inci d e nc e of ac ut e a n d c hr o nic gr aft -v ers us -h ost dis e as e ( G V H D) 
f oll o wi n g t a n d e m l u n g a n d B M T . 
•  
I niti ati o n w e a ni n g of i m m u n os u p pr essi o n b y 1 y e ar f oll o wi n g B M T . 
•  
Ti m e fr o m B M T t o wit h dr a w al of i m m u n os u p pr essi o n.  
•  
Ti m e fr o m B M T t o i n d e p e n d e nc e fr o m tr e at m e nt d os e a nti micr o bi al 
dr u gs.  
•  
F or T c ell ly m p h o p e ni as, ac hi e vi n g a g e a dj ust e d, l o w li mit n or m al 
r a n g e ly m p h oc yt e c o u nt b y 1-y e ar p ost -B M T.  
•  
A si g nific a nt d e v el o p m e nt i n c hr o nic l u n g all o gr aft d ysf u ncti o n ( as 
e vi d e nc e d b y a c h a n g e i n B O S st a g e, s e e p g. 1 9 f or B O S t a bl e) or 
all o gr aft f ail ur e at 1 -y e ar  a n d u p t o 2 y e ars  p ost l u n g tr a ns pl a nt f or 
B OL T al o n e a n d B OL T -B M T s u bj ects .  
•  
I nci d e nc e of Gr a d e 4 or 5 a d v ers e e v e nts p ossi bly r el at e d t o t h e us e 
of Rit uxi m a b pri or t o t h e st art of B M T c o n diti o ni n g.  
M ec h a nistic E n d p oi nts  
T h e f oll o wi n g m ec h a nistic o bj ectiv es will b e e v al u at e d:  
•  
T h e p ac e of i m m u n e r ec o nstit uti o n as w ell as t h e i nci d e nc e a n d 
d e gr e e of mix e d d o n or c hi m eris m will b e e v al u at e d.  
•  
T h e i nci d e nc e of mix e d c hi m eris m (> 5 % h ost c ells) at M o nt hs 1, 3, 6 , 
1 2 a n d 2 4 m o nt hs  p ost B M T.  
•  
I m pr o v e m e nt i n i m m u n ol o gic m ar k er(s) u ni q u e f or t h e u n d erlyi n g 
PI D s y n dr o m e b y o n e y e ar p ost B M T (s e e A p p e n dix 5).  
Accr u al O bj ecti v e  
U p t o 3 0 s u bj ects will b e c o ns e nt e d i n or d er t o e nr oll 8  s u bj ects w h o 
r ec eiv e b ot h B OL T a n d B M T . 
St u d y D ur ati o n  
T ot al of 5  Y e ars ( 4 -y e ar  accr u al + 1 -y e ar mi ni m u m  ( u p t o 2 y e ars) f oll o w-
u p p ost -B M T ).  
Tr e at m e nt D escri pti o n   
S u bj ects will u n d er g o B M T  utilizi n g C D 3 +/ C D 1 9 + -d e pl et e d b o n e m arr o w  
wit h c o n diti o ni n g b e gi n ni n g  n o l ess t h a n 8 w e e ks aft er B OL T.  
C o n diti o ni n g r e gi m e n will b e as f oll o ws:  
•  
D ay -2 8  t o -3: H y dr oxy ur e a  
•  
D ay -2 8 , D ay + 3 5: Rit u xi m a b 
•  
Al e mt uz u m a b:  
o  
D ay -2 1, D ay -2 0 : Su bj ects wit h pri or A C R  ≥ A 2 a n d/ or ≥B 2 R  
(s e e s ecti o n 7. 2. 3 f or f urt h er d et ails) will r ec ei v e t w o d os es 
of Al e mt uz u m a b O R  
o  
D ay -1 4 : S u bj ects wit h o ut  pri or A C R  (s e e s ecti o n 7. 2. 3 f or 
f urt h er d et ails) will r ec ei v e a si n gl e d os e of Al e mt uz u m a b  
•  
D ay -3  t o -1 : A T G A M 
•  
D ay -2: T hi ot e p a  

 
C o nfi d e nti al  
P a g e 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
•  
D ay -1: T BI 2 5 0 c Gy ( 2 0 0c Gy f or r a di os e nsitiv e s u bj ects) wit h l u n g 
s hi el di n g. L u n g s hi el di n g will n ot b e c o m pl et e d f or s u bj ects wit h 
pr e vi o us A C R of ≥ A 2 a n d/ or ≥B 2 R. A d diti o n a l or g a n s hi el di n g f or 
f ertility pr es er v ati o n will b e all o w e d b as e d u p o n t h e i n v esti g at or’s 
discr eti o n.   
I ncl usi o n Crit eri a: St u d y E ntr y a n d 
L u n g Tr a ns pl a nt 
I n divi d u als m ust m e et all of t h e f oll o wi n g crit eri a i n or d er t o b e eli gi bl e 
f or t his st u d y.  
1.  S u bj ect a n d/ or p ar e nt g u ar di a n m ust b e a bl e t o u n d erst a n d a n d 
pr o vi d e i nf or m e d c o ns e nt.  
2.  M al e or f e m al e, 1 0  t hr o u g h 4 5 y e ars ol d, i ncl usiv e, at t h e ti m e of 
i nf or m e d c o ns e nt. 
3.  M e et crit eri a f or U N O S listi n g.  
4.  P ati e nts m ust h av e e vi d e nc e of a n u n d erlyi n g pri m a r y 
i m m u n o d efici e nc y f or w hic h B M T is cli nic ally i n dic at e d.  
Ex a m pl es of s uc h dis e as es i ncl u d e, b ut ar e n ot li mit e d t o:  
•  
S e v er e C o m bi n e d I m m u n o d efici e nc y  
•  
C o m bi n e d i m m u n o d efici e nc y wit h d ef ects i n T -c ell-
m e di at e d i m m u nity, i ncl u di n g O m e n n s y n dr o m e a n d 
Di G e or g e Sy n dr o m e  
•  
S e v er e C hr o nic N e utr o p e ni a  
•  
C hr o nic Gr a n ul o m at o us Dis e as e  
•  
H y p er I g E Sy n dr o m e or J o b Sy n dr o m e  
•  
C D 4 0 or C D 4 0L d efici e nc y  
•  
Wis k ott -Al dric h Sy n dr o m e  
•  
M e n d eli a n S usc e pti bility t o Myc o b act eri al Dis e as e [ 6]  
•  
G A T A 2  Ass oci at e d I m m u n o d efici e nc y  
N O T E: A g e n etic  di a g n osis is r ec o m m e n d e d, b ut n ot r e q uir e d.  
5.  P ati e nts m ust h av e e vi d e nc e of e n d -st a g e l u n g dis e as e a n d b e 
c a n di d at es f or bil at er al ort h ot o pic l u n g tr a ns pl a nt as d et er mi n e d b y 
t h e l u n g tr a ns pl a nt t e a m. 
6.  G F R ≥5 0 mL/ mi n/ 1. 7 3 m 2.  
7.  A S T, AL T ≤4x u p p er li mit of n or m al, t ot al bilir u bi n ≤ 2. 5 m g/ dL, 
n or m al I N R.  
8.  C ar di ac ej ecti o n fr acti o n ≥ 4 0 % or s h ort e ni n g fr acti o n ≥2 6 %.  
9.  N e g ativ e pr e g n a nc y t est f or f e m al es > 1 0 y e ars ol d or w h o h av e 
r e ac h e d m e n arc h e, u nl ess s ur gic ally st eriliz e d. 
1 0.  All f e m al es of c hil d b e ari n g p ot e nti al a n d s ex u ally activ e m al es m ust 
a gr e e t o us e a F D A a p pr o v e d m et h o d of birt h c o ntr ol f or u p t o 2 4 
m o nt hs aft er B M T or f or as l o n g as t h e y ar e t a ki n g a n y m e dic ati o n 
t h at m ay h ar m a pr e g n a nc y, a n u n b or n c hil d or m a y c a us e birt h 
d ef ect.  
1 1.  S u bj ect a n d/ or p ar e nt g u ar di a n will als o b e c o u ns el e d r e g ar di n g t h e 
p ot e nti al ris ks of i nf ertility f oll o wi n g B M T a n d a d vis e d t o disc uss 
s p er m b a n ki n g or o oc yt e h ar v esti n g.  

 
C o nfi d e nti al  
P a g e 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
E xcl usi o n Crit eri a : St u d y E ntr y a n d 
L u n g Tr a ns pl a nt 
I n divi d u als w h o m e et a n y of t h es e crit eri a ar e n ot eli gi bl e f or t his st u d y:  
1.  I n a bility or u n willi n g n ess of a p artici p a nt t o giv e writt e n i nf or m e d 
c o ns e nt or c o m ply wit h st u d y pr ot oc ol.  
2.  P ati e nts w h o h av e u n d erlyi n g m ali g n a nt c o n diti o ns.  
3.  P ati e nts w h o h av e n o n -m ali g n a nt c o n diti o ns n ot r e q uiri n g 
h e m at o p oi etic st e m c ell tr a ns pl a nt ati o n.  
4.  HI V p ositiv e b y s er ol o g y or P C R, H TL V p ositiv e b y s er ol o g y.  
5.  F e m al es w h o ar e pr e g n a nt or w h o ar e l act ati n g.  
6.  All er g y t o D M S O or a n y ot h er i n gr e di e nt us e d i n t h e m a n uf act uri n g 
of t h e st e m c ell pr o d uct.  
7.  U nc o ntr oll e d p ul m o n ar y i nf ecti o n, as d et er mi n e d b y r a di o gr a p hic 
fi n di n gs a n d/ or si g nific a nt cli nic al d et eri or ati o n.  N O T E: P ul m o n ar y 
c ol o niz ati o n wit h m ulti pl e or g a nis ms is c o m m o n a n d will n ot b e 
c o nsi d er e d a n excl usi o n crit eri o n.  
8.  U nc o ntr oll e d s yst e mic i nf ecti o n, as d et er mi n e d b y t h e a p pr o pri at e 
c o nfir m at or y t esti n g e. g.  bl o o d c ult ur es, P C R t esti n g, etc.   
9.  R ec e nt r eci pi e nt of a n y lic e ns e d or i n v esti g ati o n al liv e att e n u at e d 
v acci n e(s) wit hi n 4 w e e ks of tr a ns pl a nt.  
1 0.  P ast or c urr e nt m e dic al pr o bl e ms or fi n di n gs fr o m p h ysic al 
ex a mi n ati o n or l a b or at or y t esti n g t h at ar e n ot list e d a b ov e, w hic h, i n 
t h e o pi ni o n of t h e i n v esti g at or, m ay p os e a d diti o n al ris ks fr o m 
p artici p ati o n i n t h e st u d y, m ay i nt erf er e wit h t h e p artici p a nt’s a bility 
t o c o m ply wit h st u d y r e q uir e m e nts or t h at m ay i m p act t h e q u ality or 
i nt er pr et ati o n of t h e d at a o bt ai n e d fr o m t h e st u d y. 
Eli gi bilit y: D o n or  
D o n or m ust b e a ≥2/ 6 ( A, B, D R) HL A -m atc h e d c a d av eric or g a n d o n or 
wit h a n i d e ntic al A B O bl o o d ty p e as t h e r eci pi e nt.  
Eli gi bilit y: B o n e M arr o w Tr a ns pl a nt  
T h e d ecisi o n t o pr oc e e d wit h t h e B M T  will b e at t h e discr eti o n of t h e l u n g 
tr a ns pl a nt t e a m f oll o wi n g cl e ar a nc e b y t h e b o n e m arr o w t e a m b as e d o n 
t h e crit eri a b el o w. T h e c o n diti o ni n g f or t h e B M T  will b e gi n n o l ess t h a n 8 
w e e ks f oll o wi n g t h e  l u n g tr a ns pl a nt.  
1.  G F R > 5 0 mL/ mi n/ 1. 7 3 m 2. 
2.  A S T, AL T < 4x u p p er li mit of n or m al, T ot al bilir u bi n < 2. 5 m g/ dL.  
3.  C ar di ac ej ecti o n fr acti o n ≥ 4 0 % or s h ort e ni n g fr acti o n of at l e ast 2 6 %.  
4.  F V C a n d F E V 1 ≥4 0 % pr e dict e d f or a g e a n d S p O 2 of > 9 0 % at r est o n 
r o o m air A N D wit h cl e ar a nc e b y t h e l u n g tr a ns pl a nt t e a m.  
5.  HI V n e g ativ e b y s er ol o g y a n d P C R.  
6.  H TL V s er ol o g y n e g ativ e.  
7.  A bs e nc e of u nc o ntr oll e d i nf ecti o n as d et er mi n e d b y p ositi v e bl o o d 
c ult ur es a n d r a di o gr a p hic pr o gr essi o n of pr e vi o us sit es i n p artic ul ar 
p ul m o n ar y d e nsit i es d uri n g t h e p ast 2  w e e ks pri or t o c h e m ot h er a p y.  
8.  A bs e nc e of cli nic ally si g nific a nt ac ut e c ell ul ar r ej ecti o n ( < A 2 -A 4 
a n d/ or B 2 R r ej ecti o n).  
9.  B o n e m arr o w pr oc essi n g (s ecti o n 6. 1. 2) h as b e e n c o m pl et e d, a n d a n 
a p pr o pri at e st e m c ell pr o d uct is av ail a bl e f or a d mi nistr ati o n (s ecti o n 
6. 1. 3).  
1 0.  A n y m e dic al iss u e or fi n di n g n ot list e d a b ov e, w hic h, i n t h e o pi ni o n of 
t h e i n v esti g at or, m ay p os e a d diti o n al ris ks fr o m p artici p ati o n i n t h e 

 
C o nfi d e nti al  
P a g e 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
st u d y, m ay i nt erf er e wit h t h e p artici p a nt’s a bility t o c o m ply wit h 
st u d y r e q uir e m e nts or t h at m ay i m p act t h e q u alit y or i nt er pr et ati o n 
of t h e d at a o bt ai n e d fr o m t h e st u d y.                
St u d y St o p pi n g R ul es  
A. T e m p or ar y S us p e nsi o n of E nr oll m e nt  
If a n y gr a d e 4 or 5 a d v ers e e v e nts t h at ar e at l e ast p ossi bly r el at e d t o t h e 
us e of r it uxi m a b pri or t o B M T, occ ur i n at l e ast 2 s u bj ects , a s af ety-r el at e d 
s us p e nsi o n of e nr oll m e nt 
will occ ur p e n di n g n otific ati o n t o t h e 
I nstit uti o n al R e vi e w B o ar d (I R B) a n d a n  ex p e dit e d r e vi e w of all p erti n e nt 
d at a b y t h e N ati o n al I nstit ut e of All er g y a n d I nf ecti o us  Dis e as es ( NI AI D)  
M e dic al M o nit or  a n d t h e NI AI D D at a S af ety M o nit ori n g B o ar d ( D S M B) .  
 
B. T e m p or ar y S us p e nsi o n of E nr oll m e nt a n d B M T  
If a n y of t h e f oll o wi n g occ ur i n t h e first 1 0 0 d ays p ost-B M T a m o n g t h e first 
t hr e e s u bj ects r ec eivi n g B M T, a s af ety-r el at e d s us p e nsi o n of e nr oll m e nt or 
pr oc e e di n g t o B M T will b e i niti at e d  p e n di n g  n otific ati o n t o t h e I R B a n d  a n 
ex p e dit e d r e vi e w of all p erti n e nt d at a b y t h e NI AI D M e dic al M o nit or  a n d 
t h e NI AI D D S M B . 
•  
D e at h  
•  
R es pir at or y f ail ur e as a r es ult of r ej ecti o n or i nf ecti o n r e q uiri n g 
m ec h a nic al v e ntil ati o n f or m or e t h a n 4 8 h o urs.  
•  
E n gr aft m e nt s y n dr o m e  
C. St u d y St o p pi n g R ul e  
T h e i nci d e nc e of s p ecific e v e nts 
will b e c o nti n u o usly 
m o nit or e d 
t hr o u g h o ut t h e st u d y t o d et er mi ne if a n y of t h eir o bs er v e d s u bj ect -b as e d 
i nci d e nc e r at es exc e e d a t hr es h ol d i nci d e nc e r at e. T his st o p pi n g r ul e will 
b e tri g g er e d if 2 of 2 p ati e nts, 3 or m or e of 5 p ati e nts, or 4 or m or e of 8 
p ati e nts  ex p eri e nc e o n e of t h e  f oll o wi n g s e nti n el cli nic al e v e nts. 
•  
D e at h  
•  
R es pir at or y f ail ur e as a r es ult of r ej ecti o n or i nf ecti o n r e q uiri n g 
m ec h a nic al v e ntil ati o n f or m or e t h a n 4 8 h o urs  
•  
Hi g h gr a d e ( gr a d e ≥A 3) p ersist e nt  or hi g h gr a d e  r ec urr e nt ac ut e 
l u n g r ej ecti o n p ost B M T  (i ncl u di n g p ost i m m u n os u p pr essi o n 
wit h dr a w al)   
•  
Gr a d e 4 or gr e at er l u n g i nf ecti o n p ost B M T  
•  
E n gr aft m e nt f ail ur e/f ail ur e t o ac hi e v e c hi m eris m ( < 5 % d o n or 
c ells at d ay 1 0 0 f oll o wi n g B M T, or < 1 0 % d o n or c ells at d ay 1 8 0)  
•  
E n gr aft m e nt s y n dr o m e  
 
If a st o p pi n g t hr es h ol d is m et, e nr oll m e nt a n d pr oc e e di n g t o B M T will b e 
h alt e d p e n di n g ex p e dit e d  NI AI D  D S M B r e vi e w . 

 
C o nfi d e nti al  
P a g e 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
St u d y C o nt acts: P artici p ati n g C e nt ers  
 
P RI N CI P AL IN V E S TI G A T O R  
P A UL S Z A B OL C S , M D  
C hi ef, Di visi o n of Bl o o d a n d M arr o w 
Tr a ns pl a nt a n d C ell ul ar T h er a pi es  
C hil dr e n’s H os pit al of Pitts b ur g h of 
U P M C  
O n e C hil dr e n’s H os pit al Dri v e  
4 4 0 1 P e n n Av e n u e,  
R a n g os B uil di n g, 5 t h Fl o or  
Pitts b ur g h, P A  

 
C o nfi d e nti al  
P a g e 9  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
St u d y C o nt acts: L a b or at ori es   
 
 
 
U P M C  H E M A T O P OI E TI C S T E M C ELL 
L A B O R A T O R Y 
 
Sc h o ol of M e dici n e a n d D e p art m e nt  
of I nf ecti o us Dis e as es a n d 
Micr o bi ol o g y  
Hill m a n C a nc er C e nt er  
5 1 1 7 C e ntr e Av e n u e, S uit e 4. 2 4c  
Pitts b ur g h, P A  1 5 2 1 3  
 
 
C HI M E RI S M S T U DI E S A N D T OL E R A N C E 
A S S A YS 
 
T h e C hil dr e n’s H os pit al of Pitts b ur g h  
R a n g os R es e arc h C e nt er, FL 5, B a y 1 1  
5 3 0 4 5t h St.  
Pitts b ur g h P A 1 5 2 2 4  
 
 
 
 
 
P A T H O G E N S P E CIFI C AS S A YS  
R N A  S E Q U E N CI N G  
 
 
T h e U niv ersit y  of Pitts b ur g h  
Bi o m e dic al Sci e nc es T o w er 1  
R o o m W 1 2 0 0 -2 1 A  
Pitts b ur g h , P A 1 5 2 1 3  
 
 
 

 
C o nfi d e nti al  
P a g e 1 0  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
T a bl e of C o nt e nts  
P R O T O C OL R T B -0 0 3  ....................................................................................................................................... 1  
Pr ot oc ol S y n o psis  .......................................................................................................................................... 3  
St u d y C o nt acts: P artici p ati n g C e nt ers  .......................................................................................................... 8  
St u d y C o nt acts: L a b or at o ri es ........................................................................................................................ 9  
Gl oss ary of A b br e vi ati o ns  ............................................................................................................................ 1 6  
St u dy D efi niti o ns P a g e  ................................................................................................................................. 1 9  
1  
St u dy Hy p ot h es es/ O bj ecti v es  .............................................................................................................. 2 1  
1. 1  
Hy p ot h es es  .................................................................................................................................. 2 1  
1. 2  
Pri m ary O bj ecti v e  ........................................................................................................................ 2 1  
1. 3  
S ec o n d ary O bj ecti v es  .................................................................................................................. 2 1  
1. 4  
M ec h a nistic O bj ecti v es  ................................................................................................................ 2 1  
2  
B ac k gr o u n d a n d R ati o n al e  ................................................................................................................... 2 2  
2. 1  
B ac k gr o u n d a n d Sci e ntific R ati o n al e  ........................................................................................... 2 2  
2. 2  
R ati o n al e f or S el ecti o n of I nv esti g ati o n al Pr o d uct or I nt er v e nti o n  ............................................ 2 2  
2. 3  
Cli nic al St u di es  ............................................................................................................................. 2 3  
 
Pr e vi o us Ex p eri e nc e wit h B OL T a n d B M T  ............................................................................ 2 3  
 
Ex p eri e nc e wit h R e d uc e d -I nt e nsit y C o n diti o ni n g i n Pri m ary I m m u n o d efici e nc y ............... 2 5  
 
W orl d wi d e Ex p eri e nc e wit h B o n e M arr o w Tr a ns pl a nt HL A -Mis m atc h e d at 3 or M or e L oci
 
2 5  
 
I n d ucti o n of T ol er a nc e wit h S oli d Or g a n a n d B o n e M arr o w Tr a ns pl a nt ............................ 2 5  
 
I nstit uti o n al Ex p eri e nc e wit h t h e Cli ni M A C S ® d e vic e ......................................................... 2 6  
 
W orl d wi d e Ex p eri e nc e wit h C D 3/ C D 1 9 D e pl eti o n  .............................................................. 2 6  
3  
St u dy D esi g n  ........................................................................................................................................ 2 8  
3. 1  
D escri pti o n of St u dy D esi g n  ......................................................................................................... 2 8  
3. 2  
Pri m ary E n d p oi nts  ....................................................................................................................... 3 0  
 
S af et y E n d p oi nt  .................................................................................................................... 3 0  
 
Effic ac y E n d p oi nts ( all s u bj ects w h o r ec ei v e d b ot h B OL T a n d B M T)  .................................. 3 0  
3. 3  
S ec o n d ary E n d p oi nts ( all e nr oll e d s u bj ects, as a p plic a bl e)  ......................................................... 3 0  
3. 4  
M ec h a nistic E n d p oi nts ................................................................................................................. 3 0  
3. 5  
Str atific ati o n, R a n d o miz ati o n, a n d Bli n di n g/ M aski n g  ................................................................. 3 1  
4  
S el ecti o n of P artici p a nts a n d Cli nic al Sit es/L a b or at ori es  .................................................................... 3 2  
4. 1  
R ati o n al e f or St u dy P o p ul ati o n  .................................................................................................... 3 2  

 
C o nfi d e nti al  
P a g e 1 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
_ T oc 5 1 7 3 6 1 2 5 9  
4. 2  
Eli gi bilit y f or St u dy E ntry a n d L u n g Tr a ns pl a nt  ............................................................................ 3 2  
 
I ncl usi o n Crit eri a .................................................................................................................. 3 2  
 
Excl usi o n Crit eri a  ................................................................................................................. 3 3  
4. 3  
Eli gi bilit y f or B o n e M arr o w Tr a ns pl a nt  ........................................................................................ 3 3  
4. 4  
S el ecti o n of Cli nic al Sit es/L a bs  .................................................................................................... 3 4  
5  
K n o w n a n d P ot e nti al Risks a n d B e n efits t o P artici p a nts  ..................................................................... 3 5  
5. 1  
Risks of C D 3 + a n d C D 1 9 + D e pl et e d B M T  ..................................................................................... 3 5  
5. 2  
Risks of Cry o pr es erv e d D o n or L e u k oc yt e I nf usi o n ( DLI)  ............................................................. 3 5  
5. 3  
Risks of Ot h er Pr ot oc ol S p ecifi e d M e dic ati o ns  ........................................................................... 3 5  
 
Al e mt uz u m a b ® ( C a m p at h -1 H ®)  ........................................................................................... 3 5  
 
A nti -t h y m oc yt e Gl o b uli n, H ors e ( A T G, At g a m ®) ................................................................. 3 6  
 
Hy dr ox y ur e a ( H U, Hy dr e a ®)  ................................................................................................ 3 7  
 
Rit uxi m a b ( Rit ux a n ®)  ........................................................................................................... 3 7  
 
T acr oli m us ( Pr o Gr af ®)  .......................................................................................................... 3 8  
 
T hi ot e p a  ............................................................................................................................... 3 8  
5. 4  
Risks of S t u dy Pr oc e d ur es ............................................................................................................ 4 0  
 
Bl o o d Dr a w  .......................................................................................................................... 4 0  
 
Br o nc h osc o p y a n d Br o nc h o alv e ol ar L a v a g e  ........................................................................ 4 0  
 
B o n e M arr o w As pir at e ......................................................................................................... 4 0  
5. 5  
P ot e nti al B e n efits  ........................................................................................................................ 4 0  
6  
I nv esti g ati o n al I nt erv e nti o n ................................................................................................................ 4 1  
6. 1  
C a d a v eric B o n e M arr o w H arv est a n d Pr e p ar ati o n of C D 3 +/ C D 1 9 + H e m at o p oi etic St e m C ells  4 1  
 
B o n e M arr o w H arv est .......................................................................................................... 4 1  
 
B o n e M arr o w Pr oc essi n g  ..................................................................................................... 4 1  
6. 1. 2  
B M T D os a g e a n d A d mi nistr ati o n  ......................................................................................... 4 2  
 
Cry o pr es erv e d D o n or L e u k oc yt e I nf usi o n ( DLI) ................................................................... 4 2  
6. 2  
Dr u g Acc o u nt a bilit y  ..................................................................................................................... 4 3  
6. 3  
T oxicit y Pr e v e nti o n a n d M a n a g e m e nt  ........................................................................................ 4 3  
 
Ac ut e C ell ul ar R ej ecti o n ( A C R) Pri or t o t h e B M T  ................................................................. 4 3  
6. 4  
Pr e m at ur e Disc o nti n u ati o n of I n v esti g ati o n al A g e nt  .................................................................. 4 3  
 
Pr e m at ur e Disc o nti n u ati o n of t h e B M T  .............................................................................. 4 3  
7  
Pr ot oc ol M a n d at e d M e dic ati o ns  ......................................................................................................... 4 4  

 
C o nfi d e nti al  
P a g e 1 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
7. 1  
L u n g Tr a ns pl a nt I m m u n os u p pr essi o n  ......................................................................................... 4 4  
 
I n d ucti o n T h er a py ................................................................................................................ 4 4  
 
M ai nt e n a nc e I m m u n os u p pr essi o n  ...................................................................................... 4 4  
7. 2  
C o n diti o ni n g R e gi m e n f or B M T  ................................................................................................... 4 4  
 
Hy dr ox y ur e a ......................................................................................................................... 4 4  
 
Rit uxi m a b  ............................................................................................................................. 4 4  
 
Al e mt uz u m a b  ....................................................................................................................... 4 5  
 
A nti -t h y m oc yt e Gl o b uli n, H ors e (A T G, At g a m ®)  ................................................................. 4 5  
 
T hi ot e p a  ............................................................................................................................... 4 5  
 
T ot al B o dy Irr a di ati o n ( T BI) .................................................................................................. 4 5  
7. 3  
Gr o wt h F act or S u p p ort  ................................................................................................................ 4 5  
7. 4  
I nf ecti o n Pr o p hyl axis ................................................................................................................... 4 5  
 
P n e u m oc ystis jir ov ecii ( P C P)  ................................................................................................ 4 5  
 
H er p es Si m pl ex Vir us ( HS V) a n d/ or V aric ell a Z ost er Vir us ( V Z V)  ........................................ 4 5  
 
F u n g al Pr o p hyl axis  ............................................................................................................... 4 6  
 
T ox o pl as m osis  ...................................................................................................................... 4 6  
 
C yt o m e g al ovir us ( C M V)  ....................................................................................................... 4 6  
 
E pst ei n -B arr Vir us ( E B V) a n d A d e n ovir us I nf ecti o ns  ........................................................... 4 6  
 
I ntr a v e n o us I m m u n o gl o b uli n (I VI G) .................................................................................... 4 6  
7. 5  
V e n o -occl usi v e Dis e as e Pr o p hyl axis  ............................................................................................ 4 6  
7. 6  
Pr o hi bit e d M e dic ati o ns  ............................................................................................................... 4 6  
7. 7  
Wit h dr a w al of I m m u n os u p pr essi o n P ost -B M T  ........................................................................... 4 7  
8  
St u dy Pr oc e d ur es  ................................................................................................................................. 4 8  
8. 1  
E nr oll m e nt  ................................................................................................................................... 4 8  
8. 2  
Scr e e ni n g/ B as eli n e Visit Pr e -L u n g Tr a ns pl a nt ............................................................................. 4 8  
8. 3  
Scr e e ni n g/ B as eli n e Visit Pr e -B M T  ............................................................................................... 4 8  
8. 4  
St u dy Visits or St u dy Ass ess m e nts ............................................................................................... 4 8  
 
P ost -L u n g Tr a ns pl a nt St u dy Ass ess m e nts  ........................................................................... 4 8  
 
F oll o w -u p Visits P ost B o n e M arr o w Tr a ns pl a nt  .................................................................. 4 9  
8. 5  
U nsc h e d ul e d Visits  ....................................................................................................................... 4 9  
8. 6  
Visit Wi n d o ws  .............................................................................................................................. 4 9  
9  
M ec h a nistic Ass a ys  .............................................................................................................................. 5 1  
9. 1  
C hi m eris m  .................................................................................................................................... 5 1  

 
C o nfi d e nti al  
P a g e 1 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
9. 2  
Gl o b al C el l ul ar I m m u nit y ............................................................................................................. 5 1  
9. 3  
T h y mic F u ncti o n  ........................................................................................................................... 5 1  
 
T -c ell R ec ov ery ..................................................................................................................... 5 1  
 
Fl o w C yt o m etry  .................................................................................................................... 5 1  
9. 4  
P at h o g e n S p ecific I m m u nit y  ........................................................................................................ 5 2  
9. 5  
R N A S e q u e nci n g ( br o nc hi al br us hi n gs)  ....................................................................................... 5 2  
9. 6  
T ol er a nc e Ass a ys  .......................................................................................................................... 5 2  
9. 7  
Ex pr essi o n Pr ofili n g ...................................................................................................................... 5 3  
1 0  
Bi os p eci m e n St or a g e  ....................................................................................................................... 5 4  
1 1  
Crit eri a f or P artici p a nt a n d St u dy C o m pl eti o n a n d Pr e m at ur e St u dy T er mi n ati o n  ........................ 5 5  
1 1. 1  
P artici p a nt C o m pl eti o n  ................................................................................................................ 5 5  
1 1. 2  
Pr e m at ur e T er mi n ati o n  ............................................................................................................... 5 5  
1 1. 3  
P artici p a nt R e pl ac e m e nt  ............................................................................................................. 5 5  
1 1. 4  
F oll o w -u p aft er E arl y St u dy Wit h dr a w al  ..................................................................................... 5 5  
1 1. 5  
St u dy St o p pi n g R ul es  ................................................................................................................... 5 5  
 
T e m p or ary S us p e nsi o n of E nr oll m e nt  ................................................................................. 5 5  
 
T e m p or ary S us p e nsi o n of E nr oll m e nt a n d B M T .................................................................. 5 6  
 
St u dy St o p pi n g R ul e  ............................................................................................................. 5 6  
1 2  
S af et y M o nit ori n g a n d R e p orti n g  .................................................................................................... 5 7  
1 2. 1  
O v ervi e w  ...................................................................................................................................... 5 7  
1 2. 2  
D efi niti o ns  .................................................................................................................................... 5 7  
 
A d v ers e E v e nt ( A E) ............................................................................................................... 5 7  
 
S us p ect e d A d v ers e R e acti o n (S A R)  ...................................................................................... 5 7  
 
U n ex p ect e d A d v ers e E v e nt  .................................................................................................. 5 8  
 
S eri o us A d v ers e E v e nt ( S A E)  ................................................................................................ 5 8  
1 2. 3  
Gr a di n g a n d Attri b uti o n of A d v ers e E v e nts  ................................................................................. 5 8  
 
Gr a di n g Crit eri a  .................................................................................................................... 5 8  
 
Attri b uti o n D efi niti o ns  ......................................................................................................... 5 9  
T a bl e 1 2. 3. 2 Attri b uti o n of A d v ers e E v e nts  ............................................................................................... 5 9  
1 2. 4  
C oll ecti o n a n d R ec or di n g of A d v ers e E v e nts  ............................................................................... 5 9  
 
C oll ecti o n P eri o d  .................................................................................................................. 5 9  
 
C oll ecti n g A d v ers e E v e nts  .................................................................................................... 6 0  
 
R ec or di n g A d v ers e E v e nts  ................................................................................................... 6 0  

 
C o nfi d e nti al  
P a g e 1 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 2. 5  
R e p orti n g of S eri o us A d v ers e E v e nts a n d A d v ers e E v e nts  .......................................................... 6 0  
 
R e p orti n g of S eri o us A d v ers e E v e nts t o S p o ns or  ................................................................ 6 0  
 
R e p orti n g t o H e alt h A ut h orit y  ............................................................................................. 6 0  
 
R e p orti n g of A d v ers e E v e nts t o I R Bs/I E Cs  ........................................................................... 6 1  
1 2. 6  
Pr e g n a nc y R e p orti n g  ................................................................................................................... 6 1  
1 2. 7  
R e p orti n g of Ot h er S af et y I nf or m ati o n  ....................................................................................... 6 2  
1 2. 8  
R e vi e w of S af et y I nf or m ati o n  ...................................................................................................... 6 2  
 
M e dic al M o nit or R e vi e w  ..................................................................................................... 6 2  
 
D S M B R e vi e w  ....................................................................................................................... 6 2  
1 3  
St atistic al C o nsi d er ati o ns a n d A n al ytic al Pl a n  ................................................................................. 6 4  
1 3. 1  
O v ervi e w  ...................................................................................................................................... 6 4  
1 3. 2  
E n d p oi nts  ..................................................................................................................................... 6 4  
 
Pri m ary E n d p oi nts  ............................................................................................................... 6 4  
 
M e as ur es t o Mi ni miz e Bi as  .................................................................................................. 6 5  
1 3. 3  
A n al ysis Pl a n  ................................................................................................................................ 6 5  
 
A n al ysis of S af et y a n d Effic ac y  ............................................................................................. 6 5  
 
St o p pi n g r ul es f or s af et y:  ..................................................................................................... 6 5  
 
A n al ysis P o p ul ati o ns  ............................................................................................................ 6 5  
 
A n al ys es of S ec o n d ary a n d Ot h er E n d p oi nt(s)/ O utc o m e(s)  ............................................... 6 6  
 
A n al ys es of M ec h a nistic E n d p oi nts  ..................................................................................... 6 6  
 
D escri pti v e A n al ys es  ............................................................................................................ 6 7  
1 3. 4  
I nt eri m A n al ys es .......................................................................................................................... 6 7  
 
I nt eri m A n al ysis of Effic ac y D at a ......................................................................................... 6 7  
 
I nt eri m A n al ysis of S af et y D at a ............................................................................................ 6 7  
 
F utilit y A n al ysis  .................................................................................................................... 6 7  
 
St atistic al Hy p ot h es es  .......................................................................................................... 6 7  
1 3. 5  
S a m pl e Siz e C o nsi d er ati o ns  ......................................................................................................... 6 8  
1 4  
I d e ntific ati o n a n d Acc ess t o S o urc e D at a ........................................................................................ 6 9  
1 4. 1  
S o urc e D at a  .................................................................................................................................. 6 9  
1 4. 2  
Acc ess t o S o urc e D at a  .................................................................................................................. 6 9  
1 5  
Pr ot oc ol D e vi ati o ns  .......................................................................................................................... 7 0  
1 5. 1  
Pr ot oc ol D e vi ati o n D efi niti o ns  ..................................................................................................... 7 0  
1 5. 2  
R e p orti n g a n d M a n a gi n g Pr ot oc ol D e vi ati o ns  ............................................................................. 7 0  

 
C o nfi d e nti al  
P a g e 1 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 6  
Et hic al C o nsi d er ati o ns a n d C o m pli a nc e wit h G o o d Cli nic al Pr actic e  .............................................. 7 1  
1 6. 1  
St at e m e nt of C o m pli a nc e  ............................................................................................................ 7 1  
1 6. 2  
I nf or m e d C o ns e nt Pr oc ess ........................................................................................................... 7 1  
1 6. 3  
Pri v ac y a n d C o nfi d e nti alit y  .......................................................................................................... 7 1  
1 7  
P u blic ati o n P olic y  ............................................................................................................................. 7 2  
1 8  
R ef er e nc es  ....................................................................................................................................... 7 3  
A p p e n dix 1.  Sc h e d ul e of E v e nts ( R eci pi e nt: R el ati v e t o B OL T)  .................................................................. 7 6  
A p p e n dix 2 . Sc h e d ul e of E v e nts ( R eci pi e nt: R el ati v e t o B M T) .................................................................... 7 9  
A p p e n dix 3 .  C o n diti o ni n g R e gi m en  ............................................................................................................ 8 2  
A p p e n dix 4 .  D o n or Ass ess m e nts ................................................................................................................ 8 3  
A p p e n dix 5.   Dis e as e S p ecific P ost -B M T O utc o m es  .................................................................................... 8 4  
 

 
C o nfi d e nti al  
P a g e 1 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
Gl oss ar y of A b br e vi ati o ns  
A B O  
A, B, O bl o o d t y p es  
A E  
A d v ers e e v e nt  
AL T  
Al a ni n e a mi n otr a ns a mi n as e  
A N C  
A bs ol ut e n e utr o p hil c o u nt  
AS T  
As p art at e a mi n otr a nsf er as e  
A T G  
A nti -t h y m oc yt e gl o b uli n 
A T G A M  
A nti -t h y m oc yt e gl o b uli n, H ors e 
β -h C G  
H u m a n c h ori o nic g o n a d otr o pi n  
B M T  
B o n e M arr o w Tr a ns pl a nt  
B OL T  
Bil at er al ort h ot o pic l u n g tr a ns pl a nt  
C F R  
C o d e of F e d er al R e g ul ati o ns  
C B C  
C o m pl et e bl o o d c o u nt  
C D  
Cl ust er of diff er e nti ati o n  
G C D  
C hr o nic gr a n ul o m at o us dis e as e  
C H P  
C hil dr e n’s H os pit al of Pitts b ur g h  
CI B M T R  
C e nt er f or I nt er n ati o n al Bl o o d a n d M arr o w Tr a ns pl a nt R es e arc h  
CLI A  
Cli nic al L a b or at ory I m pr ov e m e nt Act  
C O R E  
C e nt er f or Or g a n R ec ov ery a n d E d uc ati o n  
C M V  
C yt o m e g al ovir us  
C R F  
C as e r e p ort f or m 
C R S S  
C o m p osit e R ej ecti o n St a n d ar diz e d Sc or e  
C S F  
C er e br os pi n al fl ui d  
C T  
C o m p ut e d t o m o gr a p h y  
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts  
D  
D a y  
D AI T  
Divisi o n of All er g y, I m m u n ol o g y, a n d Tr a ns pl a nt ati o n  
DLI  
D o n or L e u k oc yt e I nf usi o n  
D M S O  
Di m et h yl s ulf oxi d e  
D N A  
D e ox yri b o n ucl eic aci d  
D S M B  
D at a S af et y M o nit ori n g B o ar d  
E B V  
E pst ei n -B arr vir us  
E K G  
El ectr oc ar di o gr a m  

 
C o nfi d e nti al  
P a g e 1 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
F D A  
F o o d a n d Dr u g A d mi nistr ati o n  
F E V 1  
F orc e d ex pir at ory v ol u m e  
F K B P  
F K bi n di n g pr ot ei n  
F V C  
F orc e d vit al c a p acit y  
G C P  
G o o d Cli nic al Pr actic e  
G -C S F  
Gr a n ul oc yt e c ol o n y sti m ul ati n g f act or  
G F R  
Gl o m er ul ar filtr ati o n r at e  
G V H D  
Gr aft v ers us h ost dis e as e  
H C V  
H e p atitis C vir us  
H e p Bs A g  
H e p atitis B s urf ac e a nti g e n  
HI V  
H u m a n I m m u n o d efici e nc y Vir us  
HL A  
H u m a n L e u k oc yt e A nti g e n  
H P C  
H e m at o p oi etic pr o g e nit or c ell  
HS C  
H e m at o p oi etic st e m c ell  
HS C T  
H e m at o p oi etic st e m c ell tr a ns pl a nt  
HS V  
H er p es si m pl ex vir us  
H TL V  
H u m a n T -l y m p h otr o pic vir us 
H U  
Hy dr ox y ur e a  
I g A 
I m m u n o gl o b uli n A 
I g E 
I m m u n o gl o b uli n E 
I g G 
I m m u n o gl o b uli n G 
I g M 
I m m u n o gl o b uli n M 
I C H 
I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n 
I N D 
I nv esti g ati o n al N e w Dr u g 
I R B 
I nstit uti o n al R e vi e w B o ar d 
I V  
I ntr a v e n o us 
I VI G 
I ntr a v e n o us I m m u n o gl o b uli n 
L F T 
Li v er F u ncti o n T ests 
M O P  
M a n u al of Pr oc e d ur es  
N A T  
N ucl eic Aci d T esti n g  
NI AI D  
N ati o n al I nstit ut e of All er g y a n d I nf ecti o us Dis e as e s 
N K  
N at ur al kill er  
N R M  
N o n -r el a ps e m ort alit y 
O P O  
Or g a n Pr oc ur e m e nt Or g a niz ati o n  

 
C o nfi d e nti al  
P a g e 1 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
P B S C  
P eri p h er al bl o o d st e m c ell  
P C R  
P ol y m er as e c h ai n r e acti o n  
P C P  
P n e u m oc ystis c ari nii p n e u m o ni a  
P R N  
Pr o r e n at a ( as n e e d e d)  
P TL D  
P ost -tr a ns pl a nt l y m p h o pr olif er ati v e dis e as e 
PI  
Pri nci p al I nv esti g at or  
PI D  
Pri m ary I m m u n o d efici e nc y Dis e as e  
Q  
Q u a q u e ( e v ery)  
RI C  
R e d uc e d i nt e nsit y c o n diti o ni n g  
R N A  
Ri b o n ucl eic aci d  
R P MI  
R os w ell P ark M e m ori al I nstit ut e (c ult ur e m e di u m)  
S A E  
S eri o us A d v ers e E v e nt  
S A P  
St atistic al A n al ysis Pl a n  
S A R  
S us p ect e d A d v ers e R e acti o n  
S C N  
S e v er e c o n g e nit al n e utr o p e ni a  
S O P  
St a n d ar d O p er ati n g Pr oc e d ur e  
S T A T 3  
Si g n al tr a ns d uc er a n d acti v at or of tr a nscri pti o n 3 
S T R  
S h ort t a n d e m r e p e at  
S U S A R  
S eri o us U n ex p ect e d S us p ect e d A d v ers e R e acti o n  
T BI  
T ot al b o d y irr a di ati o n  
TLI  
T ot al l y m p h oi d r a di ati o n  
T N C  
T ot al n ucl e at e d c ells  
U N O S  
U nit e d N et w ork of Or g a n S h ari n g  
U P M C  
U niv ersit y of Pitts b ur g h M e dic al C e nt er  
 

 
C o nfi d e nti al  
P a g e 2 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1  St u d y H y p ot h es es/ O bj ecti v es  
1. 1  
H y p ot h es es  
L u n g tr a ns pl a nt pri or t o b o n e m arr o w tr a ns pl a nt ( B M T)  w o ul d all o w f or r est or ati o n of p ul m o n ary 
f u ncti o n pri or t o B M T , all o wi n g p ati e nts t o pr oc e e d t o B M T , w hic h w o ul d b e c ur ati v e f or t h e p ati e nt’s 
u n d erl yi n g i m m u n o d efici e nc y.   
1. 2  
Pri m ar y O bj ecti v e  
T h e pri m ary o bj ecti v es ar e t o e v al u at e t h e s af et y a n d effic ac y of p erf or mi n g bil at er al ort h ot o pic l u n g 
tr a ns pl a nt ati o n f oll o w ed by c a d a v eric, p arti ally HL A -m atc h e d ( ≥2/ 6 HL A -m atc h wit h a n i d e ntic al A B O 
bl o o d t y p e) C D 3 +/ C D 1 9 + d e pl et e d b o n e m arr o w tr a ns pl a nt f or p ati e nts wit h pri m ary i m m u n o d efici e nc y 
a n d e n d -st a g e l u n g dis e as e. 
1. 3  
S ec o n d ar y O bj ecti v e s 
T h e s ec o n d ary o bj ecti v es ar e t o e v al u at e t h e f e asi bilit y a n d l o n g -t er m c o m plic ati o ns ass oci at e d wit h 
c o m bi n e d s oli d or g a n a n d B M T i ncl u di n g t h e a bilit y t o i niti at e a n d s ucc essf ull y wit h dr a w s u bj ects fr o m 
i m m u n os u p pr essi o n f oll o wi n g B M T a n d t o att ai n i n d e p e n d e nc e fr o m tr e at m e nt d os e a nti micr o bi al 
dr u gs.   
1. 4  
M ec h a nistic O bj ecti v es  
T h e m ec h a nistic o bj ecti v es ar e t o e v al u at e t h e  p ac e of i m m u n e r ec o nstit uti o n as w ell as t h e i nci d e nc e 
a n d d e gr e e of mix e d d o n or c hi m eris m.  
 

 
C o nfi d e nti al  
P a g e 2 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
2  B ac k gr o u n d a n d R ati o n al e   
2. 1  
B ac k gr o u n d  a n d Sci e ntific R ati o n al e  
F or m a n y p ati e nts wit h pri m ary i m m u n o d efici e nci es, B M T is a c ur ati v e, lif e-s a vi n g t h er a py, r es ulti n g i n 
r est or ati o n of f u ncti o n i n t h e i m m u n e syst e m [ 2]. Alt h o u g h hist oric all y p ati e nts h a v e r ec ei v e d 
my el o a bl ati v e c o n diti o ni n g pri or t o tr a ns pl a nt, t h er e h as b e e n i ncr e asi n g i nt er est i n r e d uc e d i nt e nsit y 
c o n diti o ni n g f or p ati e nts wit h pri m ary i m m u n o d efici e nci es i n a n eff ort t o d ecr e as e t oxicit y a n d l at e 
eff ects f oll o wi n g tr a ns pl a nt.  Usi n g t h es e r e gi m e ns i n p ati e nts wit h pri m ary i m m u n o d efici e nci es, t h e 
l ar g est st u dies h a v e s h o w n ov er all s urvi v al r at es of 6 9 -9 4 % at a m e di a n f oll o w -u p of 3 -5 y e ars; h o w e v er, 
mix e d c hi m eris m is i ncr e as e d c o m p ar e d t o m y el o a bl ati v e c o n diti o ni n g r e gi m e ns.  T his c a n r es ol v e wit h 
r e d uc e d i m m u n os u p pr essi o n, a n d if st a bl e, m a y n ot pr ecl u d e f u ncti o n al i m m u n e r ec o nstit uti o n [ 3, 4].  
P ati e nts wit h pri m ary i m m u n o d efici e nci es oft e n d e v el o p p ul m o n ary c o m plic ati o ns as a r es ult of c hr o nic 
or r ec urr e nt i nf ecti o ns [ 6] , a n d b et w e e n 2 1-3 3 % of p ati e nts wit h n o n -c ystic fi br osis br o nc hi ect asis h a v e 
a n u n d erl yi n g i m m u n o d efici e nc y  [ 7, 8]. P ot e nti al B M T  c a n di d at es wit h s e v er e l u n g dis e as e h av e 
hist oric all y b e e n i n eli gi bl e f or tr a ns pl a nt d u e t o t h e u n ac c e pt a bl y hi g h risk of m ort alit y ass oci at e d wit h 
t h e c o n diti o ni n g r e gi m e n a n d t h e p ossi bilit y of d e v el o pi n g br o nc hiolitis o blit er a ns sy n dr o m e f oll o wi n g 
B M T , l e a di n g t o f urt h er p ul m o n ary c o m pr o mis e a n d ov er all f utilit y.  C o n v ers el y, p ati e nts i nflict e d wit h 
PI D sy n dr o m es a n d c o nc o mit a nt p ul m o n ary f ail ur e h av e b e e n i n eli gi bl e f or B OL T as t h e u n d erl yi n g 
i m m u n o d efici e nc y w oul d l e a d t o r ec urr e nt i nf ecti o ns of t h e n e wl y tr a ns pl a nt e d l u n gs.  T h es e c hil dr e n 
a n d y o u n g a d ults h a v e h a d p alli ati v e c ar e as t h eir o nly o pti o n.  
L u n g tr a ns pl a nt pri or t o B M T  w o ul d all o w f or r est or ati o n of p ul m o n ary f u ncti o n pri or t o b o n e m arr o w 
tr a ns pl a nt, d ecr e asi n g t h e risk of t h e ov er all h e m at o p oi etic st e m c ell tr a ns pl a nt pr oc e d ur e, w hic h is 
c ur ati v e f or t h e p ati e nt’s u n d erl yi n g i m m u n o d efici e nc y. Alt h o u g h l u n g tr a ns pl a nt ati o n is t y pic all y 
p erf or m e d wit h o ut HL A -m atc hi n g crit eri a as l o n g as A B O t y pi n g, s iz e, a n d l u n g f u ncti o n ar e a p pr o pri at e, 
e nr oll e d s u bj ects will r ec ei v e p arti ally HL A -m atc h e d l u n gs a n d b o n e m arr o w.  P ati e nts r ec ei vi n g l u n g 
tr a ns pl a nt ati o n ar e t y pic all y m ai nt ai n e d o n lif el o n g i m m u n os u p pr essi o n t o r e d uc e t h e risk of r ej ecti o n 
b y h ost T c e lls.  P ersist e nt e n gr aft m e nt of h e m at o p oi etic st e m c ells fr o m a h e alt h y, i m m u n e c o m p et e nt 
l u n g d o n or s h o ul d r es ult i n t h e est a blis h m e nt of d o n or d eri v e d c ell ul ar i m m u nit y. A h e alt h y d o n or-
d eri v e d i m m u n e syst e m s h o ul d n ot o nly pr ot ect fr o m i nf ecti o ns b ut s h o ul d als o f acilit at e t h e gr aft 
s urvi v al of t h e tr a ns pl a nt e d a ut ol o g o us l u n gs a n d is ex p ect e d t o p er mit pl a n n e d r e m ov al of 
i m m u n os u p pr essi v e dr u gs t o est a blis h lif el o n g t ol er a nc e as w e h av e r ec e ntl y d e m o nstr at e d. 
2. 2  
R ati o n al e f or S el ecti o n of I n v esti g ati o n al Pr o d uct or I nt er v e nti o n 
T h e c urr e nt pr ot oc ol i n v ol v es a  c a d a v eric, p arti all y HL A-m atc h e d l u n g tr a ns pl a nt f oll o w e d b y  a  
C D 3 +/ C D 1 9 + d e pl et e d b o n e m arr o w tr a ns pl a nt usi n g h y dr ox y ur e a, rit uxi m a b, al e mt uz u m a b, a nti -
t h y m oc yt e gl o b uli n, t hi ot e p a, a n d l o w -d os e T BI ( 2 5 0 c G y) wit h l u n g-s hi el di n g as c o n diti o ni n g i n p ati e nts 
wit h pri m ary i m m u n o d efici e nci es.  T his r e gi m e n mi ni miz es t h e risk of t oxicit y t o t h e tr a ns pl a nt e d l u n gs, 
a n d is h e a vily i m m u n os u p pr essi v e, wit h a nti -t h y m oc yt e gl o b uli n a n d al e mt uz u ma b t o r e d uc e h ost N K 
c ells al o n g wit h T c ells of eit h er h ost or d o n or ori gi n t o mi ni miz e t h e risk of gr aft r ej ecti o n a n d G V H D. 
T h e p ur p os e of rit uxi m a b  is t o d e pl et e h ost a n d d o n or B c ells, p ot e nti ally d ecr e asi n g t h e risk of p ost -
tr a ns pl a nt l y m p h o pr olif er ati v e dis e as e ( P TL D) d e v el o pi n g fr o m E B V-i nf ect e d B c ells a n d m a y r e d uc e 
e arl y d e n ov o all o s e nsitiz ati o n t o t h e l u n g gr aft [ 1 5, 3 7, 3 8, 3 9].  F urt h er m or e, t h e us e of Rit uxi m a b m a y 

 
C o nfi d e nti al  
P a g e 2 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
r e d uc e t h e p ot e nti al d a n g er of pr e-B M T all os e nsitiz ati o n, w hic h is ass oci at e d wit h p o or m arr o w gr aft 
f u ncti o n [ 4 0]. As n ot e d a b ov e, t h er e h as b e e n r e p ort e d a l o w risk of G V H D i n t h e h a pl oi d e ntic al s etti n g 
w h e n usi n g C D 3 4 s el ect e d gr afts  [ 1 4, 1 5].  D e pl eti o n  of C D 3 + c ells will r e m ov e p ot e nti ally all or e acti v e T 
c ells, t h e pri m ary eff ect ors of G V H D, fr o m t h e gr aft, t h er e b y d ecr e asi n g t h e risk of G V H D. I n a d diti o n, 
d u e t o t h e risk of E B V -dri v e n P TL D, w e will p erf or m C D 1 9 + c ell d e pl eti o n t o r e m ov e a r es erv oir of  l at e nt 
E B V i nf ect e d B c ells.  Als o, as o p p os e d t o C D 3 4 + s el ecti o n, w hic h r e m ov es all b ut t h e C D 3 4 + c ells, t his 
d e pl eti o n pr oc ess will r et ai n l ar g e n u m b ers of ot h er i m m u n e c ells, s uc h as d o n or N K c ells ( w hic h ar e 
i m p ort a nt f or f acilit ati n g e n gr aft m e nt), d en dritic c ells, gr a n ul oc yt es a n d m o n oc yt es i n t h e gr aft  [ 2 2], 
p ot e nti ally pr ovi di n g a d diti o n al pr ot ecti v e i m m u nit y e arl y aft er tr a ns pl a nt.  W e a ntici p at e t h at b y 
pr oc essi n g t h e st e m c ell pr o d uct i n t his m a n n er i n c o m bi n ati o n wit h a g gr essi v e s er ot h er a p y as p art of 
t h e c o n diti o ni n g r e gi m e n, w e will si g nific a ntl y d ecr e as e t h e risk of b ot h G V H D a n d P TL D.  As s e e n i n 
ot h er st u di es, t his will all o w f or t h e d e v el o p m e nt of a f u ncti o n al i m m u n e syst e m fr o m t h e e n gr afti n g 
d o n or -d eri v e d b o n e m arr o w  [ 2 3], a n d pr ot ecti o n fr o m r ej ecti o n a n d G V H D of t h e tr a ns pl a nt e d l u n gs as 
t h e y will b e HL A-i d e ntic al t o e ac h ot h er.  I n a d diti o n t o t h e d ecr e as e d risk of r ej ecti o n i n t his s etti n g, 
t h er e is a hi g h li k eli h o o d t h at if n o G V H D w er e t o d e v el o p, p ati e nts c o ul d ac hi e v e o p er ati o n al tol er a nc e 
a n d b e r e m ov e d fr o m all i m m u n os u p pr essi v e m e dic ati o ns.   
2. 3  
Cli nic al St u di es  
 
Pr e vi o us E x p eri e nc e wit h B OL T a n d B M T  
Dr. Sz a b olcs d esi g n e d a n ov el r e d uc e d -i nt e nsit y c o n diti o ni n g r e gi m e n i n 2 0 0 9 a n d w as t h e s p o ns or a n d 
PI of a n F D A a p pr ov e d tr e at m e nt pl a n (I D E: 1 4 2 0 6) titl e d: Si n gl e -p ati e nt us e of Cli ni M A C S ® C D 3/ C D 1 9 
d e pl eti o n d e vic e f or T c ell d e pl eti o n o n c a d a v eric u nr el at e d b o n e m arr o w b ef or e tr a ns pl a nt ati o n i nt o a 
l u n g tr a ns pl a nt r eci pi e nt at D u k e U niv ersit y. Bil at er al ort h ot o pic l u n g tr a ns pl a nt ati o n ( D ec e m b er 2 0 0 9)  
f oll o w e d b y c a d a v eric 4/ 8 HL A-m atc h e d  ( A, B, C, D R), C D 3 + a n d C D 1 9 + d e pl et e d b o n e m arr o w 
tr a ns pl a nt ( A pril 2 0 1 0) fr o m t h e s a m e d o n or w as s ucc essf ull y p erf or m e d usi n g a tr e at m e nt pl a n wit h 
rit uxi m a b, al e mt uz u m a b, a ntit h y m oc yt e gl o b uli n, hy dr ox y ur e a, t hi ot e p a, a n d l o w-d os e T BI as 
c o n diti o ni n g.  Alt h o u g h 4 m o nt hs l at er t h e p ati e nt d e v el o p e d s e v er e g astr oi nt esti n al G V H D, t h er e w as 
r a pi d a n d c o m pl et e r es p o ns e f oll o wi n g a si n gl e d os e of I nflixi m a b a n d a s h ort c o urs e of st er oi ds. S h e h as 
b e e n off all i m m u n os u p pr essi v e m e dic ati o ns a n d b act eri al/ vir al/f u n g al/ P C P pr o p hyl axis f or > 4  y e ars 
wit h o ut e vi d e nc e of G V H D, r ej ecti o n, or i nf ecti o ns a n d is c urr e ntl y e nr oll e d i n c oll e g e .  T his is t h e first 
e v er -s ucc essf ul h u m a n c as e a n d it d e m o nstr at es t h e f e asi bi lit y a n d i m m u n e c o ns e q u e nc es of t a n d e m 
c a d a v eric l u n g a n d T-c ell-d e pl et e d m arr o w tr a ns pl a nt ati o n fr o m t h e s a m e HL A -mis m atc h e d u nr el at e d 
d o n or t o cr e at e s oli d or g a n a n d r eci pi e nt -s p ecific t ol er a nc e i n t h e a bs e nc e of syst e mic 
i m m u n os u p pr essi o n.  
W hil e at D u k e U niv ersit y, Dr. Sz a b olcs r ec ei v e d F D A/I R B a p pr ov al f or a s ec o n d p ati e nt  t o b e tr e at e d b y 
t h e s a m e tr e at m e nt pl a n, h o w e v er, f oll o wi n g his d e p art ur e fr o m D u k e U niv ersit y, i n N ov e m b er 2 0 1 1 h e 
tr a nsf err e d t h e s p o ns ors hi p of t h e I N D a p plic ati o n ( 1 4 6 4 3) t o Dr. G wy n n L o n g fr o m t h e Divisi o n of 
C ell ul ar T h er a py i n t h e D e p art m e nt of I nt er n al M e dici n e. B OL T  w as p erf or m e d i n A pril 2 0 1 2 wit h 
dr a m atic cli nic al i m pr ov e m e nt i n l u n g f u ncti o n a n d e v e nt u al n utriti o n al r e h a bilit ati o n, h o w e v er, t h e 
ext er n ally h arv est e d m arr o w  d os e w as b el o w t h e t ar g et of 1x 1 0 e 6 C D 3 4 +/ k g.  F oll o wi n g r ec ei pt of t h e 
F D A/I R B exc e pti o n a p pr ov al t o p er mit t his d e vi ati o n , t h e B M T w as p erf or m e d 3 m o nt hs aft er B OL T i n 
l at e J ul y 2 0 1 2 wit h ~ 0. 3x 1 0 e 6/ k g C D 3 4 + c ells. T h e p ati e nt e n gr aft e d r a pi dl y wit h o ut a n y s e v er e A Es, 

 
C o nfi d e nti al  
P a g e 2 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
h o w e v er, w as f o u n d wit h 5 % d o n or c ells at e n gr aft m e nt t h at w er e r a pi dl y l ost by  d ay + 5 0 w h e n o nly 
h ost c ells w er e i d e ntifi e d.  I n M a y 2 0 1 3,  t h e D uk e PI  r e p ort e d n o s eri ous, ex p ect e d ( ≥gr a d e 3) a d v ers e 
e v e nt s t h at w er e p ossi bl y r el at e d t o st u dy i nt erv e nti o n.  T h er e w er e n o I N D s af et y r e p orts s u b mitt e d 
d uri n g t h e p eri o d u p t o M a y 2 0 1 3.  H e r e m ai n e d o n F K 5 0 6 f or l u n g r ej ecti o n pr o p hyl axis h o w e v er, 
d e v el o p e d all o gr aft r ej ecti o n a n d di e d  i n his h o m e st at e i n M arc h 2 0 1 4  d u e t o V R E s e psis a n d r e n al 
f ail ur e.  
Dr. Sz a b olcs a n d Dr. Mc D y er r ec ei v e d F D A/I R B a p pr ov al f or a n a d diti o n al si n gl e c as e tr e at m e nt (I N D: 
1 5 2 2 1) titl e d: Si n gl e p ati e nt us e of Cli ni M A C S ® C D 3 a n d C D 1 9 d e pl eti o n d e v ic e f or T a n d B c ell d e pl eti o n 
o n c a d a v eric u nr el at e d b o n e m arr o w b ef or e tr a ns pl a nt ati o n i nt o a l u n g tr a ns pl a nt r eci pi e nt wit h J o b’s 
Sy n dr o m e.  T his p ati e nt  r ec ei v e d B OL T u n d er t h e c ar e of Dr. J o h n Mc D y er fr o m a 2 of 6 HL A-m atc h e d 
c a d a v eric d o n or, h o w e v er, d ecli n e d t o u n d er g o B M T s u bs e q u e ntl y d u e t o a pr otr act e d a n d diffic ult p ost -
B OL T c o urs e c o m plic at e d b y e arl y Ps e u d o m o n as p n e u m o ni a. T h e p ati e nt r ec ov er e d h o w e v er w as f o u n d 
t o h a v e s e v er al ri g ht s u pr a di a p hr a g m atic As p er gill us a bsc ess es t h at r es p o n d e d t o 3  m o nt hs of I V 
li p os o m al a m p h ot erici n.  S h e di d w ell u ntil a b o ut 2 ½ y e ars p ost-tr a ns pl a nt w h e n s h e d e v el o p e d 
r ec urr e nt pl e ur al eff usi o ns a n d w as f o u n d t o h a v e i nv asi v e As p er gill osis e nc asi n g h er ri g ht p ul m o n ary 
art ery. D es pit e a g gr essi v e m e dic al m a n a g e m e nt  s h e di e d j ust pri or t o h er 3 r d y e ar p ost -tr a ns pl a nt.  
T h e f o urt h p ati e nt w as t h e first t o e nr oll i n t h e P h as e 1/ 2 cli nic al tri al i niti at e d i n 2 0 1 3 at t h e U niv ersit y 
of Pitts b ur g h  ( PI P a ul Sz a b olcs) u n d er I N D 1 5 4 1 4. T his p ati e nt h a d i nt er mitt e nt n e utr o p e nia, F T T, a n d 
w ei g ht l oss wit h r ec urr e nt p n e u m o ni a dri v e n b y alc ali g e n es, ps e u d o m o n as, aci n et o b act er, a n d 
as p er gill us l e a di n g t o pr o gr essi v e br o nc hi ec at asis. S h e h as t w o i n d e p e n d e nt fr a m es hift m ut ati o ns i n t h e 
IL 7 R g e n es ex pl ai ni n g h er T-­­, B +, N K + S CI D p h en ot y p e. A 2 of 6 HL A -m atc h e d d o n or w as i d e ntifi e d aft er 
> 2 y e ars o n t h e w aitlist a n d B OL T w as p erf or m e d i n S e pt e m b er 2 0 1 5 at a g e 1 4 y e ars. S h e di d w ell a n d 
w as n ot e d o nly t o h a v e i m p air e d m ov e m e nt of ri g ht h e mi di a p hr a g m c a usi n g r estricti v e p att er n o n P F Ts  
a n d l eft pl e ur al eff usi o n, wit h s u bs e q u e nt t h or ac e nt esis of t his tr a ns u d at e i n N ov e m b er 2 0 1 5. N o 
p at h o g e ns w er e i d e ntifi e d. S o f ar, t h e r o uti n e p ost-B OL T bi o psi es h a v e b e e n fr e e of A C R  as of A u g ust 
2 0 1 6 . S h e h as t hri v e d si nc e B OL T, i n f act h er w ei g ht i ncre as e d fr o m 2 9k g pr e -­­ B OL T t o ~ 3 8 k g b y t h e 
ti m e of h er B M T. Acc or di n gl y, h er B MI h as i ncr e as e d fr o m ~ 1 4. 0 t o 1 7. 5 c urr e ntl y. 
Hi g h r es ol uti o n all el e l e v el t y pi n g i d e ntifi e d HL A A 0 2 0 1 as a “tr u e” m atc h w hil e t h e U N O S l o w r es ol uti o n 
m atc h at t h e HL A -­­ D R l oc us w as f o u n d t o b e mis m atc h e d at hi g h r es ol uti o n.  T h e r eci pi e nt all el e is 
D R B 1 1 1: 0 1 v ers us HL A -D R B 1 1 1: 0 3 d o n or all el e.  T h e p ati e nt r ec ei v e d t h e t h a w e d C D 3/ 1 9 – d e pl et e d 
c a d a v eric d o n or B M T o n J a n u ary 2 8, 2 0 1 6. S h e e n gr aft e d o n F e b 1 0, 2 0 1 6 wit h 1 0 0 % d o n or c ells b y S T R 
a n alysis. S h e r ec ei v e d cry o pr es erv e d m arr o w gr afts fr o m ext er n al h arv est of ili ac cr est al o n g wit h c ells 
extr act e d fr o m v ert e br al b o di es ( V B), h o w e v er v ert e br al b o d y d eri v e d m arr o w pr ovi d e d > 9 0 % of t h e 
c oll ect e d C D 3 4 + st e m c ell d os e.  H er  p ost -B M T i m m u n e r ec ov ery is si g nific a nt f or pr ol o n g e d T c ell 
l y m p h o p e ni a ( < 1 0 C D 3 + T c ells/ ul) u p t o d a y + 5 0. Wit h a ut ol o g o us T c ells s urvi vi n g a n d d et ect a bl e at 
D ay + 5 0 ( h ost T c ells w er e d o mi n a nt @ ~ 7 5 % r eci pi e nt). D o n or l e u k oc yt e i nf usi o n ( DLI) w as i nf us e d 
a p pr oxi m at el y 2 m o nt hs aft er B M T o bt ai n e d fr o m cry o pr es erv e d u n m o difi e d c a d a v eric b o n e m arr o w 
c o nt ai ni n g 5x 1 0 e 4 vi a bl e C D 3 + T c ells/ k g. Si nc e t h e n, T c ell c hi m eris m h as ris e n > 9 9 % d o n or si nc e DLI, 
wit h a bs ol ut e C D 3 + T c ells d et ect a bl e ~ 2 0 0/ ul, n ot a bl y, al m ost all C D 4 +. T h e DLI gi v e n 2 m o nt hs a g o 
c o m pl et el y r e v ers e d t h e h ost T c ell d o mi n a nc e, h o w e v er, d o n or m y el oi d c hi m eris m h as d ecli n e d si nc e 
d ay + 5 0, alt h o u g h, it s e e ms t o h a v e b e e n fl uct u ati n g, ~ 3 0 % ± 5 % . N K c ell c hi m eris m h as r e m ai n e d ~ 7 5­
8 0 % d o n or o ri gi n. Si g nific a ntl y, s h e d e v el o p e d st a g e 2 s ki n G V H D c ov eri n g 4 5-­­ 5 0 % of h er s ki n t h at 

 
C o nfi d e nti al  
P a g e 2 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
r es p o n d e d t o ~ 4 d a ys of 1 m g/ k g pr e d nis o n e, wit h a 5 m g d ail y m ai nt e n a nc e d os e. B esi d es F K 5 0 6 t h er e 
h av e b e e n n o ot h er I S dr u gs us e d si nc e B M T.  
 
E x p eri e nc e wit h R e d uc e d -I nt e nsit y C o n diti o ni n g i n Pri m ar y I m m u n o d efici e nc y 
R e d uc e d -i nt e nsit y c o n diti o ni n g ( RI C) r e gi m e ns h av e b e e n us e d s ucc essf ull y f or p ati e nts wit h n o n-
m ali g n a nt c o n diti o ns, i ncl u di n g pri m ary i m m u n o d efici e nci es. T h es e r e gi m e ns ar e t y pic all y hi g hly 
i m m u n os u p pr essi v e, a n d t y pic all y utiliz e s er ot h er a py wit h a g e nts s uc h as a ntit h y m oc yt e gl o b uli n or 
al e mt uz u m a b i n c o nj u ncti o n wit h ot h er i m m u n os u p pr essi v e a g e nts s uc h as fl u d ar a bi n e a n d d ecr e as e d 
i nt e nsiti es of alk yl ati n g a g e nts s uc h as b us ulf a n, m el p h al a n, or c ycl o p h os p h a mi d e [ 9]. V e ys et al . r e p ort e d 
s ucc essf ul us e of r e d uc e d i nt e nsit y c o n diti o ni n g, pri m aril y fl u d ar a bi n e, m el p h al a n a n d al e mt uz u m a b, i n 
1 1 3 p ati e nts wit h pri m ary i m m u n o d efici e nc y.  I n t his gr o u p of p ati e nts, 8 1 % h a d st a bl e d o n or c hi m eris m 
a n d ov er all s urvi v al w as 8 2 % at a m e di a n of 2. 9 y e ars p ost -B M T  [ 3].  Si mil ar r es ults h av e b e e n r e p ort e d 
b y ot h er gr o u ps  [ 1 0], s u g g esti n g t h at RI C r e gi m e ns ar e eff ecti v e f or pri m ary i m m u n o d efici e nci es, 
p artic ul arl y i n p ati e nts wit h ot h er c o m or bi diti es a n d r ec ov ery of s o m e h ost -d eri v e d l e u k oc yt es d o es n ot 
di mi nis h t h e c ur ati v e p ot e nti al of tr a ns pl a nt. L o n g -t er m st a bl e c o exist e nc e of r eci pi e nt a n d d o n or 
h e m at o p oi etic c ells i n t h e a bs e nc e of a ny i m m u n os u p pr essi v e dr u gs a n d wit h o ut cli nic al e vi d e nc e of 
i m m u n e-m e di at e d p at h o l o g y is oft e n r ef err e d as “p ersist e nt mix e d c hi m eris m” . T his p h e n o m e n o n of 
t ol er a nt st at e w as alr e a d y r ec o g niz e d l o n g b ef or e t h e a d v a nc es of RI C r e gi m e ns.   D es pit e u n d er g oi n g 
my el o a bl ati v e c o n diti o ni n g, a siz e a bl e pr o p orti o n of p ati e nts wit h β -t h al ass e mi a1 1 or sic kl e c ell dis e as e 1 2   
r ec o nstit ut e wit h mix e d h ost a n d d o n or h e m at o p oi etic c ells. I nt er esti n gl y, d o n or c ells c o ntri b uti n g i n 
exc ess of 1 0 % l e a d t o tr a nsf usi o n i n d e p e n d e nc e a n d fr e e d o m fr o m p at h ol o gic al sy m pt o ms.  
 
W orl d wi d e E x p eri e nc e wit h B o n e M arr o w Tr a ns pl a nt HL A -Mis m atc h e d at 3 or M or e L oci  
H a pl oi d e ntic al ( 3 of 6 HL A-m atc h e d ) d o n ors ar e a n est a blis h e d s o urc e of st e m c ells, a n d h av e b e e n us e d 
s ucc essf ull y usi n g b ot h my el o a bl ati v e a n d r e d uc e d i nt e nsit y c o n diti o ni n g.  S o m e ex p eri e nc e d c e nt ers ar e 
n o w r e p orti n g o utc o m es usi n g h a pl oi d e ntic al gr afts si mil ar t o t h os e s e e n i n m atc h e d -u nr el at e d d o n ors  
[ 1 3]. I n a d diti o n, usi n g C D 3 4 s el ect e d, h a pl oi d e ntic al gr afts wit h a my el o a bl ati v e c o n diti o ni n g r e gi m e n, 
Av ers a et al . r e p ort e d a v ery l o w i nci d e nc e of G V H D, d es pit e t h e a bs e nc e of G V H D pr o p hyl axis, a n d 
tr e at m e nt-r el at ed m ort alit y of 3 6 %, wit h m ost d e at hs d u e t o i nf ecti o n  [ 1 4]. D e pl eti o n of C D 3 + a n d C D 1 9 + 
c ells i n h a pl oi d e ntic al gr afts h as als o b e e n us e d s ucc essf ully i n 6 1 p ati e nts wit h hi g h -risk m ali g n a nc y usi n g 
a r e d uc e d -i nt e nsit y c o n diti o ni n g r e gi m e n c o nt ai ni n g fl u d ar a bi n e, m el p h al a n, t hi ot e p a, a n d A T G.  I n t his 
st u dy, 5 6/ 6 1 p ati e nts e n gr aft e d wit h f ull d o n or c hi m eris m at a m e di a n of 1 2 d ays p ost -tr a ns pl a nt.  I n 
a d diti o n, t h er e w as r a pi d r ec o nstit uti o n of N K c ells, wit h sl o w er r ec o nstit uti o n of T a n d B c ells.  T h e 
i ncid e nc e of gr a d e II -I V G V H D w as 4 6 %, a n d w as r el at e d t o t h e ext e nt of T-c ell d e pl eti o n, wit h m or e 
eff ecti v e T -c ell d e pl eti o n r es ulti n g i n l ess G V H D.  T h e i nci d e nc e of n o n -r el a ps e m ort alit y ( N R M) w as l o w, 
at 2 3 % at 1 0 0 d ays a n d 4 2 % at t w o y e ars  [ 1 5]. C h e n et al . als o r e p ort e d m or e r a pi d i m m u n e r ec o nstit uti o n 
f oll o wi n g C D 3 + d e pl et e d h a pl oi d e ntic al st e m c ell tra ns pl a nt usi n g r e d uc e d-i nt e nsit y c o n diti o ni n g 
r e gi m e ns c o m p ar e d t o my el o a bl ati v e c o n diti o ni n g r e gi m e ns [ 1 6]. U m bilic al c or d bl o o d is als o a c o m m o nly 
us e d st e m c ell s o urc e.  E a p e n et al . r ec e ntl y r e p ort e d t h e r es ults of mis m atc h e d u m bilic al c or d bl o o d 
tr a ns pl a nt ati o n.  I n h er a n al ysis of CI B M T R d at a, 3 2 8 p ati e nts r ec ei v e d a n u m bilic al c or d bl o o d tr a ns pl a nt 
wit h at l e ast 3 of 8 mis m atc h e d l oci.  Tr e at m e nt m or t alit y w as 3 3 % ( 8 3/ 2 5 3) f or 3 mis m atc h e d l oci, a n d 
3 7 % ( 2 8/ 7 5) f or 4 mis m atc h e d l oci  [ 1 7].  
 
I n d ucti o n of T ol er a nc e wit h S oli d Or g a n a n d B o n e M arr o w Tr a ns pl a nt  

 
C o nfi d e nti al  
P a g e 2 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 6 p ati e nts wit h at l e ast 1 0/ 1 0 HL A -m atc h e d ( A, B, C, D R , D Q), livi n g r e n al a n d p eri p h er al bl o o d st e m c ell 
d o n ors u n d er w e nt r e n al tr a ns pl a nt f oll o w e d b y c o n diti o ni n g wit h TLI a n d A T G wit h P B S C 1 1 d ays aft er 
r e n al tr a ns pl a nt ati o n.  El e v e n p ati e nts w er e t a k e n off all i m m u n os u p pr essi o n, a n d n o p ati e nts d e v el o p e d 
ac ut e or c hr o nic G V H D, w hil e m ai nt ai ni n g r es p o ns e t o t hir d-p art y all o a nti g e ns  [ 1 8]. Si mil arl y, r es e arc h ers 
at N ort h w est er n U niv ersit y a n d t h e U niv ersit y of L o uisvill e h av e r e p ort e d o p er ati o n al t ol er a nc e i n r e n al 
tr a ns pl a nt ati o n usi n g a pr e p ar ati v e r e gi m e n of c ycl o p h os p h a mi d e, fl u d ar a bi n e, a n d t otal -b o d y irr a di ati o n 
( T BI) f oll o w e d b y r e n al tr a ns pl a nt ati o n a n d HL A mis m atc h e d m o biliz e d p eri p h er al bl o o d st e m c ells.  Usi n g 
t his a p pr o ac h, 5 of 8 p ati e nts e n gr aft e d a n d w er e a bl e t o b e r e m ov e d fr o m all i m m u n os u p pr essi o n.  N o 
p ati e nts d e v el o p e d G V H D i n t hi s s etti n g, e v e n wit h as littl e as a 1/ 6 HL A m atc h, m e a ni n g t h at o nly 1 of 
t h e 6 HL A a nti g e ns w er e a m atc h b et w e e n d o n or a n d r eci pi e nt, a n d p ati e nts m ai nt ai n e d r es p o ns e i n 
mix e d l y m p h oc yt e r e acti o n t o t hir d p art y sti m ul at or c ells  [ 1 9-2 1].   
 
I nstit uti o n al E x peri e nc e wit h t h e Cli ni M A C S ® d e vic e  
T h e Cli ni M A C S ® d e vic e h as b e e n us e d at t h e C hil dr e n’s H os pit al of Pitts b ur g h of U P M C f or t h e pr oc essi n g 
of h e m at o p oi etic st e m c ells si nc e 2 0 1 1. T h e pri m ary us e h as b e e n t h e s el ecti o n of C D 3 4 + st e m c ells fr o m 
p eri p h er al b l o o d st e m c ell pr o d ucts f or us e i n a n I R B-a p pr ov e d pr ot oc ol f or a ut ol o g o us st e m c ell 
tr a ns pl a nt ati o n f or p ati e nts wit h m e dic all y r efr act ory Cr o h n’s Dis e as e.  T o d at e, t his pr oc e d ur e h as b e e n 
p erf or m e d o n h e m at o p oi etic st e m c ell pr o d ucts fr o m 2 p ati e nts.  W hil e t h e s ec o n d p ati e nt h as n ot 
r ec ei v e d c o n diti o ni n g f or tr a ns pl a nt, t h e first o n e e n gr aft e d pr o m ptl y o n d ay 1 2. I n a d diti o n, it h as b e e n 
us e d s ucc essf ull y f or C D 3 4 + s el ecti o n i n a n F D A a p pr o v e d pr ot oc ol I N D 1 5 2 4 5 : Si n gl e P ati e nt Us e of 
A ut ol o g o us St e m C ell Tr a ns pl a nt ati o n wit h Cli ni M A C S ® C D 3 4 -S el ect e d P eri p h er al Bl o o d St e m C ells ( P B S C) 
i n a Y o u n g A d ult P ati e nt wit h R el a psi n g P ol yc h o n dritis. T his s u bj ect e n gr aft e d o n d ay + 1 0.  W e h av e als o 
s ucc essf ull y p erf or m e d a CD 3 + a n d C D 1 9 + d e pl eti o n f or a n F D A a p pr ov e d pr ot oc ol (I N D: 1 5 2 2 1) titl e d: 
Si n gl e p ati e nt us e of Cli ni M A C S ® C D 3 a n d C D 1 9 d e pl eti o n d e vic e f or T a n d B c ell d e pl eti o n o n c a d a v eric 
u nr el at e d b o n e m arr o w b ef or e tr a ns pl a nt ati o n i nt o a l u n g tr a ns pl a nt r eci pi e nt w it h J o b’s Sy n dr o m e. T his 
p ati e nt r ef us e d t h e B M T a n d s u bs e q u e ntl y di e d b ef or e h er 3 r d y e ar B OL T a n ni v ers ary.      
 
W orl d wi d e E x p eri e nc e wit h C D 3/ C D 1 9 D e pl eti o n  
D e pl eti o n of C D 3 + a n d C D 1 9 + c ells i n h a pl oi d e ntic al gr afts h as als o b e e n us e d s ucc essf ull y i n b ot h 
p e di atric a n d a d ult p ati e nts.  L a n g et al. r e p ort e d o n 4 9 p e di atric p ati e nts a g e d 1 -2 3 y e ars wit h l e u k e mi a 
or m y el o d ys p astic sy n dr o m e usi n g fl u d ar a bi n e or cl of ar a bi n e, m el p h al a n, t hi ot e p a a n d A T G or O K T 3 as 
c o n diti o ni n g.  I n t his gr o u p, 8 8 % of p ati e nts a c hi e v e d n e utr o p hil e n gr aft m e nt wit hi n t h e first 2 8 d a ys 
p ost -tr a ns pl a nt, a n d t h e r e m ai ni n g p ati e nts e n gr aft e d aft er r ec ei vi n g a s ec o n d i nf usi o n of C D 3/ C D 1 9 
d e pl et e d st e m c ells.  T w e nt y -s e v e n p erc e nt of p ati e nts d e v el o p e d gr a d e II-I V G V H D, a n d w hil e t h e 
m aj orit y of p ati e nts d e v el o p e d vir e mi a f or C M V, a d e n ovir us, or B K vir us, t h e m ort alit y r el at e d t o t h es e 
i nf ecti o ns w as extr e m el y l o w ( 2 %), w hic h w as attri b ut e d t o r a pi d i m m u n e r ec ov ery f oll o wi n g tr a ns pl a nt. 
T h e ov er all tr e at m e nt -r el at e d m ort alit y w as 8 % at 1 y e ar a n d 2 0 % at 5 y e ars  [ 2 7].  A d diti o n ally, B a d er et 
al. r e p ort e d o n 5 9 p ati e nts w h o r ec ei v e d a r e d uc e d -i nt e nsit y c o n diti o ni n g r e gi m e n utilizi n g fl u d ar a bi n e, 
m el p h al a n a n d t hi ot e p a.  N e utr o p hil e n gr aft m e nt w as r a pi d, occ urri n g at d a y + 1 2 a n d i m m u n e 
r ec o nstit uti o n als o occ urr e d r a pi dly a n d w as l o n g-l asti n g.  T h e tr e at m e nt-r el at e d m ort alit y i n t his gr o u p 
of p ati e nts w as 1 1 % at o n e y e ar p ost -tr a ns pl a nt [ 2 8].  I n a m uc h s m all er st u dy, K o h et al. r e p ort e d 3 
p e di atric p ati e nts wit h s e v er e a pl astic a n e mi a w h o r ec ei v e d h a pl oi d e ntic al C D 3/ C D 1 9 d e pl et e d st e m 
c ells gr afts f oll o wi n g a r e d uc e d -i nt e nsit y c o n diti o ni n g r e gi m e n utilizi n g fl u d ar a bi n e, c ycl o p h os p h a mi d e 
a n d A T G.  Si mil ar t o L a n g et al, t h er e w as r a pi d i m m u n e r ec ov ery a n d l o w tr e at m e nt -r el at e d m ort alit y 

 
C o nfi d e nti al  
P a g e 2 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
[ 2 9].  T his str at e g y of r e d uc e d -i nt e nsit y c o n diti o ni n g a n d h a pl oi d e ntic al tr a ns pl a nt usi n g C D 3/ C D 1 9 
d e pl eti o n h as als o b e e n s ucc essf ully e m pl oy e d i n t h e a d ult p o p ul ati o n.  B et h g e et al. r e p ort e d o n 2 9 
a d ult p ati e nts wit h hi g h -risk h e m at ol o gic m ali g n a nc y usi n g a re d uc e d -i nt e nsit y c o n diti o ni n g r e gi m e n 
c o nt ai ni n g fl u d ar a bi n e, m el p h al a n, t hi ot e p a, a n d A T G.  E n gr aft m e nt w as r a pi d wit h a m e di a n of 1 2 d a ys, 
a n d 4 8 % of p ati e nts d e v el o p e d gr a d e II -I V G V H D.  Tr e at m e nt-r el at e d m ort alit y w as 2 0 % at d a y 1 0 0 p ost-
tr a ns pl a nt [ 3 0].  F e d er m a n n et al. r e p ort e d o n 6 1 a d ult p ati e nts wit h hi g h-risk m ali g n a nc y usi n g a si mil ar 
r e d uc e d-i nt e nsit y c o n diti o ni n g r e gi m e n c o nt ai ni n g fl u d ar a bi n e, m el p h al a n, t hi ot e p a, a n d A T G. I n t his 
st u dy, 5 6/ 6 1 p ati e nts e n gr aft e d wit h f ull d o n or c hi m eris m at a  m e di a n of 1 2 d ays p ost -tr a ns pl a nt. I n 
a d diti o n, t h er e w as r a pi d r ec o nstit uti o n of N K c ells, wit h sl o w er r ec o nstit uti o n of T a n d B c ells. T h e 
i nci d e nc e of gr a d e II-I V G V H D w as 4 6 % a n d  w as r el at e d t o t h e ext e nt of T -c ell d e pl eti o n, wit h m or e 
eff ecti v e T -c ell d e pl eti o n r es ulti n g i n l ess G V H D. T h e i nci d e nc e of n o n-r el a ps e m ort alit y ( N R M) w as l o w, 
at 2 3 % at 1 0 0 d a ys a n d 4 2 % at t w o y e ars  [ 1 5].  T h us, d e pl eti o n of C D 3 a n d C D 1 9 p ositi v e c ells is s af e a n d 
is ass oci at e d wit h r a pi d e n gr aft m e nt a n d i m m u n e r ec o nstit utio n wit h a l o w risk of s e v er e G V H D or 
tr e at m e nt-r el at e d m ort alit y.   
 
 

 
C o nfi d e nti al  
P a g e 2 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
3  St u d y D esi g n  
3. 1  
D escri pti o n of St u d y D esi g n   
T his is a si n gl e c e nt er, P h as e I/II  st u dy i n w hic h s u bj ects r ec ei v e a c a d a v eric, p arti ally HL A-m atc h e d l u n g 
tr a ns pl a nt f oll o w e d b y a C D 3 +/ C D 1 9 + d e pl et e d B M T  fr o m t h e s a m e d o n or. I n t his st u dy, t h e 
i nv esti g at ors will us e a ≥2/ 6 ( A, B, D R) HL A -m atc h e d T c ell d e pl et e d b o n e m arr o w tr a ns pl a nt fr o m a 
c a d a v eric or g a n d o n or wit h a n i d e ntic al A B O bl o o d t y p e as t h e r eci pi e nt. 
S u bj ects  will u n d er g o B OL T utilizi n g  b asilixi m a b i n d ucti o n  or a n alt er n at e i n d ucti o n t h er a py b as e d o n t h e 
s u bj ect’s u n d erl yi n g dis e as e. Rit uxi m a b m a y b e i niti at e d pri or t o t h e l u n g tr a ns pl a nt wit h t acr oli m us as 
t he o n g oi n g m ai nt e n a nc e i m m u n os u p pr essi o n.  
S u bj ect s will u n d er g o B M T  utilizi n g C D 3 +/ C D 1 9 + -d e pl et e d b o n e m arr o w  wit h b o n e m arr o w c o n diti o ni n g 
b e gi n ni n g  n o l ess t h a n 8  w e e ks aft er B OL T. T h e c o n diti o ni n g r e gi m e n m ay b e p a us e d f or u p t o 7 
c u m ul ati v e d ays if t h er e ar e cli nic al c o m plic ati o ns e. g. i nf ecti o n. T h e r e gi m e n will r es u m e  fr o m t h e p oi nt 
it w as p a us e d o nc e t h e i nv esti g at or a n d NI AI D m e dic al m o nit or a gr e e  it is s af e t o pr oc e e d.  
T h e c o n diti o ni n g r e gi m e n will b e as f oll o ws:  
•  
D ay -2 8  t o -3: Hy dr ox y ur e a  
•  
D ay -2 8 , D a y + 3 5: Rit uxi m a b 
•  
Al e mt uz u m a b:  
o  D ay -2 1, D a y -2 0 :  S u bj ects  wit h pr e vi o us ac ut e c ell ul ar r ej ecti o n  (s e e s ectio n 7. 2. 3 
f or f urt h er d et ails) ( A C R) of ≥ A 2 a n d/ or ≥B 2 R  will r ec ei v e t w o d os es of 
Al e mt uz u m a b  O R  
o  D ay -1 4: S u bj ects wit h o ut pr e vi o us A C R of ≥ A 2 a n d/ or ≥B 2 R  (s e e s ecti o n 7. 2. 3 f or 
f urt h er d et ails) will r ec ei v e a si n gl e d os e of Al e mt uz u m a b  
•  
D ay -3  t o -1 : A T G A M 
•  
D ay -2: T hi ot e p a  
•  
D ay -1: T BI 2 5 0 c G y ( 2 0 0c G y f or r a di os e nsiti v e s u bj ects) wit h l u n g s hi el di n g.  L u n g s hi el di n g 
will n ot b e c o m pl et e d f or s u bj e cts wit h pr e vi o us A C R of ≥ A 2 a n d/ or ≥B 2 R . A d diti o n al or g a n 
s hi el di n g f or f ertilit y pr es erv ati o n will b e  all o w e d  b as e d u p o n t h e i nv esti g at or’s discr eti o n.    
 
 

 
C o nfi d e nti al  
P a g e 3 0  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
3. 2  
Pri m ar y E n d p oi nt s 
 
S af et y E n d p oi nt  
S af et y will b e d et er mi n e d b y ass essi n g t h e pr es e nc e or a bs e nc e of t h e f oll o wi n g a dv ers e e v e nts d uri n g 
t h e st u dy p eri o d ( u p t o 2 y e ars p ost-B M T):  
•  
D e at h  
•  
E n gr aft m e nt sy n dr o m e  
•  
E n gr aft m e nt f ail ur e  
•  
Gr a d e 4 or 5 e v e nts p ot e nti ally attri b ut a bl e t o Rit uxi m a b  
 
Effi c ac y E n d p oi nts  ( all s u bj ects w h o r ec ei v e d b ot h B OL T a n d B M T) 
3. 3  
S ec o n d ar y E n d p oi nt s ( all e nr oll e d s u bj ects, as a p plic a bl e) 
T h e f oll o wi n g  s ec o n d ary e n d p oi nts will b e ass ess e d:  
•  
F e asi bilit y of pr oc e e di n g t o B M T wit hi n 6 m o nt hs f oll o wi n g l u n g tr a ns pl a nt ati o n.  
•  
D e v el o p m e nt of t ol er a nc e t o b ot h t h e h ost a n d p ul m o n ary gr aft . 
•  
Lo n g -t er m c o m plic ati o ns of c o m bi n e d s oli d or g a n a n d B M T . 
•  
Inci d e nc e of ac ut e c ell ul ar r ej ecti o n a n d gr aft f ail ur e p ost B M T.  
•  
Inci d e nc e of ac ut e a n d c hr o nic gr aft -v ers us -h ost dis e as e ( G V H D) f oll o wi n g t a n d e m l u n g a n d 
B M T . 
•  
A bilit y t o i niti at e wit h dr a w al of i m m u n os u p pr essi o n by 1 y e ar f oll o wi n g B M T . 
•  
Ti m e fr o m B M T t o wit h dr a w al of i m m u n os u p pr essi o n.  
•  
Ti m e fr o m B M T t o i n d e p e n d e nc e fr o m tr e at m e nt d os e a nti micr o bi al dr u gs.  
•  
F or T c ell l y m p h o p e ni as, ac hi e vi n g a g e a dj ust e d, l o w li mit n or m al r a n g e l y m p h oc yt e c o u nt b y 
1 -y e ar p ost -B M T.  
•  
A si g nific a nt d e v el o p m e nt i n c hr o nic l u n g all o gr aft d ysf u ncti o n ( as e vi d e nc e d b y a c h a n g e i n 
B O S st a g e, s e e p g. 1 9 f or B O S t a bl e) or all o gr aft f ail ur e at 1 -y e ar a n d u p t o 2 y e ars p ost l u n g 
tr a ns pl a nt f or B OL T al o n e a n d B OL T -B M T s u bj ects . 
•  
I nci d e nc e of Gr a d e 4 or 5 a d v ers e e v e nts p ossi bl y r el at e d t o t h e us e of Rit uxi m a b pri or t o t h e 
st art of B M T c o n diti o ni n g. 
3. 4  
M ec h a nistic  E n d p oi nt s 
T h e f oll o wi n g m ec h a nistic e n d p oi nts will  b e e v al u at e d:  
•  
B O S at 1 -y e ar p ost B OL T; s u p pl e m e nt al ox y g e n r e q uir e m e nt a n d/ or v e ntil at ory s u p p ort 
( n o ni n v asi ve/i n v asi v e) at 1 -y e ar p ost B OL T.  
•  
≥ 2 5 % d o n or T -c ell c hi m eris m at 1 2 m o nt hs p ost B M T.  
•  
F or s u bj ects wit h my el oi d dis or d ers ( e. g. C G D), att ai ni n g ≥ 1 0 % my el oi d c hi m eris m at 1 2 
m o nt hs p ost B M T.  
•  
F or s u bj ects wit h B -c ell dis or d ers, att ai ni n g ≥ 1 0 % B -c ell c hi m eris m at 1 2 m o nt hs p ost B M T.  

 
C o nfi d e nti al  
P a g e 3 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
•  
T h e p ac e of i m m u n e r ec o nstit uti o n as w ell as t h e i nci d e nc e a n d d e gr e e of mix e d d o n or 
c hi m eris m will b e e v al u at e d.  
•  
T h e i nci d e nc e of mix e d c hi m eris m (> 5 % h ost c ells) at M o nt hs 1, 3, 6 , 1 2 - a n d 2 4 -m o nt hs  
p ost B M T.  
•  
I m pr ov e m e nt i n i m m u n ol o gic al m ark er(s) u ni q u e f or t h e u n d erl yi n g PI D sy n dr o m e b y o n e -
y e ar p ost B M T (s e e A p p e n dix 5).  
3. 5  
Str atific ati o n, R a n d o miz ati o n, a n d Bli n di n g / M as ki n g 
T his is a n o p e n l a b el st u dy a n d t h er e will b e n o r a n d o miz ati o n or bli n di n g as a p art o f t his st u dy.  

 
C o nfi d e nti al  
P a g e 3 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
4  S el ecti o n of P artici p a nts a n d Cli nic al Sit es/L a b or at ori es  
4. 1  
R ati o n al e f or St u d y P o p ul ati o n  
P ati e nts b et w e e n t h e a g es of 1 0  a n d 4 5  y e ars of a g e, i ncl usi v e, wit h a pri m ary i m m u n o d efici e nc y a n d 
e n d -st a g e l u n g dis e as e wit h o ut m aj or t oxicit y t o ot her or g a ns or u nc o ntr oll e d i nf ecti o ns will b e eli gi bl e 
f or t a n d e m B OL T a n d B M T  fr o m a ≥2/ 6 HL A-m atc h e d c a d a v eric or g a n d o n or wit h  a n  i d e ntic al A B O bl o o d 
t y p e as t h e r eci pi e nt. L u n g tr a ns pl a nt pri or t o B M T (i n p ati e nts wit h PI D) w o ul d all o w f or r est or ati o n of 
p ul m o n ary f u ncti o n pri or t o b o n e m arr o w tr a ns pl a nt, d ecr e asi n g t h e risk of t h e ov er all b o n e m arr o w  
tr a ns pl a nt pr oc e d ur e, w hic h is c ur ati v e f or t h e p ati e nt’s u n d erl yi n g i m m u n o d efici e nc y.  
4. 2  
Eli gi bilit y f or  St u d y E ntr y a n d L u n g Tr a ns pl a nt  
 
I ncl usi o n Crit eri a  
I n divi d u als m ust m e et all of t h e f oll o wi n g crit eri a i n or d er t o b e eli gi bl e f or t his st u dy.  
1.  S u bj ect a n d/ or p ar e nt g u ar di a n m ust b e a bl e t o u n d erst a n d a n d pr ovi d e i nf or m e d c o ns e nt . 
2.  M al e or f e m al e , 1 0  t hr o u g h 4 5  y e ars  ol d , i ncl usi v e, at t h e ti m e of i nf or m e d c o ns e nt. 
3.  M e et crit eri a f or U N O S listi n g.  
4.  P ati e nts m ust h a v e e vi d e nc e of a n u n d erl yi n g pri m ary i m m u n o d efici e nc y f or w hic h B M T  is cli nic all y 
i n dic at e d.  
Ex a m pl es of s uc h dis e as es i ncl u d e, b ut ar e n ot li mit e d t o:  
•  
S e v er e C o m bi n e d I m m u n o d efici e nc y  
•  
C o m bi n e d i m m u n o d efici e nc y 
wit h d ef ects i n T -c ell-m e di at e d i m m u nit y, i ncl u di n g O m e n n 
sy n dr o m e a n d Di G e or g e Sy n dr o m e  
•  
S e v er e C hr o nic N e utr o p e ni a  
•  
C hr o nic Gr a n ul o m at o us Dis e as e  
•  
Hy p er I g E Sy n dr o m e or J o b Sy n dr o m e  
•  
C D 4 0 or C D 4 0L d efici e nc y  
•  
Wisk ott -Al dric h Sy n dr o m e  
•  
M e n d eli a n S usc e pti bilit y t o M yc o b act eri al Dis e as e  [ 6] 
•  
G A T A 2  Ass oci at e d I m m u n o d efici e nc y  
 N O T E: A g e n etic di a g n osis is r ec o m m e n d e d, b ut n ot r e q uir e d.  
5.  P ati e nts  m ust h av e e vi d e nc e of e n d -st a g e l u n g dis e as e a n d b e c a n di d at es f or bil at er al ort h ot o pic 
l u n g tr a ns pl a nt as d et er mi n e d b y t h e l u n g tr a ns pl a nt t e a m. 
6.  G F R ≥5 0 mL/ mi n/ 1. 7 3 m 2 . 
7.  AS T, AL T ≤4x u p p er li mit of n or m al, tot al bilir u bi n ≤ 2. 5 m g/ dL , n or m al I N R. 
8.  C ar di ac ej ecti o n fr acti o n ≥ 4 0 % or s h ort e ni n g fr acti o n ≥2 6 % . 
9.  N e g ati v e pr e g n a nc y t est f or f e m al es > 1 0 y e ars ol d or w h o h a v e r e ac h e d m e n arc h e, u nl ess s ur gic all y 
st eriliz e d. 

 
C o nfi d e nti al  
P a g e 3 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 0.  All f e m al es of c hil d b e ari n g p ot e nti al a n d s ex u ally acti v e m al es m ust a gr e e t o us e a F D A a p pr ov e d 
m et h o d of birt h c o ntr ol f or u p t o 2 4 m o nt hs aft er B M T or f or as l o n g as t h e y ar e t a ki n g a n y 
m e dic ati o n t h at m ay h ar m a pr e g n a nc y, a n u n b or n c hil d or m ay c a us e birt h d ef ect.  
1 1.  S u bj ect a n d/ or p ar e nt g u ar di a n  will als o b e c o u ns el e d r e g ar di n g t h e p o t e nti al risks of i nf ertilit y 
f oll o wi n g B M T a n d  a dvis e d t o disc uss s p er m b a nki n g or o oc yt e h arv esti n g.  
 
E xcl usi o n Crit eri a   
I n di vi d u als w h o m e et a n y of t h es e crit eri a ar e n ot eli gi bl e f or t his st u d y.  
1.  I n a bilit y or u n willi n g n ess of a p artici p a nt t o giv e writt e n i nf or m e d c o ns e nt or c o m ply wit h st u dy 
pr ot oc ol . 
2.  P ati e nts w h o h a v e u n d erl yi n g m ali g n a nt c o n diti o ns . 
3.  P ati e nts w h o h a v e n o n -m ali g n a nt c o n diti o ns n ot r e q uiri n g h e m at o p oi etic st e m c ell tr a ns pl a nt ati o n.  
4.  HI V p ositi v e b y s er ol o g y or P C R,  H TL V p ositi v e b y s er ol o g y . 
5.  F e m al es w h o ar e pr e g n a nt or w h o ar e l act ati n g.  
6.  All er g y t o D M S O or a n y ot h er i n gr e di e nt us e d i n t h e m a n uf act uri n g of t h e st e m c ell pr o d uct . 
7.  U nc o ntr oll e d  p ul m o n ary  i nf ecti o n, as d et er mi n e d by r a di o gr a p hic fi n di n gs a n d/ or si g nific a nt cli nic al 
d et eri o r ati o n.  N O T E: P ul m o n ary c ol o niz ati o n wit h m ulti pl e or g a nis ms is c o m m o n a n d will n ot b e 
c o nsi d er e d a n excl usi o n crit eri o n.  
8.  U nc o ntr oll e d syst e mic i nf ecti o n, as d et er mi n e d b y t h e a p pr o pri at e c o nfir m at ory t esti n g e. g.  bl o o d 
c ult ur es, P C R t esti n g, etc.   
9.  R ec e nt r eci pi e nt of a n y lic e ns e d or i nv esti g ati o n al li v e att e n u at e d v acci n e(s) wit hi n 4  w e e ks of 
tr a ns pl a nt.  
1 0.  P ast or c urr e nt m e dic al pr o bl e ms or fi n di n gs fr o m p hysic al ex a mi n ati o n or l a b or at ory t esti n g t h at 
ar e n ot list e d a b ov e, w hic h, i n t h e o pi ni o n of t h e i nv esti g at or, m ay p os e a d diti o n al risks fr o m 
p artici p ati o n i n t h e st u dy, m a y i nt erf er e wit h t h e p artici p a nt’s a bilit y t o c o m ply wit h st u dy 
r e q uir e m e nts or t h at m ay i m p act t h e q u alit y or i nt er pr et ati o n of th e d at a o bt ai n e d fr o m t h e st u dy . 
 
D o n or Eli gi bil it y 
D o n or m ust b e a ≥2/ 6 ( A, B, D R) HL A -m atc h e d c a d a v eric or g a n d o n or wit h a n i d e ntic al A B O bl o o d t y p e 
as t h e r eci pi e nt.  All d o n ors will b e scr e e n e d a n d c o nfir m e d n e g ati v e f or C O VI D -1 9 .  
4. 3  
Eli gi bilit y f or B o n e M arr o w Tr a ns pl a nt  
T h e d ecisi o n t o pr oc e e d wit h t h e B M T will  b e  at t h e discr eti o n of t h e l u n g tr a ns pl a nt t e a m f oll o wi n g 
cl e ar a nc e b y t h e b o n e m arr o w t e a m b as e d o n t h e crit eri a b el o w. T h e c o n diti o ni n g f or t h e B M T will 
b e gi n n o l ess t h a n 8 w e e ks f oll o wi n g t h e l u n g tr a ns pl a nt.  
1.  G F R > 5 0 mL/ mi n/ 1. 7 3 m 2. 
2.  AS T, AL T < 4x u p p er li mit of n or m al, T ot al bilir u bi n < 2. 5 m g/ dL.  
3.  C ar di ac ej ecti o n fr acti o n ≥ 4 0 % or s h ort e ni n g fr acti o n of at l e ast 2 6 % . 
4.  HI V n e g ati v e b y s er ol o g y a n d P C R.  
5.  H TL V s er ol o g y n e g ati v e.  

 
C o nfi d e nti al  
P a g e 3 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
6.  F V C a n d F E V 1 ≥4 0 % pr e dict e d f or a g e a n d S p O 2 of > 9 0 % at r est o n r o o m air A N D wit h cl e ar a nc e b y 
t h e l u n g tr a ns pl a nt t e a m.  
7.  A bs e nc e of u nc o ntr oll e d i nf ecti o n as d et er mi n e d b y p ositi v e bl o o d c ult ur es a n d r a di o gr a p hic 
pr o gr essi o n of pr e vi o us sit es i n p artic ul ar p ul m o n ary d e nsiti es d uri n g t h e p as t 2 w e e ks pri or t o 
c h e m ot h er a py. 
8.  A bs e nc e of cli nic all y si g nific a nt ac ut e c ell ul ar r ej ecti o n ( m ost r ec e nt e v al u ati o n < A 2 -A 4 a n d  <  B 2 R 
r ej ecti o n; s e e s ecti o n 6. 3. 1).  
9.  B o n e m arr o w pr oc essi n g (s ecti o n 6. 1. 2) h as b e e n c o m pl et e d, a n d a n a p pr o pri at e st e m c ell pr o d uct is 
a v ail a bl e f or a d mi nistr ati o n (s ecti o n 6. 1. 3).  
1 0.  A n y m e dic al iss u e or fi n di n g n ot list e d a b ov e, w hic h, i n t h e o pi ni o n of t h e i nv esti g at or, m a y p os e 
a d diti o n al risks fr o m p artici p ati o n i n t h e st u dy, m a y i nt erf er e wit h t h e p artici p a nt’s a bilit y t o c o m ply 
wit h st u dy r e q uir e m e nts or t h at m a y i m p act t h e q u alit y or i nt er pr et ati o n of t h e d at a o bt ai n e d fr o m 
t h e st u dy.                
4. 4  
S el ecti o n of Cli nic al Sit es/L a bs  
C hil dr e n's H os pit al of Pitts b ur g h  ( C H P) of U P M C a n d Pr es b yt eri a n H os pit al of U P M C ar e w orl d -r e n o w n e d 
f or l u n g tr a ns pl a nt ati o n. A d ult p ati e nts will u n d er g o B OL T at Pr es byt eri a n H os pit al of U P M C w hil e 
c hil dr e n will r ec ei v e B OL T at C H P of U P M C as it is st a n d ar d pr actic e at b ot h i nstit uti o ns. All s u bj ects  will 
r ec ei v e t h e B M T at C H P of U P M C r e g ar dl es s of r eci pi e nt a g e. C H P of U P M C h as ric h cli nic al ex p eri e nc e i n 
m a n a gi n g m e dic all y c h all e n gi n g a d ult p ati e nts i n t h e A d ult C o n g e nit al H e art Dis e as e ( A C H D) C e nt er. 
M or e o v er, cli nici a ns fr o m e ac h h os pit al will b e a bl e t o f oll o w e nr oll e d s u bj ects at all ti m es  d u e t o t h e 
i nt e gr at e d h e alt h c ar e syst e m of t h e U niv ersit y of Pitts b ur g h M e dic al C e nt er.  

 
C o nfi d e nti al  
P a g e 3 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
5  K n o w n a n d P ot e nti al Ris ks a n d B e n efits t o P artici p a nts  
5. 1  
Ris ks of C D 3 + a n d C D 1 9 + D e pl et e d B M T  
T h e risks ass oci at e d wit h a  C D 3 + a n d C D 1 9 + d e pl et e d B M T ar e si mil ar t o a st a n d ar d B M T a n d i ncl u d e 
b o n e m arr o w d e pr essi o n, gr aft f ail ur e, Gr aft V ers us H ost Dis e as e, V e n o -Occl usi v e dis e as e of t h e liv er, 
i nt erstiti al p n e u m o ni a, dis e as e r ec urr e nc e, m ali g n a nc y, c e ntr al n erv o us syst e m d a m a g e, s eri o us 
i nf ecti o n(s), or g a n d a m a g e, a n d ge n etic dis e as e tr a ns missi o n. D u e t o t h e HL A mis m atc h, t h e risk of gr aft 
f ail ur e m a y b e sli g htl y hi g h er wit h t his pr oc e d ur e t h a n t h e st a n d ar d B M T . C o n v ers el y, t h e risk of G V H D is 
ex p ect e d t o b e l o w er wit h t h e C D 3 + a n d C D 1 9 + d e pl eti o n. T h er e c o ul d als o b e u nf or es e e n risks t h at 
h av e n ot y et b e e n i d e ntifi e d.  
5. 2  
Ris ks of Cr y o pr es er v e d D o n or L e u k oc yt e  I nf usi o n ( DLI) 
T h e DLI is fr o m n o n T -c ell d e pl et e d fr acti o n of c a d a v eric b o n e m arr o w  a n d m a y  b e a d mi nist er e d i n 
s u bj ects w h o ex p eri e nc e a si g nific a nt vir al i nf ecti o n, a d ecli n e i n d o n or c hi m eris m , or s h o w n o e vi d e nc e 
of C D 3 + r ec o nstit uti o n aft er d a y 3 0 . T h er e is a risk of tr a ns mitt e d dis e as e a n d/ or i nf ecti o n, Gr aft V ers us 
H ost Dis e as e, b o n e m arr o w d e pr essi o n, gr aft f ail ur e a n d e n gr aft m e nt sy n dr o m e  as w ell as a d v ers e 
eff ects r el at e d t o t h e D M S O us e d f or cry o pr es erv ati o n .   
5. 3  
Ris ks of Gr a n ul oc yt e I nf usi o n  
Gr a n ul oc yt es  ( w hit e bl o o d c ells) ar e a p art of t h e i m m u n e syst e m a n d ai d i n fi g hti n g b act eri al a n d f u n g al 
i nf ecti o ns.  
Gr a n ul oc yt es ar e n ot pr ot oc ol m a n d at e d b ut m a y b e a d mi nist er e d i n s u bj ects f oll o wi n g B M T w h o 
ex p eri e nc e s e v er e i nf ecti o ns, h a v e b e e n u nr es p o nsi v e t o a nti bi otics, a n d / or n e utr o p e ni a . Gr a n ul oc yt es 
ar e a w hit e c ell c o nc e ntr at e c oll ect e d b y d o n or a p h er esis.  
T h er e ar e risks ass oci at e d wit h t h e tr a nsf usi o n of gr a n ul oc yt es. Mil d r e acti o ns i ncl u d e r as h, urtic ari a, 
fe v er, c hills a n d h e a d ac h e.  L ess c o m m o n r e acti o ns i ncl u d e r es pir at ory distr ess or l u n g i nj ury, ex p os ur e 
t o bl o o d b or n e micr o or g a nisms ( b act eri a, p ar asit es) t h at c o ul d r es ult i n i nf ecti o n, p ossi bl e eff ects o n t h e 
i m m u n e syst e m w hic h m a y d ecr e as e t h e b o d y’s a bilit y t o fi g ht i nf ecti o n, ex p os ur e t o bl o o d b or n e 
vir us es s uc h as H e p atitis B a n d s h oc k.  Extr e m el y r ar e si d e eff ects ar e ex p os ur e t o bl o o d b or n e vir us es 
s uc h as H e p atitis C a n d H u m a n I m m u n o d efici e nc y Vir us ( HI V), c ar di ac e v e nts s uc h as m y oc ar di al 
i nf arcti o n, a n d d e at h.   
5. 4  
Ris ks of Ot h er Pr ot oc ol S p ecifi e d M e dic ati o ns  
 
Al e mt uz u m a b ® ( C a m p at h -1 H ®)  
Al e mt uz u m a b is a n a nti b o d y a g ai nst C D 5 2, a n o n -m o d ul ati n g a nti g e n pr es e nt o n t h e s urf ac e of ess e nti ally 
all T a n d B l y m p h oc yt es, t h e m aj orit y of m o n oc yt es, m acr o p h a g es, a n d N K c ells, a n d a s u b p o p ul ati o n of 
gr a n ul oc yt es.  T h e m ec h a nis m of acti o n is ex p ect e d  t o t h e a nti b o d y-d e p e n d e nt l ysis f oll o wi n g c ell s urf ac e 
bi n di n g.  Al e mt uz u m a b bi n di n g w as s e e n i n l y m p h oc yt e tiss u es a n d t h e m o n o n ucl e ar p h a g oc yt e syst e m.  
A pr o p orti o n of b o n e m arr o w c ells, i ncl u di n g s o m e C D 3 4 + c ells ex pr ess v ari a bl e l e v els of C D 5 2.   

 
C o nfi d e nti al  
P a g e 3 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
A d v ers e E v e nts : C ar di ov asc ul ar: C h est p ai n, h y p er-/ h y p ot e nsi o n, p eri p h er al e d e m a, t ac h yc ar di a/ S V T; 
C e ntr al n erv o us syst e m: D e pr essi o n, dizzi n ess, dr u g -r el at e d f e v er, d yst h esi as, f ati g u e, h e a d ac h e, 
i ns o m ni a, 
m al ais e, n e utr o p e nic f e v er, s o m n ol e nc e, t e m p er at ur e c h a n g e s e ns ati o n; D er m at ol o gic: 
Pr urit us, p ur p ur a, r as h, urtic ari al; G astr oi nt esti n al: A b d o mi n al p ai n, a n or exi a, c o nsti p ati o n, di arr h e a, 
d ys p e psi a, n a us e a, st o m atitis/ m uc ositis, v o miti n g; H e m at ol o gic: A ut oi m m u n e h e m ol ytic a n e mi a, 
a ut oi m m u n e t hr o m b oc yt o p e ni a, l y m p h o p e ni a, p a nc yt o p e ni a/ m arr o w h y p o pl asi a, p ositi v e C o o m bs' t est 
wit h o ut h e m ol ysis, s e v er e a n e mi a, s e v er e n e utr o p e ni a, s e v er e t hr o m b oc yt o p e ni a; N e ur o m usc ul ar & 
sk el et al: 
B ac k 
p ai n, 
my al gi a, ri g ors, sk el et al 
m uscl e 
p ai n, tr e m or, 
w e a k n ess; 
R es pir at ory: 
Br o nc hitis/ p n e u m o nitis, br o nc h os p as m, c o u g h, d ys p n e a, e pist axis, p h ary n gitis, r hi nitis; Misc ell a n e o us: 
Di a p h or esis, i nf ecti o n (i ncl u di n g s e psis, p n e u m o ni a, o p p ort u nistic i nf ecti o n; r ec ei v e d P C P p n e u m o ni a a n d 
h er p es pr o p hyl axis);  
R ar e b ut i m p ort a nt or lif e -t hr e at e ni n g: Aci d osis, ac ut e r e n al f ail ur e, a gr a n ul oc yt osis, a n a p h yl act oi d 
r e acti o ns, a n gi n a p ect oris, a n gi o e d e m a, a n uri a, ascit es, ast h m a, b o n e m arr o w a pl asi a, c ar di ac arr est, 
c ar di ac f ail ur e, c er e br al h e m orr h a g e, c o m a, d e e p v ei n t hr o m b osis, diss e mi n at e d  i ntr a v asc ul ar 
c o a g ul ati o n, 
g astr oi nt esti n al 
h e m orr h a g e, 
h e m ol ytic 
a n e mi a, 
h e m o pt ysis, 
h e p atic 
f ail ur e, 
h y p ert h yr oi dis m, h y p oxi a, i nt erstiti al p n e u m o nitis, i nt esti n al p erf or ati o n, i ntr acr a ni al h e m orr h a g e, 
m ali g n a nt l y m p h o m a, 
m arr o w d e pr essi o n, 
m e ni n gitis, 
MI, p a ncr e atitis, p ar alysis, p e ptic ulc er, 
p eric ar ditis, p erit o nitis, p n e u m ot h or ax, p ol y my ositis, pr o gr essi v e 
m ultif oc al l e u k o e nc e p h al o p at h y, 
ps e u d o m e m br a n o us c olitis, p ul m o n ary e d e m a, p ul m o n ary e m b olis m, p ul m o n ary fi br osis, r e n al 
d ysf u ncti o n, r es pir at ory alk al osis, r es pir at ory d e pr essi o n, s ec o n d ary l e u k e mi a, s eiz ur e ( gr a n d m al), 
s pl e nic i nf arcti o n, stri d or, s u b ar ac h n oi d h e m orr h a g e, s y nc o p e, t oxic n e p hr o p at h y, tr a nsf or m ati o n t o 
a g gr essi v e l y m p h o m a, tr a nsf or m ati o n t o pr ol y m p h oc ytic l e u k e mi a, t hr o m b oc yt h e mi a,  t hr o m b o p hl e bitis, 
v e ntric ul ar arr h yt h mi a, v e ntric ul ar t ac h yc ar di a  
 
A nti -t h y m oc yt e Gl o b uli n, H ors e ( A T G, At g a m ®) 
A T G is a  p urifi e d pr e p ar ati o n of h ors e g a m m a -gl o b uli n w hic h c o nt ai ns hi g h c o nc e ntr ati o ns of a nti b o di es 
a g ai nst h u m a n l y m p h oc yt es.  T h e pr e p ar ati o n m a y c o nt ai n l o w l e v els of a nti b o d y w hic h cr oss -r e act wit h 
h u m a n pl at el ets, w hit e c ells, or r e d c ells.  
A d v ers e E v e nts ass oci at e d wit h A T G i ncl u d e:   C ar di ov asc ul ar : Br a dyc ar di a, c ar di ac irr e g ul arit y, c h est p ai n, 
e d e m a, h e art f ail ur e, h y p er -/ h y p ot e nsi o n, my oc ar ditis; C e ntr al n erv o us syst e m: A git ati o n, c hills, f e v er, 
h e a d ac h e, l et h ar g y, li g ht h e a d e d n ess, listl ess n ess, s eiz ur e, vir al e nc e p h al o p at h y; D er m at ol o gic: Pr urit us, 
r as h, urtic ari al; G astr oi nt esti n al: Di arr h e a, n a us e a, st o m atitis, v o miti n g; H e m at ol o gic:  L e u k o p e ni a, 
t hr o m b oc yt o p e ni a; 
H e p atic: 
H e p at os pl e n o m e g aly, liv er f u ncti o n t ests a b n or m al; L oc al: B ur ni n g 
s ol es/ p al ms, i nj ecti o n sit e r e acti o ns ( p ai n, r e d n ess, s w elli n g), p hl e bitis, t hr o m b o p hl e bitis; N e ur o m usc ul ar 
& sk el et al: Ac h es, art hr al gi a, b ac k p ai n, j oi nt stiff n ess, my al gi a; Oc ul ar: P eri or bit al e d e m a; R e n al: 
Pr ot ei n uri a, r e n al f u ncti o n t ests a b n or m al; R es pir at ory: D ys p n e a, pl e ur al eff usi o n, r es pir at ory distr ess; 
Misc ell a n e o us: A n a p hyl actic r e acti o n, di a p h or esis, l y m p h a d e n o p at h y, ni g ht s w e ats, s er u m si c k n ess, vir al 
i nf ecti o n; R ar e b ut i m p ort a nt or lif e-t hr e at e ni n g: A b d o mi n al p ai n, ac ut e r e n al f ail ur e, a n a p h yl act oi d 
r e acti o n, a n e mi a, a pl asi a, a p n e a, c o nf usi o n, c o u g h, d e e p v ei n t hr o m b osis, dis ori e nt ati o n, dizzi n ess, 
e osi n o p hili a, e pi g astric p ai n, e pist axi s, eryt h e m a, f ai nt n ess, fl a n k p ai n, GI bl e e di n g, GI p erf or ati o n, 
gr a n ul oc yt o p e ni a, h e m ol ysis, h e m ol ytic a n e mi a, h er p es si m pl ex r e acti v ati o n, hicc u ps, h y p er gl yc e mi a, ili ac 
v ei n o bstr ucti o n, i nf ecti o n, i nv ol u nt ary m ov e m e nt, ki d n e y e nl ar g e d/r u pt ur e d, l ary n g os p as m, m al ais e, 

 
C o nfi d e nti al  
P a g e 3 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
n e utr o p e ni a, p a nc yt o p e ni a, p ar est h esi a, p ul m o n ary e d e m a, r e n al art ery t hr o m b osis, ri gi dit y, s or e 
m o ut h/t hr o at, t ac h yc ar di a, t oxic e pi d er m al n ecr osis, tr e m or, v asc ulitis, vir al h e p atitis, w e a k n ess, w o u n d 
d e hisc e nc e  
 
H y dr o x y ur e a ( H U, H y dr e a ®)  
H y dr ox y ur e a is a  sy nt h esiz e d a g e nt, w hic h  c a us es i n hi biti o n of ri b o n ucl e oti d e r e d uct as e.  It is p h as e -
s p ecific, wit h its l et h al eff ect i n S p h as e.  It r e a dil y p ass es t h e bl o o d -br ai n b arri er, ac hi e vi n g p e a k C S F l e v els 
at 3 h o urs.  A b o ut 5 0 % is d e gr a d e d i n t h e liv er a n d excr et e d i n t h e uri n e as ur e a a n d as r es pir at ory c ar b o n 
di oxi d e.   
A d v ers e E v e nts ass oci at e d wit h Hy dr ox y ur e a i ncl u d e :  C ar di ov asc ul ar: E d e m a; C e ntr al n erv o us syst e m: 
C hills, dis ori e nt ati o n, dizzi n ess, dr o wsi n ess ( d os e -r el at e d), f e v er, h all uci nati o ns, h e a d ac h e, m al ais e, 
s eiz ur e; D er m at ol o gic: Al o p eci a, c ut a n e o us v asc ulitic t oxiciti es, d er m at o my ositis -lik e ski n c h a n g es, f aci al 
eryt h e m a, g a n gr e n e, h y p er pi g m e nt ati o n, m ac ul o p a p ul ar r as h, n ail atr o p hy, n ail disc ol or ati o n, p eri p h er al 
eryt h e m a, sc ali n g , s ki n atr o p hy, s ki n c a nc er, s ki n ulc er, v asc ulitis ulc er ati o ns, vi ol et p a p ul es; E n d ocri n e & 
m et a b olic: Hy p er uric e mi a; G astr oi nt esti n al: A n or exi a, c o nsti p ati o n, di arr h e a, g astr oi nt esti n al irrit ati o n 
a n d 
m uc ositis, ( p ot e nti at e d 
wit h r a di ati o n t h er a py), n a us e a, p a ncr e atitis, st o m atitis, v o miti n g; 
G e nit o uri n ary: D ys uri a; H e m at ol o gic: M y el os u p pr essi o n ( a n e mi a, l e u k o p e ni a/ n e utr o p e ni a [c o m m o n], 
t hr o m b oc yt o p e ni a; h e m at ol o gic r ec ov ery: wit hi n 2 w e e ks); m acr oc yt osis, m e g al o bl astic eryt hr o p oi esis, 
s ec o n d ary l e u k e mi as (l o n g-t er m 
us e); 
H e p atic: 
H e p atic 
e nzy m es i ncr e as e d, 
h e p at ot oxicit y; 
N e ur o m usc ul ar & sk el et al: P eri p h er al n e ur o p at h y, w e a k n ess; R e n al: B U N i ncr e as e d, cr e ati ni n e i ncr e as e d, 
r e n al t u b ul ar d ysf u ncti o n; R es pir at ory: Ac ut e diff us e p ul m o n ary i nfiltr at es (r ar e), d ys p n e a, p ul m o n ary 
fi br osis (r ar e) N ot e : r e n al i m p air m e nt e n h a nc es t oxicit y of t h e dr u g. 
 
Rit u xi m a b ( Rit u x a n ®)  
Rit uxi m a b is a  g e n etic all y e n gi n e er e d c hi m eric 
m uri n e/ h u m a n 
m o n ocl o n al a nti b o d y, w hic h  bi n ds 
s p ecific all y t o t h e a nti g e n C 2 0 ( h u m a n B l y m p h oc yt es r estrict e d diff er e nti ati o n a nti g e n, B p 3 5) l oc at e d o n 
t h e s urf ac e of pr e B a n d m at ur e B l y m p h oc yt es of b ot h n or m al a n d m ali g n a nt c ells.  T h e a nti b o d y is a n 
IfF 1 k a p p a i m m u n o gl o b uli n c o nt ai ni n g m uri n e li g ht- a n d h e a v e -c h ai n v ari a bl e r e gi o n s e q u e nc es a n d 
h u m a n c o nst a nt r e gi o n s e q u e nc es.  Rit uxi m a b is c o m p os e d of t w o h e a v y c h ai ns of 4 5 1 a mi n o aci ds a n d 
t w o li g ht c h ai ns of 2 1 3 a mi n o aci ds a n d h as a n a p pr oxi m at e m ol ec ul ar w ei g ht of 1 4 5 k D.  It is pr o d uc e d 
i n m a m m ali a n c ell ( C hi n es e H a mst er O v ary) c ult ur e. 
A d v ers e E v e nts ass oci at e d wit h Rit uxi m a b  i ncl u d e:  C ar di ov asc ul ar: Fl us hi n g, h y p er -/ h y p ot e nsi o n, 
p eri p h er al e d e m a; C e ntr al n erv o us syst e m: A nxi et y, c hills, dizzi n ess, f ati g u e, f e v er, h e a d ac h e, i ns o m ni a, 
mi gr ai n e, p ai n; 
D er m at ol o gic: 
A n gi o e d e m a, pr urit us, r as h, u rtic ari al; E n d ocri n e 
& 
m et a b olic: 
Hy p er gl yc e mi a; G astr oi nt esti n al: A b d o mi n al p ai n, di arr h e a, d ys p e psi a, n a us e a, v o miti n g, w ei g ht g ai n; 
H e m at ol o gic: 
A n e mi a, 
c yt o p e ni a, l y m p h o p e ni a, l e u k o p e ni a, 
n e utr o p e ni a, 
n e utr o p e nic f e v er, 
t hr o m b oc yt o p e ni a; H e p atic: AL T incr e as e d; N e ur o m usc ul ar & sk el et al: Art hr al gi a, b ac k p ai n, m uscl e 
s p as m, 
my al gi a, n e ur o p at h y, p ar est h esi a, w e a k n ess; R es pir at ory: Br o nc h os p as m, c o u g h, d ys p n e a, 
e pist axis, r hi nitis, si n usitis, t hr o at irrit ati o n, u p p er r es pir at ory tr act i nf ecti o n; Misc ell a n e o us: I nf usi o n -
r el at e d r e acti o ns ( m a y i ncl u d e a n gi o e d e m a, br o nc h os p as m, c hills, dizzi n ess, f e v er, h e a d ac h e, h y p er -
/ h y p ot e nsi o n, 
my al gi a, n a us e a, pr urit us, r as h, ri g ors, urtic ari a, a n d v o miti n g); i nf ecti o n (i ncl u di n g 
b act eri al, vir al, f u n g al); ni g ht s w e ats; h u m a n a ntic hi m eric a nti b o d y ( H A C A) p ositi v e; R ar e b ut i m p ort a nt 

 
C o nfi d e nti al  
P a g e 3 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
or lif e -t hr e at e ni n g: Ac ut e r e n al f ail ur e, a n a p h yl act oi d r e acti o n/ a n a p hyl axis, a n gi n a, a pl astic a n e mi a, 
A R D S, arr h yt h mi a, b o w el o bstr ucti o n/ p erf or ati o n, br o nc hi olitis o blit er a ns, c ar di ac f ail ur e, c ar di o g e nic 
s h oc k, 
e nc e p h al o my elitis, f at al i nf usi o n-r el at e d r e acti o ns, f ul mi n a nt 
h e p atitis, g astr oi nt esti n al 
p erf or ati o n, h e m ol ytic a n e mi a, h e p atic f ail ur e, h e p atitis, h e p atitis B r e acti v ati o n, h y p ervisc osit y 
sy n dr o m e (i n 
W al d e nstr ö m’s 
m acr o gl o b uli n e mia), h y p o g a m m a gl o b uli n e mi a ( pr ol o n g e d), h y p oxi a, 
i nt erstiti al p n e u m o nitis, l ary n g e al e d e m a, lic h e n oi d d er m atitis, l u p us-lik e s y n dr o m e, m arr o w h y p o pl asi a, 
MI, m uc ositis, m uc oc ut a n e o us r e acti o n, n e utr o p e ni a (l at e -o ns et occ urri n g > 4 0 d ays aft er l ast d os e), o pt ic 
n e uritis, p a nc yt o p e ni a ( pr ol o n g e d), p ar a n e o pl astic p e m p hi g us ( u nc o m m o n), pl e uritis, p n e u m o ni a, 
p n e u m o nitis, p ol y artic ul ar art hritis, p ol y my ositis, p ost eri or r e v ersi bl e e nc e p h al o p at h y sy n dr o m e ( P R E S), 
pr o gr essi v e 
m ultif oc al l e u k o e nc e p h al o p at h y ( P ML), p ur e r e d c ell a pl asi a, r e n al t oxicity, r e v ersi bl e 
p ost eri or l e u k o e nc e p h al o p at h y sy n dr o m e ( R PL S), s er u m sic k n ess, St e v e ns -J o h ns o n sy n dr o m e, 
s u pr a v e ntric ul ar arr h yt h mi a, syst e mic v asc ulitis, t oxic e pi d er m al n ecr ol ysis, t u b erc ul osis r e acti v ati o n, 
t u m or l ysis sy ndr o m e, u v eitis, v asc ulitis wit h r as h, v e ntric ul ar fi brill ati o n, v e ntric ul ar t ac h yc ar di a, 
v esic ul o b ull o us d er m atitis, vir al r e acti v ati o n (i ncl u d es J C vir us, c yt o m e g al ovir us, h er p es si m pl ex vir us, 
p arv o vir us B 1 9, v aric ell a z ost er vir us, W est Nil e vir us, a n d h e p atitis C), w h e ezi n g .  
 
T acr oli m us ( Pr o Gr af ®)  
T acr oli m us is a m acr oli d e i m m u n os u p pr ess a nt pr o d uc e d b y Str e pt o myc es ts u k u b a e nsis . T acr oli m us 
i n hi bits T-l y m p h oc yt e acti v ati o n, alt h o u g h t h e ex act m ec h a nis m of acti o n is n ot k n o w n. Ex p eri m e nt al 
e vi d e nc e s u g g ests t h at t acr oli m us bi n ds t o a n i ntr ac ell ul ar pr ot ei n, F K B P -1 2, i n hi biti n g t h e p h os p h at as e 
acti vit y of c alci n e uri n a n d r es ulti n g i n t h e i n hi biti o n of T -l y m p h oc yt e acti v ati o n (i m m u n os u p pr essi o n). T h e 
pl as m a pr ot ei n bi n di n g of t acr oli m us is a p p r oxi m at el y 9 9 % a n d is i n d e p e n d e nt of c o nc e ntr ati o n ov er a 
r a n g e of 5-5 0 n g/ mL. T acr oli m us is b o u n d m ai nly t o al b u mi n a n d al p h a -1 -aci d gl yc o pr ot ei n, a n d h as a hi g h 
l e v el of ass oci ati o n wit h eryt hr oc yt es. T h e T½  i n a d ult p ati e nts r a n g es fr o m 1 1-1 9 h o urs. F ol l o wi n g or al 
a d mi nistr ati o n, t h e a bs ol ut e bi o a v ail a bilit y w as 3 1 ± 2 1 %. T acr oli m us is ext e nsi v el y m et a b oliz e d b y t h e 
mix e d -f u ncti o n oxi d as e syst e m, pri m arily t h e c yt oc hr o m e P-4 5 0 syst e m ( C Y P 3 A) i n t h e liv er a n d t o a l ess er 
ext e nt i n t h e i nt esti n al m uc os a. T h e m ai n r o ut e of eli mi n ati o n is vi a t h e bili ary tr act a n d excr eti o n i n f ec es.  
A d mi nistr ati o n wit h f o o d si g nific a ntl y d ecr e as es t h e r at e a n d ext e nt of a bs or pti o n Dr u gs t h at sti m ul at e or 
i n hi bit h e p atic P 4 5 0 e nzy m es will alt er cl e ar a nc e of t acr oli m us a n d clos e att e nti o n t o p ot e nti al dr u g 
i nt er acti o ns is cr uci al. 
A d v ers e E v e nts ass oci at e d wit h T acr oli m us i ncl u d e h y p ert e nti o n , n a us e a, v o miti n g, i m m u n os u p pr essi o n, 
tr e m or, ac ut e a n d c hr o nic ki d n e y i nj ury, h y p o m a g n es e mi a, h y p o/ h y p erk al e mi a, s eiz ur e, c o nf usi o n, 
s o m n ol e nc e, l e u k o p e ni a, a n e mi a, t hr o m b oc yt o p e ni a.  
 
T hi ot e p a  
T hi ot e p a is a c yt ot oxic a g e nt of t h e p ol yf u ncti o n al t y p e, r el at e d c h e mic all y a n d p h ar m ac ol o gic all y t o 
nitr o g e n m ust ar d. T h e r a di o mi m etic acti o n of t hi ot e p a is b eli e v e d t o occ ur t hr o u g h t h e r el e as e of 
et h yl e ni mi n e r a dic als w hic h, lik e irr a di ati o n, disr u pt t h e b o n ds of D N A. O n e of t h e pri nci p al b o n d 
disr u pti o ns is i niti at e d b y al kyl ati o n of g u a ni n e at t h e N -7 p ositi o n, w hic h s e v ers t h e li n k a g e b et w e e n t h e 
p uri n e b as e a n d t h e s u g ar a n d li b er at es alk yl at e d g u a ni n es. T hi ot e p a is d es ulf ur at e d b y c yt oc hr o m e P -4 5 0 
e nzy m es s uc h as 2 B 1 a n d 2 C 1 1 w hic h c at alyz e t h e c o n v ersi o n of t hi ot e p a t o t e p a. T e p a is l ess t oxic t h a n 
t hi ot e p a a n d h as b e e n d e m o nstr at e d t o pr o d uc e alk ali-l a bil e sit es i n D N A, r at h er th a n cr oss -li n ks. T h es e 
fi n di n gs i n dic at e t h at t e p a r e acts diff er e ntl y fr o m t hi ot e p a a n d pr o d uc es m o n of u ncti o n al alk yl ati o n of 

 
C o nfi d e nti al  
P a g e 3 9  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
D N A. A s ec o n d 
m et a b olit e of t hi ot e p a, a 
m erc a pt uric aci d c o nj u g at e, is f or m e d vi a gl ut at hi o n e 
c o nj u g ati o n. M o n oc hl or ot e p a is t h e t hir d m et a b olit e f o u n d i n t h e uri n e.  F oll o wi n g s h ort i ntr a v e n o us 
i nf usi o n (l ess t h a n 5 mi n ut es), p e a k c o nc e ntr ati o ns of t hi ot e p a w er e m e as ur e d wit hi n 5 mi n ut es. At st e a d y 
st at e, t h e v ol u m e of distri b uti o n w as i n d e p e n d e nt of d os e a n d r a n g e d fr o m 0. 3 t o 1. 6 lit ers p er kil o gr a m 
(L/ k g).   A p pr oxi m at el y 4. 2 % of t h e ori gi n al d os e is eli mi n at e d i n t h e uri n e wit hi n 2 4 h o urs as t e p a. T h e 
eli mi n ati o n h alf -lif e of t hi ot e p a r a n g es fr o m 2. 3 t o 2. 4 h o urs. T h e h alf-lif e of t e p a r a n g e d fr o m 3 t o 2 1. 1 
h o urs i n o n e st u dy.  
A d v ers e e v e nts ass oci at e d wit h T hi ot e p a i ncl u d e : C e ntr al n erv o us syst e m: C hills, dizzi n ess, f ati g u e, f e v er, 
h e a d ac h e; D er m at ol o gic: Al o p eci a, c o nt act d er m atitis, d e pi g m e nt ati o n ( wit h t o pic al tr e at m e nt), 
d er m atitis, r as h, urtic ari a;  E n d ocri n e 
& 
m et a b olic: 
A m e n orr h e a, s p er m at o g e n esis i n hi biti o n; 
G astr oi nt esti n al: A b d o mi n al p ai n, a n or exi a, n a us e a, v o miti n g; G e nit o uri n ary: D ys uri a, uri n ary r et e nti o n; 
H e m at ol o gic: A n e mi a, bl e e di n g, l e u k o p e ni a, t hr o m b oc yt o p e ni a; L oc al: I nj ecti o n sit e p ai n; N e ur o m usc ul ar 
& sk el et al : 
W e a k n ess; Oc ul ar: Bl urr e d visi o n, c o nj u ncti vitis; R e n al: H e m at uri a; R es pir at ory: Ast h m a, 
e pist axis, l ary n g e al e d e m a, w h e ezi n g; Misc ell a n e o us: All er gic r e acti o n, a n a p h yl actic s h oc k, i nf ecti o n; R ar e 
b ut i m p ort a nt or lif e -t hr e at e ni n g: Ac ut e my el oi d l e u k e mi a ( A ML), c h e mic al c ystitis ( bl a d d er i nstill ati o n), 
h e m orr h a gic c ystitis ( bl a d d er i nstill ati o n), m y el o d ys pl astic sy n dr o m e  
 
 

 
C o nfi d e nti al  
P a g e 4 0  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
5. 5  
Ris ks of St u d y Pr oc e d ur es  
 
Bl o o d Dr a w  
Risks of bl o o d dr a w or v e ni p u nct ur e ar e t y pic all y mi ni m al wit h t e m p or ary l oc al disc o mf ort.  M or e  s eri o us 
risks w o ul d i ncl u d e ecc h y m osis a n d, r ar el y, l oc aliz e d i nf ecti o n.  T h e a m o u nt of bl o o d t h at m a y b e dr a w n 
fr o m a d ult s u bj ects f or r es e arc h p ur p os es will n ot b e m or e t h a n 5 5 0  mL ov er a n ei g ht -w e e k p eri o d . F or 
p e di atric p ati e nts, n o m or e t h a n 3  mL/ k g m a y b e dr a w n i n a si n gl e d ay, a n d n o m or e t h a n 9. 5 mL/ k g m ay 
b e dr a w n ov er a ny ei g ht -w e e k p eri o d .  T h e a d diti o n al a m o u nt of bl o o d c o ul d c o ntri b ut e t o t h e 
d e v el o p m e nt of a n e mi a.  T h e s u bj ect’s cli nic al c o n diti o n will b e t a k e n i nt o c o nsi d er ati o n t o d et er mi n e  if 
r es e arc h bl o o d t ests c a n b e p erf or m e d. 
 
Br o nc h osc o p y a n d Br o nc h o al v e ol ar L a v a g e  
Br o nc h osc o pi es will b e p erf or m e d, a n d r es e arc h s a m pl es o bt ai n e d, u nl ess m e dic all y c o ntr ai n dic at e d, as 
p art of r o uti n e p ost -tr a ns pl a nt c ar e.  St u dy p artici p a nts will n ot u n d er g o r es e arc h br o nc h osc o pi es, 
t h er ef or e t h e risks d et ail e d b el o w will b e i nc urr e d r e g ar dl ess of st u dy p artici p ati o n.   St u dy s p ecific risk is 
li mit e d t o t h e c oll ecti o n of t h e br o nc hi al br us hi n g a n d t h e r es e arc h B AL s am pl e.  
T h e m ost c o m m o n risks ass oci at e d wit h br o nc h osc o p y i ncl u d e mi n or bl e e di n g, li mit e d t o t h e ar e a of t h e 
br o nc h osc o p e a n d occ urri n g d uri n g t h e pr oc e d ur e, s or e t hr o at, c o u g h, f e v er, f ati g u e, a n d/ or mil d 
h o ars e n ess.   T h es e ar e i nfr e q u e nt a n d us u ally dis a p p e ar b y t h e n ext d a y.    
 
B o n e M arr o w As pir at e  
A b o n e m arr o w as pir at e will b e p erf or m e d pri or t o B M T i n or d er t o o bt ai n a s a m pl e f or r es e arc h 
p ur p os es. T his t est m ay b e p ai nf ul. T h er e is als o a s m all risk of i nf ecti o n or bl e e di n g. T h e p ai n n or m all y 
l ess e ns wit hi n mi n ut es t o h o urs.    
5. 6  
P ot e nti al B e n efits  
T his pr ot oc ol m a y pr ovi d e n o dir ect b e n efit. If t h e l u n g tr a ns pl a nt a n d b o n e m arr o w tr a ns pl a nt is 
s ucc essf ul, t h e s u bj ect’s l u n g dis e as e a n d i m m u n e d efici e nc y m a y i m pr ov e. T h e r es ults of t his st u dy 
c o ul d i nfl u enc e t h e f ut ur e c ar e of tr a ns pl a nt e d p ati e nts.   

 
C o nfi d e nti al  
P a g e 4 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
6  I n v esti g ati o n al I nt er v e nti o n 
6. 1  
C a d a v eric B o n e M arr o w H ar v est a n d Pr e p ar ati o n of C D 3 +/ C D 1 9 + H e m at o p oi etic St e m 
C ell s 
 
B o n e M arr o w  H ar v est  
•  
B o n e m arr o w w ill b e h arv est e d usi n g st a n d ar d b o n e m arr o w h arv est n e e dl es fr o m t h e a nt eri or 
a n d p ost eri or ili ac cr ests.  T h e l oc al O P O will b e c o nt act e d i n a d v a nc e a n d t h eir v er b al ass e nt will 
b e o bt ai n e d n otifyi n g t h e m t h at t h e b o n e m arr o w h arv est t e a m will arri v e t o g et h e r wit h t h e 
l u n g pr oc ur e m e nt t e a m fr o m t h e U niv ersit y of Pitts b ur g h e arl y s o b o n e m arr o w h arv est c a n b e 
p erf or m e d wit h ext er n al a p pr o ac h pri or t o t h e h arv esti n g of ot h er or g a ns a n d w hil e t h e h e art is 
b e ati n g.  T h e g o al is t o h arv est  b et w e e n 1 0 a n d 2 5 mL/ k g of d o n or w ei g ht ( u p t o 4 0 ml/ k g 
r eci pi e nt w ei g ht) of m arr o w pri or t o r e m ov al of i nt er n al or g a ns. 
•  
If s uffici e nt b o n e m arr o w is h arv est e d fr o m t h e d o n or ( > 3. 0 x 1 07 M N C/ k g b o d y w ei g ht ), a 
r es erv e u p t o 5 % m a y b e fr oz e n a n d st or e d as a  s af et y m e as ur e s h o ul d t h e r eci pi e nt h a v e a n 
iss u e wit h e n gr aft m e nt or ot h er c o m plic ati o n(s) t h at n ec essit at e s a d o n or l e u k oc yt e i nf usi o n 
( DLI).   
•  
V ert e br al  b o di es  will b e r e m ov e d  f or pr oc essi n g a n d st e m c ell extr acti o n i n t h e St e m C ell 
L a b or at ory at t h e C hil dr e n’s H os pit al of Pitts b ur g h  a n d t h e pr oc ess e d pr o d uct will b e s a v e d as 
a n  a dj u nct st e m c ell u nit as d escri b e d b y D o n n e n b er g et al  [ 2 4, 2 5]. A n i nt er n al a p pr o ac h m a y 
als o b e utiliz e d f or m arr o w h arv est fr o m t h e ili ac cr ests aft er r e m ov al of i nt er n al p el vic or g a ns.  
•  
M arr o w a n d c ells will b e s us p e n d e d i n R P MI wit h h e p ari n [ 2 6].  
•  
B o n e m arr o w fr o m t h e ili ac cr ests a n d v ert e br al b o di es will b e i n d e p e n d e ntl y c oll ect e d, 
acc essi o n e d, st or e d, a n d tr a ns p ort e d.  
 
B o n e M arr o w Pr oc essi n g  
•  
B o n e m arr o w fr o m t h e ili ac cr es t a n d t h e v ert e br al b o di es will b e i n d e p e n d e ntl y pr oc ess e d a n d 
cry o pr es erv e d.  B ot h pr o d ucts will u n d er g o i n d e p e n d e nt e v al u ati o n f or r el e as e crit eri a.  
•  
B o n e m arr o w o bt ai n e d fr o m ili ac cr est a n d v ert e br al b o di es will b e d e pl et e d of C D 3 + a n d C D 1 9 + 
c ells usi n g t h e Cli ni M A C S ® d e vic e ( Milt e n yi Bi ot ec h) d escri b e d i n t h e i nstit uti o n al st a n d ar d 
o p er ati n g pr oc e d ur es ( S O P).  
•  
T h e C D 3 +/ C D 1 9 + d e pl et e d b o n e m arr o w c ells will b e t est e d f or vi a bilit y ( T N C c o u nt), P ot e nc y 
( C D 3 4 + c ell c o u nt, C D 3 + c ell c o u nt), st erilit y a n d e n dot oxi n l e v el pri or t o cry o pr es erv ati o n.  
•  
T h e C D 3 4 + c o u nt a n d C D 3 + c o u nt i n t h e n e g ati v el y s el ect e d pr o d ucts pri or t o cry o pr es erv ati o n 
will b e us e d t o c alc ul at e t h e t ot al C D 3 4 + a n d C D 3 + c ells t o b e a d mi nist er e d (s e e 6. 1. 3. B M T 
d os a g e a n d a d mi nistr ati o n).  
•  
St e m c ell pr o d ucts will b e cry o pr es erv e d p er st a n d ar d C H P st e m c ell l a b pr oc e d ur e.  
A s m all p erc e nt a g e of gr afts, fr o m t h e ili ac cr ests or v ert e br al b o di es, m a y b e p ositi v e f or c o nt a mi n ati o n. 
If t h e gr aft r el e as e t esti n g s h o ws micr o bi al c o nt a mi n ati o n, t h e st erilit y r es ults will b e r e vi e w e d b y t h e 

 
C o nfi d e nti al  
P a g e 4 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
D e p art m e nt of I nf ecti o us Dis e as es (I D) f ac ult y. T h e I nv esti g at ors will f oll o w t h e r ec o m m e n d ati o ns of t h e 
I D f ac ult y r e g ar di n g t h e cli nic all y a p pr o pri at e pr o p hyl axis or tr e at m e nt of t h e s u bj ect t h at is n ec ess ary t o 
co nti n u e wit h t h e B M T a n d t his will b e d oc u m e nt e d i n t h e m e dic al r ec or d. T his is st a n d ar d cli nic al 
pr actic e wit hi n t h e Divisi o n of B o n e M arr o w Tr a ns pl a nt a n d C ell ul ar T h er a pi es ( B M T C T).  
6. 1. 2  
B M T D os a g e a n d A d mi nistr ati o n  
I n or d er t o pr oc e e d t o c o n diti o ni n g f or BM T, t h e f oll o wi n g crit eri a s h o ul d b e m et : 
a.  T ar g et C D 3 4 +:  ≥1x 1 0 6 c ells/ k g  
b.  T ar g et C D 3 +: < 1x 1 0 5 c ells/ k g  
c. T ar g et t ot al n ucl e at e d c ells ( T N C) vi a bilit y: ≥7 0 %  
d.  N e g ati v e f or all t est e d a d v e ntiti o us a g e nts  
e.  N e g ati v e b act eri a f or 1 4 -d ay c ult ur e  
f. E n d ot oxi n l e v el: < 5 E U/ k g b o d y w ei g ht/ h o ur of a d mi nistr ati o n  
St e m c ell pr o d uct will b e us e d fr o m t h e ili ac cr ests a n d/ or v ert e br al b o di es u nl ess t h e c ell ul ar pr o d uct 
o bt ai n e d fr o m t h e v ert e br al b o di es w o ul d r es ult i n f ail ur e t o m e et r el e as e crit eri a, or if t h e us e of t h e 
c ellul ar pr o d uct fr o m t h e v ert e br al b o di es w o ul d r es ult i n exc e e di n g t h e m axi m u m all o w a bl e t hr es h ol d 
f or C D 3 + c ells. T h e c ell ul ar pr o d ucts will b e i nf us e d s e p ar at el y a n d m ay b e i nf us e d i n a n y or d er h o w e v er 
t h er e s h o ul d b e a p pr oxi m at el y 2 h o urs b et w e e n i nf usi o ns.  
Fr es hl y t h a w e d C D 3 a n d C D 1 9 n e g ati v el y s el ect e d c a d a v eric h e m at o p oi etic st e m c ell pr o d uct ( b o n e 
m arr o w fr o m ili ac cr ests a n d/ or v ert e br al b o di es) will b e  dil ut e d ( 3 -4 f ol d) wit h l o w m ol ec ul ar w ei g ht 
d extr a n i n s o di u m c hl ori d e wit h a d d e d h u m a n al b u mi n a n d  i nf us e d o n d a y 0 of t h e tr e at m e nt r e gi m e n 
vi a c e ntr al li n e, p er i nstit uti o n al g ui d eli n es.  T h er e will b e n o pr oc essi n g of t h e c ells aft er t h a wi n g.  
 
Cr y o pr e s er v e d D o n or L e u k oc yt e  I nf usi o n ( DLI) 
T h e s o urc e of DLI m a y b e fr o m eit h er t h e ili ac or v ert e br al b o n e m arr o w .  
D o n or L e u k oc yt e i nf usi o n ( DLI) fr o m n o n -T c ell d e pl et e d fr acti o n of c a d a v eric b o n e m arr o w will b e 
c o nsi d er e d f or t h os e p ati e nts w h o d e m o nstr at e:    
a) N o e vi d e nc e of C D 3 + T c ell r ec o nstit uti o n aft er d a y 3 0  p ost -B M T ( 1 0 C D 3 + T c ells p er micr olit er as c ut 
off v al u e), or  
b) Ex p eri e nc e si g nific a nt d ecli n e i n d o n or c hi m eris m ( wit h a dr o p of at l e ast 1 0 % i n m y el oi d or T c ell 
fr acti o ns fr o m t h e pr e vi o us or p e a k v al u e ), or  
c) Si g nific a nt vir al or ot h er  o p p ort u nistic i nf ecti o n w h er e a nti g e n s p ecific DLI is n ot a v ail a bl e.  
Excl usi o n crit eri a f or DLI :  A n y st a g e of visc er al G V H D or St a g e 2 or hi g h er s ki n G V H D is a n a bs ol ut e 
c o ntr ai n dic ati o n f or DLI. Pr e vi o us r ec ei pt of DLI is n ot a n excl usi o n.   
 

 
C o nfi d e nti al  
P a g e 4 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
6. 2  
Dr u g Acc o u nt a bilit y  
U n d er Titl e 2 1 of t h e C o d e of F e d er al R e g ul ati o ns ( 2 1 C F R § 3 1 2. 6 2), t h e i nv esti g at or wil l m ai nt ai n a d e q u at e 
r ec or ds of t h e dis p ositi o n of t h e C D 3 + C D 1 9 + d e pl et e d b o n e m arr o w , i ncl u di n g t h e d at e a n d q u a ntit y of 
t h e bi ol o gic r ec ei v e d, t o w h o m t h e bi ol o gic w as dis p e ns e d ( p artici p a nt-by -p artici p a nt acc o u nti n g), a n d a 
d et ail e d acc o u nti n g of a n y bi ol o gic t h at is acci d e nt all y or d eli b er at el y d estr oy e d.  
 
T h e st u dy sit e will m ai nt ai n r ec or ds f or r ec ei pt, st or a g e, us e, a n d dis p ositi o n  of t h e bi ol o gic .  A dis p e nsi n g 
l o g will b e k e pt c urr e nt f or e ac h s u bj ect.  T his l o g will c o nt ai n t h e i d e ntific ati o n of eac h s u bj ect a n d t h e 
d at e a n d q u a ntit y of bi ol o gic pr o d uct dis p e ns e d.  
 
All r ec or ds r e g ar di n g t h e dis p ositi o n of t h e i nv esti g ati o n al pr o d uct will b e a v ail a bl e f or i ns p ecti o n.  
U n us e d pr o d uct will b e d e -i d e ntifi e d a n d st or e d.  T h e y m a y b e utiliz e d f or l a b or at ory st u di es.   
6. 3  
T o xicit y Pr e v e nti o n a n d M a n a g e m e nt  
 
Ac ut e C ell ul ar R ej ecti o n  ( A C R) Pri or t o t h e B M T  
If t h e s u bj ect ex p eri e nc es A C R pri or t o r ec ei vi n g t h e B M T, t h e r ej ecti o n e pis o d e m ust r es ol v e t o a 
p at h ol o g y of < A 2 -A 4 a n d < B 2 R pri or t o pr oc e e di n g t o t h e B M T  [ 4 1]. A C R is tr e at e d p er t h e i nstit uti o n al 
st a n d ar d of c ar e, w hic h t y pic all y i ncl u d es a d e pl eti o n a g e nt. O nc e t h e f oll o w -u p bi o psy crit eri a h a v e 
b e e n m et, t h e l u n g tr a ns pl a nt t e a m will ass ess t h e st a bilit y of t h e s u bj ect t o d et er mi n e B M T eli gi bilit y.  
6. 4  
Pr e m at ur e Disc o nti n u ati o n of I n v esti g ati o n al A g e nt  
 
Pr e m at ur e Disc o nti n u ati o n of t h e  B M T  
T h e i nf usi o n of h e m at o p oi etic st e m c ells m a y  b e disc o nti n u e d if t h e s u bj ect h as a h y p ers e nsiti vit y 
r e acti o n, a ny i nf usi o n r el at e d s eri o us a d v ers e e v e nt, or a n y ot h er m e dic al c o n diti o n t h at, i n t h e o pi ni o n 
of t h e i nv esti g at or , w o ul d pr ecl u d e c o nti n u e d p artici p ati o n.  If t h e s u bj ect r ec ei v e d a ny p orti on of t h e 
i nf usi o n, h e/s h e will b e f oll o w e d p er t h e m ai n Sc h e d ul e of E v e nts o utli n e d i n A p p e n dix 2 . 

 
C o nfi d e nti al  
P a g e 4 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
7  Pr ot oc ol M a n d at e d M e dic ati o ns  
7. 1  
L u n g Tr a ns pl a nt I m m u n os u p pr essi o n  
 
I n d ucti o n T h er a p y  
B asilixi m a b is t h e t y pic al i n d ucti o n t h er a py a n d will b e a d mi nist er e d p er t h e p ac k a g e i ns ert a n d a dj ust e d 
f or a g e, if t his is us e d f or i n d ucti o n. Ot h er i n d ucti o n t h er a pi es s uc h as Al e mt uz u m a b m ay b e c o nsi d er e d 
if t h er e is j ustific ati o n b as e d o n t h e s u bj ect’s u n d erl yi n g dis e as e. T his will b e at t h e discr eti o n of t h e l u n g 
tr a ns pl a nt p hysici a n.  
 
M ai nt e n a nc e I m m u n os u p pr essi o n  
I n a d diti o n t o t h e T acr oli m us o utli n e d b el o w, s u bj ects m ay b e o n c o nc urr e nt m ai nt e n a nc e 
i m m u n os u p pr essi v e m e dic ati o ns p ost B OL T a n d s u bs e q u e ntl y p ost B M T as cli nic all y i n dic at e d. T his m ay 
i ncl u de myc o p h e n ol at e m of etil or m yc o p h e n olic aci d as w ell as pr e d nis o n e.  
 
T acr oli m us  
T acr oli m us will b e st art e d at t h e ti m e of l u n g tr a ns pl a nt a n d will b e c o nti n u e d wit h o ut i nt err u pti o n 
t hr o u g h t h e B M T c o n diti o ni n g a n d p ost-tr a ns pl a nt p eri o d. D os e a dj ust m e nt f or  t wic e d aily d osi n g will ai m 
f or tacr oli m us  tr o u g h l e v els b et w e e n 8-1 2 n g/ ml if t ol er at e d.  D os e a dj ust m e nts m a y b e m a d e o n t h e b asis 
of t oxicit y. W h e n t h e s u bj ect  is a d mitt e d o n d ay -4  pri or t o B M T , t acr oli m us m a y b e a d mi nist er e d I V t o 
m ai nt ai n a st e a d y st at e of 1 2-1 8 n g/ ml or alt er n at el y, t h e s u bj ect m a y r e m ai n o n or al t acr oli m us  at t h e 
discr eti o n of t h e I nv esti g at or.  
A n alt er n at e 
m ai nt e n a nc e i m m u n os u p pr essi v e 
m e dic ati o n(s) 
m a y b e c o nsi d er e d if t h e s u bj ect 
ex p eri e nc es a cli nic al c o m plic ati o n or t o xicit y.  
 
Rit uxi m a b  
A  si n gl e d os e of rit uxi m a b will b e a d mi nist er e d j ust pri or t o t h e l u n g tr a ns pl a nt  or u p t o 4 8 h o urs p ost -
tr a ns pl a nt at a d os e of 3 7 5 m g/ m 2. T h e n , as cli nic all y i n dic at e d if t h er e ar e si g ns of B c ell r ec ov ery ( ≥ 1 0 
c ells/ µL). R it uxi m a b m ay b e h el d as l o n g as t h e s u bj ect h as n o B c ells ( < 1 0  c ells/µL).  Pr e -m e dic ati o ns f or 
Rit uxi m a b will f oll o w t h e i nstit uti o n al st a n d ar d of c ar e.  
7. 2  
C o n diti o ni n g R e gi m e n f or  B M T  
 
H y dr o x y ur e a  
Hy dr ox y ur e a will b e gi v e n or all y at a si n gl e d aily d os e of 3 0 m g/ k g, r o u n d e d t o t h e n e ar est pill siz e, st arti n g 
o n d ay  -2 8 a n d c o nti n ui n g t hr o u g h d ay -3.  Fil gr asti m at 2 -5 mc g/ k g d os e will b e a d mi nist er e d as n e e d e d 
e v ery 2 -3 d ays if t h e A N C is <1 5 0 0 c ells/ µL  a n d/ or f or a ny ot h er si g ns of b o n e m arr o w s u p pr essi o n.  
Hy dr ox y ur e a will b e h el d f or A N C < 5 0 0 c ells/ µL a n d r es u m e d w h e n A N C > 1 0 0 0 c ells/ µL . 
 
Rit u xi m a b  
I n pr e p ar ati o n f or B M T, Rit uxi m a b will b e a d mi nist er e d o n d ay -2 8 at a d os e of 3 7 5 m g/ m 2 a n d t h e n a g ai n 
at d ay + 3 5 t o pr e v e nt t h e d e v el o p m e nt of P TL D i n t h e s et ti n g of a T c ell d e pl et e d gr aft. Pr e-m e dic ati o ns 
m a y b e gi v e n as o utli n e d a b ov e i n S ecti o n 7. 1. 2. 2 .   

 
C o nfi d e nti al  
P a g e 4 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
 
Al e mt uz u m a b  
O n e d os e of Al e mt uz u m a b will b e gi v e n I V at a d os e of 0. 5 m g/ k g o n d a y -1 4  t o s u bj ects wit h o ut 
pr e vi o us A C R . S u bj ect s wit h pr e vi o us A C R  of ≥A 2 -A 4 a n d/ or ≥B 2 R  will r ec ei v e t w o d os es of 
Al e mt uz u m a b o n D ays -2 1 a n d -2 0  at 0. 5 m g/ k g .  Pr e-m e dic ati o ns f or Al e mt uz u m a b will f oll o w t h e 
i nstit uti o n al st a n d ar d of c ar e.    
 
A nti -t h y m oc yt e Gl o b uli n, H ors e ( A T G, At g a m ®)  
A T G ( A T G A M) will b e gi v e n I V o n d ay s -3  t o -1  at a d os e of 3 0 m g/ k g .  Pr e-m e dic ati o ns f or A T G will f oll o w 
t h e i nstit uti o n al st a n d ar d of c ar e.  
 
T hi ot e p a  
T hi ot e p a will b e gi v e n I V at a d os e of 2 5 0 m g/ m 2 dil ut e d t o a fi n al c o nc e ntr ati o n of 2 m g/ mL i n 0. 9 % 
s o diu m c hl ori d e gi v e n ov er 2 h o urs x  1 d os e o n d a y -2.  
 
T ot al B o d y Irr a di ati o n ( T BI)  
T BI  at  2 5 0 c G y ( 2 0 0c G y f or s u bj ects wit h a r a di ati o n s e nsiti v e c o n diti o n) wit h l u n g s hi el di n g will b e gi v e n 
o n d a y -1 ; liv er s hi el di n g will n ot b e utiliz e d.   
L u n g s hi el di n g will n ot b e utiliz e d  f or s u bj ects wit h pr e vi o us A C R of ≥ A 2 a n d/ or ≥B 2 R; t his is i nt e n d e d t o 
miti g at e t h e p ot e nti al eff ects of pri or all oi m m u nit y . A d diti o n al or g a n s hi el di n g e. g. g o n a d al s hi el di n g  o nly  
f or f ertilit y pr es erv ati o n will b e all o w e d  b as e d u p o n t h e i nv esti g at or’s discr eti o n.      
7. 3  
Gr o wt h F act or S u p p ort  
S u bj ect s will r ec ei v e G-C S F 5 mc g/ k g/ d ay I V fr o m d ay + 1 u ntil e n gr aft e d a n d t h e n t a p er e d acc or di n g t o 
i nstit uti o n al pr actic e or as cli nic all y i n dic at e d . D os e a dj ust m e nt is p er mitt e d as  cli nic all y i n dic at e d.  
7. 4  
I nf ecti o n Pr o p h yl a xis 
I nf ecti o n pr o p hyl axis f oll o ws t h e i nstit uti o n al st a n d ar d of c ar e at U P M C.  
 
P n e u m oc ystis jir o v ecii ( P C P)  
Tri m et h o pri m/ s ulf a m et h ox az ole  will b e  i niti at e d wit hi n t h e first a p pr oxi m at el y 2 -3 w e e ks  f oll o wi n g l u n g 
tr a ns pl a nt a n d c o nti n u e u ntil d a y -2 pr e -B M T.  It will r es u m e p ost B M T  at 3  d ays/ w e e k o nc e A N C > 2 0 0 0 
a n d pl at el ets > 5 0, 0 0 0 a n d c o nti n u e u ntil 6 m o nt hs p ost B M T or u ntil off all i m m u n os u p pr e ssi o n, 
w hic h e v er c o m es l at er.  P e nt a mi di n e , at 4 m g/ k g I V , will b e gi v e n e v ery 3 w e e ks st arti n g o n D a y 2 8  a n d 
c o nti n u e u ntil p ati e nts ar e a bl e t o t a k e  tri m et h o pri m/ s ulf a m et h ox az ol e. If a s u bj ect i n u n a bl e t o 
t ol er at e t h es e r e gi m e ns, ot h er r e gi m e ns m ay b e s u bstit ut e d at t h e discr eti o n of t h e st u dy p h ysici a n.  
 
H er p es Si m pl e x Vir us ( H S V) a n d/ or V aric ell a Z ost er Vir us ( V Z V)  
Or al ac ycl ovir or v al ac ycl ovir will b e i niti at e d f oll o wi n g t h e l u n g tr a ns pl a nt p er i nstit uti o n al g ui d eli n es  
a n d c o nti n u e f or 3 m o nt hs or l o n g er as cli nic all y i n dic at e d . F oll o wi n g B M T, Ac ycl ovir pr o p hyl axis at 2 5 0 
m g/ m 2/ d os e I V e v ery 1 2 h o urs  will b e gi v e n t o a n y  s u bj ect w h os e pr e -tr a ns pl a nt s er ol o gi es or P C R w er e 
p osit i v e f or H er p es Si m pl ex Vir us ( HS V) or V aric ell a Z ost er Vir us ( V Z V). Ac ycl ovir will b e c o nti n u e d f or at 
l e ast 1 -y e ar p ost b o n e m arr o w tr a ns pl a nt, or l o n g er as cli nic all y i n dic at e d.  T h e s u bj ect will b e 
tr a nsiti o n e d t o or al ac ycl ovir or v al ac ycl ovir o nc e t h ey ar e  a bl e t o  t ol er at e or al m e dic ati o ns. If s u bj ects 

 
C o nfi d e nti al  
P a g e 4 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
ar e t a ki n g  a n a nti vir al f or a n ot h er i n dic ati o n ( e. g. C M V t h er a py) t h at pr ovi d es a d e q u at e c ov er a g e f or 
HS V a n d V Z V, a d diti o n al pr o p hyl axis is n ot n ec ess ary.   
 
F u n g al Pr o p h yl a xis    
S u bj ect s will b e m ai nt ain e d o n a p pr o pri at e f u n g al pr o p h yl axis f oll o wi n g l u n g tr a ns pl a nt ati o n, a n d will 
r e m ai n o n c as p of u n gi n, v oric o n az ol e, or a n ot h er a p pr o pri at e a g e nt u ntil t h e C D 4 + T-c ell c o u nt is > 2 0 0 or 
l o n g er as cli nic all y i n dic at e d. 
 
T o x o pl as m osis  
All p ati e nts s h o ul d h a v e t ox o pl as m a s er ol o g y e v al u at e d pri or t o B M T .  S er o p ositi v e p ati e nts s h o ul d 
r ec ei v e pr o p hyl axis wit h tri m et h o pri m/s ulf a m et h ox az ol e ( or a n  a p pr o pri at e s u bstit ut e) b ef or e a n d aft er 
tr a ns pl a nt ati o n p er t h e i nstit uti o n al st a n d ar d of c ar e . 
 
C yt o m e g al o vir us ( C M V)  
All  s u bj ects s h o ul d b e m o nit or e d f or r e acti v ati o n or pri m ary  i nf ecti o n b as e d o n t h e c urr e nt i nstit uti o n al 
st a n d ar d of c ar e fr o m p ost l u n g tr a ns pl a nt t hr o u g h d ay 1 0 0 p ost B M T .  F oll o wi n g l u n g tr a ns pl a nt, all 
s u bj ects will b e o n C M V pr o p hyl axis b as e d o n t h e U P M C l u n g tr a ns pl a nt g ui d eli n es. All s u bj ects at risk 
f or C M V dis e as e ( e. g.,  eit h er r eci pi e nt or d o n or s er o p ositi v e f or C M V)  will r ec ei v e I V g a ncicl ovir or or al 
v al g a ncicl ovir d ail y d uri n g B M T c o n diti o ni n g r e gi m e n u ntil D a y -2 f oll o w e d b y F osc ar n et or Ci d of ovir as 
cli nic all y i n dic at e d.   O nc e e n gr aft m e nt occ urs, s u bj ects m a y b e s witc h e d b ac k t o g a ncicl ovir  or 
v al g a ncicl ovir .  
 
E pst ei n -B arr Vir us  ( E B V) a n d A d e n o vir us I nf ecti o ns   
All s u bj ects s h o ul d b e m o nit or e d f or r e acti v ati o n or i nf ecti o n b as e d o n t h e  c urr e nt i nstit uti o n al st a n d ar d 
of c ar e .  T his i ncl u d es t esti n g p ost l u n g tr a ns pl a nt t hr o u g h d a y 1 0 0 p ost B M T .    
 
Intr a v e n o us I m m u n o gl o b uli n (I VI G ) 
F oll o wi n g B M T, I VI G at 5 0 0 m g/ k g/ d os e s h o ul d b e gi v e n e v ery 2 w e e ks u ntil d a y + 1 0 0, t h e n e v ery 4 
w e e ks u ntil f u ncti o n al B c ell r ec ov ery ( pr o d ucti o n of I g M a n d I g A) acc or di n g t o i nstit uti o n al pr actic e 
p ost -tr a ns pl a nt. 
7. 5  
V e n o -occl usi v e Dis e as e Pr o p h yl a xis  
All  s u bj ects will r ec ei v e urs o di ol f or pr o p hyl axis of v e n o -occl usi v e dis e as e ( V O D)  ar o u n d t h e ti m e of B M T .  
Urs o di ol will b e gi v e n or ally fr o m d ay -2 t o d ay + 1 0 0.  Urs o di ol m a y b e h el d f or p ati e nts u n a bl e t o t a k e 
or al m e dic ati o ns.  S u bj ect s m e eti n g crit eri a f or V O D ( h y p er bilir u bi n e mi a, p ai nf ul h e p at o m e g aly, ascit es, 
a n d fl ui d r et e nti o n) will b e tr e at e d acc or di n g t o l oc al i nstit uti o n al g ui d eli n es.  M o d er at e t o s e v er e V O D 
m a y b e tr e at e d wit h d efi br oti d e .    
7. 6  
Gr a n ul oc yt e I nf usi o n(s)  
Gr a n ul oc yt e s u p p ort is n ot pr ot oc ol m a n d at e d b ut m ay b e a d mi nist er e d at t h e discr eti o n of t h e B M T 
p hysici a n a n d i n acc or d a nc e wit h l oc al i nstit uti o n al g ui d eli n es. S u bj ects will r ec ei v e p uls e oxi m etry 
t hr o u g h o ut t h e i nf usi o n a n d c o nti n u o us c ar di ac m o nit ori n g  for  3 0 mi n ut es pri or t o t h e gr a n ul oc yt e 
i nf usi o n t hr o u g h 6 0 mi n ut es f oll o wi n g t h e gr a n ul oc yt e i nf usi o n.  
7. 7  
Pr o hi bit e d M e dic ati o ns  

 
C o nfi d e nti al  
P a g e 4 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
Pr o hi bit e d m e dic ati o ns f or t his pr ot oc ol, exc e pt as s p ecific all y i n dic at e d i n t his pr ot oc ol i ncl u d e:  
•  
Li v e v acci n es 
7. 8  
Wit h dr a w al of I m m u n os u p pr essi o n P ost -B M T  
Wit h dr a w al of t acr oli m us or t h e c urr e nt m ai nt e n a nc e i m m u n os u p pr essi o n will b e c o nsi d er e d n o l ess 
t h a n 1 2  m o nt hs p ost B OL T a n d at m o nt h 9  p ost B M T if all t h e f oll o wi n g crit eri a ar e m et.  
•  
> 5 % d o n or T -c ell c hi m eris m  
•  
N o e vi d e nc e of Gr a d e 2 or > ac ut e G V H D  a n d/ or ext e nsi v e c hr o nic G V H D  i n t h e pr e vi o us 3 
m o nt hs  
•  
N o l u n g r ej ecti o n  ( gr a d e A 2 or hi g h er) i n t h e pr e vi o us 3 m o nt hs 
•  
At t h e ti m e of i m m u n os u p pr essi o n w e a n i niti ati o n, F E V 1 ≥ 0. 9 * F E V 1 of t h e m ax F E V 1 d uri n g t h e 
pri or 9 0 d a ys   
If t h e su bj ect m e ets t h e wit h dr a w al crit eri a, i m m u n os u p pr essi o n m a y b e t a p er e d b y a p pr oxi m at el y 1 0 % 
w e e kly or as cli nic all y i n dic at e d. D uri n g t his ti m e, s u bj ects will c o nti n u e t o r ec ei v e s urv eill a nc e bi o psi es 
a n d c h est x -r a ys as cli nic all y i n dic at e d, wit h r e g ul ar P F Ts a n d bl o o d t ests  i n acc or d a nc e wit h t h e p ost 
l u n g tr a ns pl a nt st a n d ar d of c ar e t o m o nit or f or si g ns of all o gr aft r ej ecti o n at t h e discr eti o n of t h e st u dy 
p hysici a n.  
A n y s u bj ect w h o ex p eri e nc es l u n g all o gr aft r ej ecti o n d uri n g i m m u n os u p pr essi o n w e a ni n g or aft er 
i m m u n os u p pr essi o n wit h dr a w al will h a v e m ai nt e n a nc e i m m u n os u p pr essi o n r ei nst at e d, t h e r ej ecti o n 
will b e tr e at e d, a n d m ai nt e n a nc e i m m u n os u p pr essi o n will n ot b e dis c o nti n u e d d uri n g t h e pr ot oc ol 
m a n d at e d f oll o w -u p p eri o d.    

 
C o nfi d e nti al  
P a g e 4 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
8  St u d y Pr oc e d ur es  
8. 1  
E nr oll m e nt  
T h e r es e arc h st u dy will b e ex pl ai n e d i n l ay t er ms t o e ac h p ot e nti al r es e arc h s u bj ect. T h e p ot e nti al 
s u bj ect will si g n a n i nf or m e d c o ns e nt f or m b ef or e u n d er g oi n g a n y st ud y pr oc e d ur es . T h e s u bj ect a n d/ or 
g u ar di a ns will m e et wit h a p h ysici a n t o disc uss t h e tr e at m e nt r ec o m m e n d ati o ns a n d alt er n ati v e 
tr e at m e nt o pti o ns.  T h e risks of b ot h t h e l u n g a n d b o n e m arr o w tr a ns pl a nt  will b e o utli n e d s e p ar at el y, 
i ncl u di n g t h e risks of t oxiciti es ass ociat e d wit h t h e pr oc e d ur es  a s w ell as t h eir p ost -tr a ns pl a nt m e dic al 
t h er a pi es.  C o ns e nt will b e o bt ai n e d usi n g f or ms a p pr ov e d by t h e U niv ersit y of Pitts b ur g h I nstit uti o n al 
R e vi e w B o ar d.  If t h e p ot e nti al s u bj ect a n d/ or p ar e nt/ g u ar di a n(s) ar e n ot a bl e t o c o m e  t o C H P t o h a v e 
t h e i nf or m e d c o ns e nt disc ussi o n i n p ers o n (i. e. o ut of  st at e r esi d e nts, t o o ill t o tr a v el, etc.), t h e 
disc ussi o n m a y  b e c o n d uct e d vi a t el ec o nf er e nc e wit h all of t h e s a m e m e m b ers (s u bj ect, 
p ar e nt / g u ar di a n, p hysici a n, r es e arc h t e a m). C o ns e nt d oc u m e nts will b e si g n e d at b ot h l oc ati o ns as 
a p pr o pri at e a n d t h e s u bj ect a n d/ or  p ar e nt/ g u ar di a n  will s e n d t h eir ori gi n al si g n e d c o ns e nt t o t h e 
r es e arc h t e a m. T h e ori gi n al si g n e d c o ns e nts will b e c o m bi n e d a n d a c o p y will b e s e nt b ac k t o t h e s u bj ect 
a n d/ or p ar e nt / g u ar di a n.   
8. 2  
Scr e e ni n g/ B as eli n e Visit  Pr e -L u n g Tr a ns pl a nt 
T h e i niti al scr e e ni n g visit (V isit L-1 ) t a k es pl ac e pri or t o t h e l u n g tr a ns pl a nt a n d b e gi ns w h e n t h e s u bj ect 
si g ns t h e i nf or m e d c o ns e nt u ntil all eli gi bilit y crit eri a ar e a v ail a bl e. D uri n g t h e  scr e e ni n g p eri o d, st u dy 
p ers o n n el will r e vi e w t h e s u bj ect’s m e dic al r ec or d f or p ast a n d c urr e nt m e dic al hist ory, p erf or m a 
p hysic al ex a m a n d c oll ect a n y n ec ess ary l a b w ork/st u dy pr oc e d ur es as o utli n e d i n t h e Sc h e d ul e of 
E v e nts ( A p p e n dix 1 ). T h e s u bj ect m a y h a v e h a d c ert ai n ass ess m e nts c o n d uct e d as a p art of t h eir r o uti n e 
cli nic al c ar e a n d t h es e r es ults m ay b e us e d if t h e y f all wit hi n a n acc e pt a bl e wi n d o w as o utli n e d i n t h e 
Sc h e d ul e of E v e nts.   
8. 3  
Scr e e ni n g/ B as eli n e Visit Pr e -B M T  
S u bj ects w h o c o ns e nt t o t h e s t u dy a n d r ec ei v e a l u n g tr a ns pl a nt m ust m e et s p ecific eli gi bilit y crit eri a i n 
or d er m ov e o nt o t h e b o n e m arr o w tr a ns pl a nt. St u dy ass ess m e nts ar e o utli n e d i n t h e Sc h e d ul e of E v e nts 
( A p p e n dix 2 ). I n a d diti o n, all eli gi bilit y as o utli n e d i n S ecti o n 4. 3 m ust b e m et. T his i nv olv es cl e ar a nc e 
fr o m t h e l u n g tr a ns pl a nt t e a m i n or d er t o m ov e o nt o t h e B M T. S u bj ects w h o d o n ot m e et eli gi bilit y 
a n d/ or ar e n ot cl e ar e d b y t h e l u n g tr a ns pl a nt t e a m c a n n ot m ov e  o nt o t h e n ext p orti o n of t h e st u dy a n d 
will b e f oll o w e d acc or di n g t o A p p e n dix 1. T his als o p ert ai ns t o s u bj ects w h o c a n n ot b e tr a ns pl a nt e d d u e 
t o a n i ns uffici e nt d o n or b o n e m arr o w h arv est.  
S u bj ects m ay b e gi n B M T c o n diti o ni n g n o l ess t h a n 8 w e e ks p ost l u n g tr a ns pl a nt . I d e ally s u bj ects will 
r ec ei v e t h eir B M T  n o l at er t h a n 9 m o nt hs p ost -tr a ns pl a nt; h o w e v er, s u bj ects m ay b e c o nsi d er e d b e y o n d 
t his ti m e-p oi nt wit h t h e a p pr ov al of t h e B M T T e a m.    
8. 4  
St u d y Visits or St u d y Ass ess m e nts  
 
P ost -L u n g Tr a ns pl a nt St u d y Ass ess m e nts  

 
C o nfi d e nti al  
P a g e 5 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
9   M ec h a nistic Ass a ys  
9. 1  
C hi m eris m  
C hi m eris m will b e ass ess e d usi n g  P C R b as e d S T R ass a y fr o m w h ol e bl o o d, C D 3 3 + e nric h e d my el oi d c ells, 
a n d C D 3 + T -c ells i n t h e cli nic al HL A l a b pr e -B OL T a n d 3 m o nt hs p ost B OL T. Aft er B M T it will b e t est e d at 
m o nt hs 1,  3,  6,  1 2 a n d t h e n y e arl y. S m all r es e arc h s p eci m e ns fr o m B AL  a n d m atc h e d bl o o d s a m pl es will 
b e s u bj ect e d t o hi g h -r es ol uti o n m elt pr ofili n g ( H R M) P C R  ass a ys  i nt err o g ati n g d o n or ori gi n i n l e u k oc yt e 
s u bs ets. If f e asi bl e, F A C S s ort e d C D 1 2 3+/ C D 1 1c - pl as m ac yt oi d D C a n d C D 4 +/ C D 1 2 7 -/ C D 4 9 d-/ C D 2 5bri g ht 
“T -r e gs” will b e t est e d . W h e n d o n or -r eci pi e nt s p ecific r e a g e nts ar e a v ail a bl e, HL A-s p ecific a nti b o di es will 
i nt err o g at e f or d o n or ori gi n wit h o ut t h e n e e d f or F A C s orti n g.  
9. 2  
Gl o b al C ell ul ar I m m u nit y  
T esti n g f or gl o b al/syst e mic i m m u nit y will b e p erf or m e d fr o m p eri p h er al bl o o d.  
L y m p h oc yt e s u bs ets, i ncl u di n g p erc e nt a g e a n d a bs ol ut e n u m b ers of C D 3 +, C D 4 +, C D 8 +, C D 1 9 +, a n d 
C D 1 6/ 5 6 + c ells al o n g wi t h N K T c ells a n d ga m m a d elt a T c ells.  
Dis e as e -s p ecific ass ess m e nts of i m m u n e f u ncti o n i n p ati e nts wit h T-c ell l y m p h o p e ni a (S CI D, CI D i n 
p artic ul ar) n or m aliz ati o n of C D 4 +, C D 8 + T c ell c o u nts ar e i n dic ati v e of s ucc essf ul B M T.  D e m o nstr ati o n of 
IL-7 R al p h a ex pr essi n g T c ells will b e a d o n or -s p ecific m ark er of i m m u n e c orr ecti o n i n IL-7 R al p h a n ull 
S CI D. Si mil arl y, acti v ati o n i n d uc e d C D 4 0 li g a n d ex pr essi o n will d e m o nstr at e c orr ecti o n of C D 4 0L 
d efici e nc y, i n d e p e n d e nt of t h e c hi m eris m st u di es. F A C S b as e d n e utr o p h il oxi d ati v e b urst t esti n g will 
d e m o nstr at e c orr ecti o n f or p ati e nts wit h C G D a n d r est or e d IL -1 7, IL -2 2 s ecr eti o n i n r es p o ns e t o 
C D 3/ C D 2 8 a n d micr o bi al sti m ul ati o n i n p ati e nts wit h S T A T 3 d efici e nt J o b’s sy n dr o m e. T h e pr es e nc e of 
I g A i n p ati e nts wit h C VI D alo n g wit h I VI G i n d e p e n d e nc e t o m ai nt ai n n or m al I g G l e v els ar e als o s p ecific 
m ark ers . 
B c ell r ec ov ery: 8 c ol or B c ell F A C S p a n el  will m o nit or B  c ell r ec o nstit uti o n t hr o u g h a p pr o pri at e 
d e v el o p m e nt al st a g es.  
9. 3  
T h y mic F u ncti o n  
 
T -c ell R ec o v er y 
T R E C ass a y, T C R V b et a , T C R Vg a m m a/ d elt a  B C R r e p ert oir e ( all est a blis h e d , u p a n d r u n ni n g i n t h e 
Sz a b olcs L a b).  
 
Fl o w C yt o m etr y  
Ass ess m e nt of t h y m us f u ncti o n a n d m e m ory, i ncl u di n g 8 c ol or fl o w c yt o m etry f or n aiv e, c e ntr al 
m e m ory, eff ect or m e m ory p h e n ot y p es . C ell t ur n ov er i n s u bs ets will b e m e as ur e d b y st ai ni n g f or 
i ntr ac ell ul ar m ark ers of pr olif er ati o n a n d a p o pt osis (Ki -6 7, a cti v at e d C as p 3)  ( all est a blis h e d, u p a n d 
r u n ni n g i n t h e Sz a b olcs L a b). 
 
 

 
C o nfi d e nti al  
P a g e 5 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
9. 4  
P at h o g e n S p ecific I m m u nit y  
P at h o g e n -s p ecific i m m u nit y will b e t est e d wit h micr o bi al a nti g e ns t h at s u bj ects h a v e b e e n ex p os e d t o 
pri or t o tr a ns pl a nt. T h es e m a y i ncl u d e b ut n ot n ec ess aril y li mit e d t o As p er gill us, Ps e u d o m o n as, 
St a p h yl oc occ us, C a n di d a, a d e n ovir us, i nfl u e nz a, R S V, a n d h e r p es vir us es ( HS V, C M V, a n d E B V). T h e 
pr o p os e d ass a ys ar e:   
•  
C yt o ki n e fl o w c yt o m etry ( C F C) or T etr a m er st ai ni n g ( Mc D y er L a b) t o d et ect p at h o g e n s p ecific T h 1, 
T h 1 7 c ells, pr ovi d e d ly m p h oc yt e n u m b ers p er mit t his ass a y. HL A -s p ecific M o A bs will t est f or d o n or 
ori gi n of t h es e c ells i n c as es of mix e d T c ell c hi m eris m.  
•  
L u mi n ex b as e d m ulti pl ex c yt oki n e d et ecti o n i n micr oc ult ur e s u p er n at a nts.  
•  
ELI S P O T ass a y t o e n u m er at e I F N -s ecr eti n g a nti vir al c ells if C F C or T etr a m er st ai ni n g n ot f e asi bl e   
•  
A nti g e n s p ecific h u m or al i m m u nit y will b e t est e d o nc e p ati e nts ar e off I VI G ( ~ 6-1 2 m o nt hs aft er 
B M T) m e as uri n g tit ers b ef or e a n d aft er v acci n ati o n wit h D T a P a n d h e p atitis B v acci n es.  
•  
I ntr ac ell ul ar fl o w c yt o m etry or L u mi n ex/ Bi o Pl ex c yt oki n e d et ecti o n will i d e ntify IL-1 7, I F N -, IL-2 2, 
T NF - s ecr eti n g c ells i n B AL, i n r es p o ns e t o Ps e u d o m o n as, As p er gill us, C a n di d a, a n d ot h er 
p at h o g e ns, pr e vi o usl y e nc o u nt er e d b y e nr oll e d s u bj ects. At ti m es of l y m p h o p e ni a, Bi o Pl ex a n d 
ELI S P O T will r e pl ac e F A C S ass a ys.  
•  
Vir al/ p at h o g e n s p ecific t etr a m er s t ai n, C F C if a p plic a bl e a n d f e asi bl e t o d et ect m e m ory r es p o ns es i n 
vir us -s p ecific C D 4 + a n d C D 8 + c ells i n b ot h P B M C a n d B AL c ells, as pr e vi o usl y d escri b e d. W e will 
ass ess  f or t h e pr es e nc e of ex -vi v o m ultif u ncti o n al ( T c ells t h at pr o d uc e I F N-, T NF-, IL-2 , gr a nzy m e 
B, C D 1 0 7 a ( m ark er of c yt ot oxic d e gr a n ul ati o n ) a n d at 6 d a ys i n c o nj u ncti o n wit h ass ess m e nt of 
pr olif er ati o n usi n g C F S E -dil uti o n.  A n i n a bilit y t o pr olif er at e a n d pr o d uc e m ulti pl e c yt oki n es w o ul d 
w arr a nt t h e e v al u ati o n f or p ot e nti al ex h a usti o n or a p o pt osis of  T c ells, vi a  P D -1 , F as or ot h er 
m ec h a nis ms as pr e vi o usl y p u blis h e d . T c ell p h e n ot y pi n g ( e. g. C D 2 7, C D 2 8, C D 5 7) i n c o nj u ncti o n wit h 
C M V cl ass I t etr a m er ( or ot h er cl ass I t etr a m ers a v ail a bl e) st ai ni n g at d a ys 0 a n d 6 ( ass essi n g 
pr olif er ati o n) ar e als o r o uti n e p erf or m e d.  
9. 5  
R N A S e q u e nci n g ( br o nc hi al br us hi n gs)  
T h er e ar e  R N As e q a p pr o ac h es t o m e as ur e T c ell r ec o nstit uti o n i n pri m at e l u n g e pit h eli u m ( b ot h h u m a n 
a n d n o n -h u m a n) t o ass ess t h e i nt e grit y of T h 1, T h 2, T h 1 7, T h 2 2 r es p o ns es i n l u n g usi n g cli nic al br o nc hi al 
br us hi n gs. P r eli mi n ary d at a i n h u m a ns s h o w t h at t his a n alysis c a n als o m e as ur e t h e pr es e nc es of s p ecific 
T c ell r ec e pt or g e n es a n d T c ell eff ect or c yt oki n es i n t h e l u n g m uc os a. T h us, t his will b e a r o b ust w a y t o 
m e as ur e i m m u n e r ec o nstit uti o n a s w ell as r es ol uti o n of fr ustr at e d h y p er i m m u n e r es p o ns es i n t h e 
m uc os a as h as b e e n s h o w n t o occ ur i n C G D, m or e o v er, as t h es e p ati e nts u n d er g o r e g ul arl y sc h e d ul e d 
br o nc h osc o p y, w e c a n ass ess m uc os al i m m u n e r ec o nstit uti o n i n s eri al s a m pl es.  
9. 6  
T ol er a nc e Ass a ys  
N e w ass a ys wit h p urifi e d p ot e nt A P C ( m o n oc yt e -d eri v e d or C D 3 4 + -d eri v e d  d e n dritic c ells  fr o m d o n or 
a n d  h ost b o n e m arr o w ) h a v e b e e n d e v el o p e d t o est a blis h  v ery s e nsiti v e i n vitr o m o d els c a p a bl e t o 
m o nit or f or alt er ati o ns i n all or e acti vit y  Hi g h r es ol uti o n s e q u e nc e b as e d T C R V b et a r e p ert oir e  a n alysis 
will m o nit or f or pr es e nc e , ki n etics, a n d q u a ntit y of all or e ac ti ve cl o n es t hr o u g h s eri al ti m e p oi nts t h at ar e 

 
C o nfi d e nti al  
P a g e 5 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
c al e n d ar dri v e n a n d/ or pr o m pt e d b y t a p er of i m m u n os u p pr essi o n.  A d diti o n al ass a ys will  b e pr o m pt e d 
b y n e w o ns et l u n g r ej ecti o n or G V H D. 
At fix e d p oi nts,  w e will q u a ntit at e a n d c h ar act eriz e p urifi e d T c ell s, eit h er fr o m d o n o r, h ost or b ot h (i n 
c as e of mix e d T c ell c hi m eris m),  all or e acti vit y i n m o difi e d mix e d l y m p h oc yt e c ult ur es ( ML C) .  Micr o 
c ult ur es of o n e -w a y  ML C will b e s et u p a g ai nst h ost d e n dritic c ells t o st u dy G V H r e acti o ns. I n c as es of 
mix e d T c ell c hi m eris m i n p ar all el micr oc ult ur es T  c ells will b e t est e d a g ai nst  d o n or A P Cs as w ell . 
R es p o n d ers will b e p urifi e d  T c ells fr o m  circ ul ati o n or fr o m B AL is ol at es if f e asi bl e.  
W e will a n al yz e a n d c o m p ar e t h e d o n or -h ost r ati o of T c ells, A P Cs i n t h e circ ul ati o n a n d als o fr o m B AL.  
W e will a n al yz e t h e n u m b ers , t ur n ov er, a n d  d o n or -h ost ori gi n of Tr e gs, q u a ntit at e t h e ex pr essi o n of 
F ox p P 3 a n d H eli os a n d will m e as ur e HL A -G ex pr essi o n i nt e nsit y of circ ul ati n g m y el oi d D C ( m D C). HL A -G 
ex pr essi o n w as f o u n d t o c orr el at e wit h F ox P 3 ex pr essi o n i n t h e t ol er a nt s u bs et of p e di atric liv er S O T 
r eci pi e nts ( 4 6). HL A-s p ecific a nti b o di es s ho ul d assist i n t h e si m ult a n e o us i d e ntific ati o n of 
C D 1 2 3 + pl as m ac yt oi d D C, ( p D C) a n d C D 1 2 3 -/ C D 1 1c + m D C s u bs ets al o n g wit h t h eir h ost-d o n or ori gi ns. 
I nt er esti n gl y, i n a C H P p ati e nt c o h ort, hi g h p D C/ m D C r ati o h as b e e n o bs erv e d t o pr e dict s ucc essf ul 
wit h dr a w al of I S T i n liv er tr a ns pl a nt p ati e nts. W e will t est d o n or p D C/ m D C r ati o fr o m d o n or bl o o d 
o bt ai n e d at t h e ti m e of or g a n pr oc ur e m e nt a n d t h e n s eri all y t o t est f or si mil ar c orr el ati o n wit h 
t ol er a nc e i n t h e l u n g + b o n e m arr o w tr a ns pl a nt s etti n g. 
All or e acti v e T c el l r es p o ns es will b e c at e g oriz e d as eit h er pr o-i nfl a m m at ory b as e d o n (I F N, T NF, IL-1 7 , 
G M -C S F ) or a nti-i nfl a m m at ory (IL-1 0 , T G F b et a ) a g ai nst t h e all o g e n eic h ost-r eci pi e nt t ar g et. T h e f or m er 
pr ofil e h as b e e n ass oci at e d wit h r ej ecti o n a n d/ or G V H D, w hil e t h e  l att er h as b e e n d escri b e d t o pr o m ot e 
acti v e t ol er a nc e wit h n o ass oci at e d c yt ot oxicit y b et w e e n d o n or a n d r eci pi e nt.  
S u p er n at a nts will b e a n al yz e d b y Bi o Pl ex f or T h 1/ Tc 1, T h 2/ Tc 2, T h 1 7, Tr 1 , a n d Tr e g si g n at ur e c yt oki n es. 
I n p ar all el, micr oc yt oxicit y ass a ys  ( E ur o pi u m l a b ell e d t ar g ets a d d e d t o ML C) will ex a mi n e c yt ol ytic 
p ot e nti al of t h e s a m e p o p ul ati o n a n d c orr el at e wit h t h e c yt oki n e si g n at ur e, as pr e vi o usl y p u blis h e d.  
W h e n t esti n g b ul k p o p ul ati o ns, t h e c yt oki n e pr ofil e a n d c yt ot oxicit y  ass a ys will b e p erf or m e d wit h or 
wit h o ut Tr e g d e pl eti o n, tri g g er e d b y IL -2 -i m m u n ot oxi n a n d wit h or wit h o ut IL -1 0 r ec e pt or bl oc k a d e  t o 
t est f or Tr 1 c ell acti vit y. 
9. 7  
Ex pr essi o n Pr ofili n g  
Fr o m r eci pi e nt P B M C dr a w n pr e -B OL T , fr acti o n at e d c ells will b e fr oz e n for R N A a n al ysis a n d 
u nfr acti o n at e d c ells will b e cry o pr es erv e d.  Si mil arl y, B OL T d o n or m arr o w M N C or  P B M C will b e 
fr acti o n at e d i nt o m aj or l y m p h s u bs ets ( C D 4+, C D 8 +, C D 1 9 +) a n d cry o pr es erv e d  t o m ak e t h e m acc essi bl e 
f or f ut ur e st u di es t h at m ay i n v ol v e i d e ntific ati o n of g e n e si g n at ur e s a n d i m m u n e p at h w a ys of 
t ol er a nc e/ all or e acti vit y. A n y r e m ai ni n g l y m p h oc yt es a n d D Cs m ay b e cry o pr es erv e d f or g e n e ex pr essi o n 
pr ofili n g ass a ys.  

 
C o nfi d e nti al  
P a g e 5 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 0  Bi os p eci m e n  St or a g e  
Bi ol o gic al s p eci m e ns (i. e., w h ol e bl o o d, pl as m a, s er u m, tiss u e, B AL fl ui d a n d b o n e m arr o w) o bt ai n e d 
u n d er t his pr ot oc ol m a y b e us e d i n f ut ur e ass a ys t o r e e v al u at e bi ol o gic al r es p o ns es as a d diti o n al 
r es e arc h t ests ar e d e v el o p e d ov er ti m e. T h es e s p eci m e ns will b e c oll ect e d at ti m e p oi nts alr e a d y 
sc h e d ul e d f or t h e ce ntr al  m ec h a nistic st u di es, i n o r d er t o all o w s p eci m e ns t o b e st or e d f or us e i n n e w 
ass a ys t h at h a v e y et t o b e o pti miz e d or c o nc ei v e d, or ass a ys p erf or m e d b y ot h er I nv esti g at ors f or cr oss-
v ali d ati o n st u di es.  A p pr o pri at e i nf or m e d c o ns e nt will b e o bt ai n e d f or b ot h t h e c oll ecti o n a n d st ori n g of 
s a m pl es.  T h e s p eci m e ns fr o m t h es e e v al u ati o ns m ay b e st or e d b e y o n d t h e f u n di n g p eri o d. D uri n g t h e 
f u n di n g p eri o d, s a m pl es will b e i d e ntifi a bl e, w hic h m e a ns s a m pl es will b e c o d e d wit h a s u bj ect I D 
n u m b er t h at c o ul d b e dir ectl y li n k e d t o t h e s u bj ect a n d t h e s u bj ect’s m e dic al r ec or d. W h e n t h e f u n di n g 
p eri o d is ov er, s a m pl es will b e a n o n y miz e d, w hic h m e a ns a s a m pl e t h at w as pr e vi o usl y i d e ntifi a bl e, h as 
h a d all i d e ntifi ers r e m ov e d a n d c a n n o l o n g er b e li n k e d b ac k t o t h e s u bj ect or t h e s u bj ect’s m e dic al 
r ec or d by a n y m e a ns.  
St u dy s u bj ects will b e i nf or m e d t h at t h e y m a y b e a p pr o ac h e d a b o ut a d diti o n al cli nic al e v al u ati o ns or 
st u di es t h at h a v e r ec ei v e d t h e f ull a p pr ov al of t h e NI AI D as n e w e v al u ati o ns ar e i d e ntifi e d.  If a d diti o n al 
e v al u ati o ns ar e d et er mi n e d t o b e d esir a bl e, t his pr ot oc ol ( a n d ot h er a p pr o pri at e st u dy d oc u m e nts, e. g., 
t h e i nf or m e d c o ns e nt a n d t h e st atistic al a n al ysis pl a n) will b e a m e n d e d a n d s u b mitt e d t o t h e 
a p pr o pri at e r e g ul at ory a ut h oriti es, et hics c o m mitt e es, a n d I R Bs f or a p pr ov al.  E ac h s u bj ect’s si g n at ur e 
will b e o bt ai n e d o n t h e r e vis e d i nf or m e d c o ns e nt f or m b ef or e a d diti o n al e v al u ati o ns ar e p erf or m e d.  
T h e s p eci m e ns fr o m t h es e e v al u ati o ns m ay b e st or e d u p t o t h e e n d of t h e gr a nt or l o n g er d e p e n di n g o n 
f u n di n g.  
 

 
C o nfi d e nti al  
P a g e 5 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 1  Crit eri a f or P artici p a nt a n d St u d y C o m pl eti o n a n d Pr e m at ur e St u d y 
T er mi n ati o n  
1 1. 1  P artici p a nt C o m pl eti o n  
A s u bj ect h as c o m pl et e d t h e st u dy o nc e t h e y c o m pl et e  t h e r e q uir e d t w o-y e ar f oll o w-u p. F or s u bj ects 
w h o r ec ei v e b ot h B OL T a n d B M T, all st u dy visits i n b ot h A p p e n dix 1 a n d A p p e n dix 2 w ill b e c o m pl et e d. 
F or s u bj ects w h o d o n ot r ec ei v e t h e B M T, o nly visits i n A p p e n dix 1 will b e c o m pl et e d.  
1 1. 2  Pr e m at ur e T er mi n ati o n  
P artici p a nts m ay b e pr e m at ur el y t er mi n at e d fr o m t h e st u dy f or t h e f oll o wi n g r e as o ns:  
1.  T h e p artici p a nt el ects t o wit h dr a w c o ns e nt fr o m all f ut ur e st u dy acti viti es, i ncl u di n g f oll o w -u p.  
2.  T h e p artici p a nt is n o l o n g er eli gi bl e f or tr a ns pl a nt.  
3.  T h e p artici p a nt is “l ost t o f oll o w -u p” (i. e., n o f urt h er f oll o w -u p is p ossi bl e b ec a us e att e m pts t o 
r e est a blis h c o nt act wit h t h e p artici p a nt h a v e f ail e d).  
4.  T h e p artici p a nt di es.  
5.  T h e I nv esti g at or n o l o n g er b eli e v es p artici p ati o n is i n t h e b est i nt er est of t h e p artici p a nt. 
1 1. 3  P artici p a nt R e pl ac e m e nt  
C o m pl et e e nr oll m e nt  is a t ot al of 8 s u bj ects w h o r ec ei v e b ot h B OL T a n d B M T. If a s u bj ect r ec ei v es B OL T 
b ut d o es n ot pr oc e e d t o B M T, a n a d diti o n al s u bj ect m ay b e e nr oll e d i n or d er t o m e et c o m pl et e 
e nr oll m e nt.  S u bj ects w h o r ec ei v e B OL T b ut d o n ot pr oc e e d t o B M T  will b e f oll o w e d acc or di n g t o 
A p p e n dix 1 a n d t h e r e as o n f or n ot r ec ei vi n g a B M T will b e r ec ord e d  i n t h e cli nic al d at a b as e.   
1 1. 4  F oll o w -u p aft er E arl y St u d y Wit h dr a w al  
A n y s u bj ect w h o r ec ei v es B OL T a n d/ or B M T will b e ask e d t o c o m pl et e t h e 2 -y e ar f oll o w-u p p eri o d. If a 
s u bj ect is pr e m at ur el y t er mi n at e d e. g. wit h dr a ws c o ns e nt, t h e y will b e ask e d t o c o m pl et e t h e n ext 
sc h e d ul e d visit f or a fi n al dis p ositi o n b ut will n o l o n g er b e f oll o w e d o n pr ot oc ol. If a s u bj ect wit h dr a ws 
c o ns e nt t o s p ecific ass ess m e nts/ pr oc e d ur es b ut a gr e es t o c ert ai n f oll o w -u p, t h e y will r e m ai n i n t h e 
st u dy.  
1 1. 5  St u d y St o p pi n g R ul es  
 T e m p or ar y S us p e nsi o n of E nr oll m e nt  
If a ny gr a d e 4 or 5 a d v ers e e v e nts  t h at ar e at l e ast p ossi bl y r el at e d t o t h e us e of rit uxi m a b pri or t o B M T, 
occ ur i n at l e ast 2 s u bj ects, a s af et y -r el at e d s us p e nsi o n of e nr oll m e nt will occ ur p e n di n g n otific ati o n t o 
t h e I nstit uti o n al R e vi e w b o ar d (I R B) a n d  a n ex p e dit e d r e vi e w of all p erti n e nt d at a b y t h e N ati o n al 
I nstit ut e of All er g y a n d I nf ecti o us Dis e as es ( NI AI D) M e dic al M o nit or  a n d t h e NI AI D D at a S af et y 
M o nit ori n g B o ar d ( D S M B) .  
 

 
C o nfi d e nti al  
P a g e 5 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
 T e m p or ar y S us p e nsi o n of E nr oll m e nt a n d B M T  
If a n y of t h e f oll o wi n g occ ur i n t h e first 1 0 0 d a ys p ost-B M T a m o n g t h e first t hr e e s u bj ects r ec ei vi n g B M T , 
a  s af et y-r el at e d s us p e nsi o n of e nr oll m e nt or pr oc e e di n g t o B M T will b e i niti at e d p e n di n g n otific ati o n t o 
t h e I R B a n d a n ex p e dit e d r e vi e w of all p erti n e nt d at a b y t h e NI AI D M e dic al M o nit or a n d t h e NI AI D D S M B.  
•  
D e at h  
•  
R es pir at ory f ail ur e as a r es ult of r ej ecti o n or i nf ecti o n r e q uiri n g m ec h a nic al v e ntil ati o n f or m or e 
t h a n 4 8 h o urs.  
•  
E n gr aft m e nt sy n dr o m e  
 St u d y St o p pi n g R ul e  
T h e i nci d e nc e of s p ecific e v e nts will b e c o nti n u o usl y m o nit or e d t hr o u g h o ut t h e st u dy t o d et er mi n e if a n y 
of t h eir o bs erv e d s u bj ect -b as e d i nci d e nc e r at es exc e e d a t hr es h ol d i nci d e nc e r at e. T his st o p pi n g r ul e will 
b e tri g g er e d if 2 of 2 p ati e nts, 3 or m or e of 5 p ati e nts, or 4 or m or e of 8 p ati e nts  ex p eri e nc e o n e of t h e 
f oll o wi n g s e nti n el cli nic al e v e nts. 
•  
D e at h  
•  
R es pir at ory f ail ur e as a r es ult of r ej ecti o n or i nf ecti o n r e q uiri n g m ec h a nic al v e ntil ati o n f or m or e 
t h a n 4 8 h o urs  
•  
Hi g h gr a d e ( gr a d e ≥A 3) p ersist e nt or hi g h gr a d e r e c urr e nt ac ut e l u n g r ej ecti o n p ost B M T ( i ncl u di n g 
p ost i m m u n os u p pr essi o n wit h dr a w al)  
•  
Gr a d e 4 or gr e at er l u n g i nf ecti o n p ost B M T  
•  
E n gr aft m e nt f ail ur e/f ail ur e t o ac hi e v e c hi m eris m ( < 5 % d o n or c ells at d ay 1 0 0 f oll o wi n g B M T, or 
< 1 0 % d o n or c ells at d a y 1 8 0)  
•  
E n gr aft m e nt sy n dr o m e  
If a st o p pi n g t hr es h ol d is m et, e nr oll m e nt a n d pr oc e e di n g t o B M T will b e h alt e d p e n di n g ex p e dit e d NI AI D 
D S M B r e vi e w.  T h e st u dy r e gi m e n will b e d e e m e d i n eff ecti v e or t o o t oxic if a n ex act o n e -si d e d 8 0 % 
c o nfi d e nc e i nt erv al f or t h e tr u e r at e of e v e nts excl u d es v al u es of 0. 3 0 or l o w er.  T h e pr o b a bilit y of 
c o ncl u di n g t h at t h e t h er a py is t o o t oxic is 0. 1 0 if t h e tr u e r at e of u n acc e pt a bl e t oxicit y is 2 0 %, a n d 0. 6 9 if 
t h e tr u e r at e is 5 0 %.   
 
 
 

 
C o nfi d e nti al  
P a g e 5 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 2  S af et y M o nit ori n g  a n d R e p orti n g  
1 2. 1  O v er vi e w  
T his s ecti o n d efi n es t h e t y p es of s af et y d at a t h at will b e c oll ect e d u n d er t his pr ot oc ol a n d o utli n es t h e 
pr oc e d ur es f or a p pr o pri at el y c oll ecti n g, gr a di ng, r ec or di n g, a n d r e p orti n g t h os e  d at a. A d v ers e e v e nts 
t h at ar e cl assifi e d as s eri o us acc or di n g t o t h e d efi niti o n of h e alt h a ut h oriti es m ust b e re p ort e d pr o m ptl y 
( p er S ecti o n 1 2. 5, R e p orti n g of S eri o us A d v ers e E v e nts a n d A d v ers e E v e nts ) to t h e s p o ns or D AI T/ NI AI D .  
A p pr o pri at e n otific ati o ns will  als o b e m a d e t o t h e I nstit uti o n al R e vi e w B o ar d (I R B) a n d h e alt h 
a ut h oriti es.  
I nf or m ati o n i n t his s ecti o n c o m pli es wit h I C H G ui d eli n e E 2 A: Cli nic al S af et y D at a M a n a g e m e nt: 
D efi niti o ns a n d St a n d ar ds f or Ex p e dit e d R e p orti n g, I C H G ui d eli n e E-6: G ui d eli n e f or G o o d Cli nic al 
Pr actic e, 2 1 C F R P arts 3 1 2 a n d 3 2 0, a n d a p pli es t h e st a n d ar ds s et f ort h i n t h e N ati o n al C a nc er I nstit ut e 
( N CI), C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts ( C T C A E), V ersi o n 4. 0: 
htt p://ct e p.c a nc er. g ov/r e p orti n g/ctc. ht ml . 
1 2. 2  D efi niti o ns  
 A d v ers e E v e nt ( A E)  
A n y u nt o w ar d or u nf a v or a bl e m e dic al occ urr e nc e ass oci at e d wit h t h e s u bj ect’s p artici p ati o n i n t h e 
r es e arc h, w h et h er or n ot c o nsi d er e d r el at e d t o t h e s u bj ect’s p artici p ati o n i n t h e r es e arc h ( m o difi e d 
fr o m t h e d efi niti o n of a d v ers e e v e nts i n t h e 1 9 9 6 I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n E-6 
G ui d eli n e s f or G o o d Cli nic al Pr actic e) (fr o m O H R P " G ui d a nc e o n R e vi e wi n g a n d R e p orti n g U n a ntici p at e d 
Pr o bl e ms I nv olvi n g Risks t o S u bj ects or Ot h er s a n d A d v ers e E v e nts ( 1/ 1 5/ 0 7)" 
htt p:// w w w. h hs. g ov/ o hr p/ p olic y/ a d v e v nt g ui d. ht ml # Q 2 )  
F or t his st u dy, a n a dv ers e e v e nt will i n cl u d e a n y u nt o w ar d or u nf a v or a bl e m e dic al occ urr e nc e ass oci at e d 
wit h:  
•  
Bil at er al ort h ot o pic l u n g tr a ns pl a nt  
•  
I m m u n os u p pr essi v e r e gi m e n: in d ucti o n wit h b asilixi m a b ( or alt er n at e t h er a py), t acr oli m us a n d 
Rit uxi m a b  
•  
B M T c o n diti o ni n g r e gi m e n: Hy dr ox y ur e a, Rit uxi m a b, Al e mt uz u m a b, A T G A M, T hi ot e p a, a n d T BI  
•  
C D 3 + a n d C D 1 9 + d e pl et e d B M T  
•  
D o n or L e u k oc yt e I nf usi o n ( DLI)  
•  
I m m u n os u p pr essi o n wit h dr a w al 
•  
Br o nc h osc o p y/ B AL  
•  
B o n e m arr o w as pir at e  
 S us p ect e d A d v ers e R e acti o n ( S A R)  
A n y a dv ers e e v e nt f or w hic h t h er e is a r e as o n a bl e p ossi bilit y t h at t h e i nv esti g ati o n al dr u g or 
i nv esti g ati o n al st u dy t h er a py r e gi m e n c a us e d t h e a d v ers e e v e nt. F or t h e p ur p os es of s af et y r e p orti n g, 
‘r e as o n a bl e p ossi bilit y’ m e a ns t h er e is e vi d e nc e t o s u g g est a c a us al r el ati o ns hi p b et w e e n t h e dr u g a n d 
t h e a d v ers e e v e nt. A s us p ect e d a d v ers e r e acti o n i m pli es a l ess er d e gr e e of c ert ai nt y a b o ut c a us alit y 
t h a n a dv ers e r e acti o n, w hic h m e a ns a n y a dv ers e e v e nt c a us e d b y a dr u g ( 2 1 C F R 3 1 2. 3 2( a)).  

 
C o nfi d e nti al  
P a g e 5 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
 U n e x p ect e d A d v ers e E v e nt   
A n a dv ers e e v e nt or s us p ect e d a d v e rs e r e acti o n is c o nsi d er e d “ u n ex p ect e d” if it is n ot list e d i n t h e 
p ac k a g e i ns ert  or is n ot list e d at t h e s p ecificit y, s e v erit y or r at e of occ urr e nc e t h a t h as b e e n o bs erv e d; or  
is n ot c o nsist e nt wit h t h e risk i nf or m ati o n d escri b e d i n t h e g e n er al i nv esti g ati o n al pl a n or els e w h er e i n 
t h e I N D.  
 “ U n ex p ect e d” als o r ef ers t o a d v ers e e v e nts or s us p ect e d a d v ers e r e act i o ns t h at ar e m e nti o n e d i n t h e 
p ac k a g e i ns ert as occ urri n g wit h a cl ass of dr u gs or as a ntici p at e d fr o m t h e p h ar m ac ol o gic al pr o p erti es 
of t h e dr u g b ut  ar e n ot s p ecific all y m e nti o n e d as occ urri n g wit h t h e p artic ul ar dr u g u n d er i nv esti g ati o n 
( 2 1 C F R 3 1 2. 3 2( a). 
  
 S eri o us A d v ers e E v e nt ( S A E)  
A n a dv ers e e v e nt or s us p ect e d a d v ers e r e acti o n is c o nsi d er e d “s eri o us” if, i n t h e vi e w of eit h er t h e 
i nv esti gat or or D AI T/ NI AI D as t h e I N D S p o ns or , it r es ults i n a ny of t h e f oll o wi n g o utc o m es ( 2 1 C F R 
3 1 2. 3 2( a)):  
1.  D e at h.  
2.  A lif e -t hr e at e ni n g e v e nt: A n A E or S A R is c o nsi d er e d “lif e-t hr eat e ni n g” if, i n t h e vi e w of eit h er t h e 
i nv esti g at or or S p o ns or [ a d d D AI T/ NI AI D or ot h er S p o ns or, if a p plic a bl e], its occ urr e nc e pl ac es t h e 
s u bj ect at i m m e di at e risk of d e at h. It d o es n ot i ncl u d e a n A E or S A R t h at, h a d it occ urr e d i n a m or e 
s e v er e f or m, mi ght h a v e c a us e d d e at h.  
3.  I n p ati e nt h os pit aliz ati o n or pr ol o n g ati o n of existi n g h os pit aliz ati o n. 
4.  P ersist e nt or si g nific a nt i nc a p acit y or s u bst a nti al disr u pti o n of t h e a bilit y t o c o n d uct n or m al lif e 
f u ncti o ns. 
5.  C o n g e nit al a n o m aly or b irt h d ef ect.  
6.  I m p ort a nt m e dic al e v e nts t h at m ay n ot r es ult i n d e at h, b e lif e t hr e at e ni n g, or r e q uir e h os pit aliz ati o n 
m a y b e c o nsi d er e d s eri o us w h e n, b as e d u p o n a p pr o pri at e m e dic al j u d g m e nt, t h e y m a y j e o p ar diz e 
t h e s u bj ect a n d m ay r e q uir e m e dic al or s ur gic al i nt erv e nti o n t o pr e v e nt o n e of t h e o utc o m es list e d 
a b ov e.  
A n y i nst a nc e of C O VI D -1 9, r e g ar dl ess of gr a d e, will b e r e p ort e d as a S eri o us A d v ers e E v e nt.  
El ecti v e h os pit aliz ati o ns or h os pit al a d missi o ns f or t h e p ur p os e of c o n d uct i n g a pr ot oc ol m a n d at e d 
pr oc e d ur e ar e n ot t o b e r e p ort e d as a n S A E u nl ess  t h e h os pit aliz ati o n is pr ol o n g e d d u e t o c o m plic ati o ns.  
1 2. 3  Gr a di n g a n d Attri b uti o n of A d v ers e E v e nts  
 Gr a di n g Crit eri a  
T h e st u dy sit e will gr a d e t h e s e v erit y of a d v ers e e v e nts ex p eri e nc e d b y t h e st u dy s u bj ects acc or di n g t o 
t h e crit eri a s et f ort h i n t h e N ati o n al C a nc er I nstit ut e’s C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts 
( C T C A E) V ersi o n 4. 0 .  T his d oc u m e nt (r ef err e d t o h er ei n as t h e N CI -C T C A E m a n u al) pr ovi d es a c o m m o n 
l a n g u a g e t o d escri b e l e v els of s e v erit y, t o a n al yz e a n d i nt er pr et d at a, a n d t o artic ul at e t h e cli nic al 
si g nific a nc e of all a d v ers e e v e nts. T h e N CI-C T C A E h as b e e n r e vi e w e d b y t h e  Pri nci p al I nv esti g at or  a n d 
h as b e e n d e e m e d a p pr o pri at e f or t h e s u bj ect p o p ul ati o n t o b e st u di e d i n t his pr ot oc ol.  
A d v ers e e v e nts will b e gr a d e d o n a sc al e fr o m 1 t o 5 acc or di n g t o t h e f oll o wi n g st a n d ar ds i n t h e N CI -
C T C A E m a n u al:  

 
C o nfi d e nti al  
P a g e 5 9  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
Gr a d e 1 = mil d a d v ers e e v e nt.  
Gr a d e 2 = m o d er at e a dv ers e e v e nt.  
Gr a d e 3 = s e v er e a n d u n d esir a bl e a dv ers e e v e nt.  
Gr a d e 4 = lif e -t hr e at e ni n g or dis a bli n g a d v ers e e v e nt. 
 
 
Gr a d e 5 = d e at h.  
F or  gr a di n g a n a b n or m al v al u e or r es ult of  a cli nic al or l a b or at ory e v al u ati o n (i ncl u di n g, b ut n ot li mit e d 
t o, a r a di o gr a p h, a n ultr as o u n d, a n el ectr oc ar di o gr a m etc. ), a tr e at m e nt-e m er g e nt a d v ers e e v e nt is 
d efi n e d as a n i ncr e as e i n gr a d e fr o m b as eli n e or fr o m t h e l ast p ost -b as eli n e v al u e t h at d o es n’t m e et 
gr a di n g crit eri a. C h a n g es i n gr a d e fr o m scr e e ni n g t o b as eli n e  will als o b e r ec or d e d as a d v ers e e v e nts b ut  
ar e n ot tr e at m e nt -e m er g e nt. If a s p ecific e v e nt or r es ult fr o m a gi v e n cli nic al  or l a b or at ory e v al u ati o n is 
n ot i ncl u d e d i n t h e N CI -C T C A E m a n u al, t h e n a n a b n or m al r es ult w o ul d b e c o nsi d er e d a n a d v ers e e v e nt if 
c h a n g es i n t h er a py or m o nit ori n g ar e i m pl e m e nt e d  as a r es ult of t h e e v e nt/r es ult . 
 Attri b uti o n D efi niti o ns  
T h e r el ati o ns hi p, o r attri b uti o n, of a n a d v ers e e v e nt t o t h e st u dy t h er a py r e gi m e n or st u dy pr oc e d ur e(s) 
will i niti ally b e d et er mi n e d b y t h e sit e i nv esti g at or a n d r ec or d e d o n t h e a p pr o pri at e A E / S A E C as e R e p ort 
F or m .  Fi n al d et er mi n ati o n of attri b uti o n f or s af et y r e p orti n g will b e d et er mi n e d b y t h e I N D S p o ns or.  
T h e r el ati o ns hi p of a n a d v ers e e v e nt t o st u dy t h er a py r e gi m e n or pr oc e d ur es will b e d et er mi n e d usi n g 
t h e d escri pt ors a n d d efi niti o ns pr ovi d e d i n T a bl e 1 2 . 3. 2.  
F or a d diti o n al i nf or m ati o n a n d a pri nt a bl e v ersi o n of t h e N CI -C T C A E m a n u al, c o ns ult t h e N CI -C T C A E w e b 
sit e: htt p://ct e p.c a nc er. g ov/r e p orti n g/ctc. ht ml . 
       
T a bl e 1 2. 3. 2 Attri b uti o n of A d v ers e E v e nts  
C o d e  
D escri pt or  
R el ati o ns hi p (t o pri m ar y i n v esti g ati o n al pr o d uct 
a n d/ or ot h er c o nc urr e nt m a n d at e d st u d y t h er a p y  or 
st u d y pr oc e d ur e) 
U N R EL A T E D C A T E G O R Y  
1  
U nr el at e d  
T h e a d v er s e e v e nt is cl e arl y n ot r el at e d:  t h er e is 
i ns uffici e nt e vi d e nc e t o s u g g est a c a us al r el ati o ns hi p. 
 R EL A T E D C A T E G O RI E S  
2  
P ossi bl e  
T h e a d v ers e e v e nt h as a r e as o n a bl e p ossi bilit y t o b e 
r el at e d; t h er e is e vi d e nc e t o s u g g est a c a us al 
r el ati o ns hi p. 
3  
D efi nit e  
T h e a d v ers e e v e nt is cl e arl y r el at e d.  
1 2. 4  C oll ecti o n a n d R ec or di n g of A d v ers e E v e nts  
 C oll ecti o n P eri o d  
A d v ers e e v e nts will b e c oll ect e d fr o m t h e ti m e of t h e i niti al Rit uxi m a b i nf usi o n ( or B OL T i n d ucti o n if a 
s u bj ect di d n ot r ec ei v e pr e-tr a ns pl a nt Rit uxi m a b) u ntil a s u bj ect  c o m pl et es st u dy p artici p ati o n or u ntil 
3 0 d a ys aft er h e/s h e pr e m at ur el y wit h dr a ws ( wit h o ut wit h dr a wi n g c o ns e nt) or is wit h dr a w n fr o m t h e 
st u dy.  

 
C o nfi d e nti al  
P a g e 6 0  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
 C oll ecti n g A d v ers e E v e nts  
A d v ers e e v e nts (i ncl u di n g S A Es) m a y b e disc ov er e d t hr o u g h a ny of t h es e m et h o ds:  
•  
O bs e rvi n g t h e s u bj ect. 
•  
I nt ervi e wi n g t h e s u bj ect [ e.g., usi n g a c h ec klist, str uct ur e d q u esti o ni n g, di ary, etc.]  . 
•  
R ec ei vi n g a n u ns olicit e d c o m pl ai nt fr o m t h e s u bj ect.  
•  
I n a d diti o n, a n a b n or m al v al u e or r es ult fr o m a cli nic al or l a b or at ory e v al u ati o n c a n als o i n dic at e a n 
a dv ers e  e v e nt, as d efi n e d i n S ecti o n 1 2 . 3, Gr a di n g a n d Attri b uti o n of  A d v ers e E v e nts.  
 R ec or di n g A d v ers e E v e nts  
T hr o u g h o ut t h e st u dy, t h e i nv esti g at or will r ec or d a dv ers e e v e nts a n d s eri o us a d v ers e e v e nts as 
d escri b e d pr e vi o usl y ( S ecti o n 1 2 . 2, D efi niti o ns) o n t h e el ectr o nic a d v ers e e v e nt c as e r e p ort f or m 
r e g ar dl ess of t h e r el ati o ns hi p t o st u dy t h er a py r e gi m e n or st u dy pr oc e d ur e.  
O nc e r ec or d e d, a n A E/ S A E will b e f oll o w e d u ntil it r es ol v es wit h or wit h o ut s e q u el a e, or u ntil t h e e n d of 
st u dy p artici p ati o n, or u ntil 3 0 d a ys aft er t h e s u bj ect pr e m at ur el y wit h dr a ws ( wit h o ut wit h dr a wi n g 
c o ns e nt)/ or is wit h dr a w n fr o m t h e st u dy, w hic h e v er occ urs first.  
1 2. 5  R e p orti n g of S eri o us A d v ers e E v e nts  a n d A d v ers e E v e nts  
 R e p orti n g of S eri o us A d v ers e E v e nts t o S p o ns or  
T his s ecti o n d escri b es t h e r es p o nsi biliti es of t h e sit e i nv esti g at or t o r e p ort s eri o us a d v ers e e v e nts t o t h e 
NI AI D as t h e I N D s p o ns or vi a e m ail n otific ati o n a n d c as e r e p ort f or m.   Ti m el y r e p orti n g of a d v ers e 
e v e nts is r e q uir e d b y 2 1 C F R a n d I C H E 6 g ui d eli n es.  
T h e sit e i nv esti g at or  will  r e p ort all s eri o us a d v ers e e v e nts (s e e S ecti o n 1 2. 2. 3, S eri o us A d v ers e E v e nt), 
r e g ar dl ess of r el ati o ns hi p or ex p ect e d n ess wit hi n 2 4 h o urs of disc ov eri n g t h e e v e nt. W h e n a n e v e nt 
m e eti n g s eri o us crit eri a is e nt er e d  i nt o t h e cli nic al d at a b as e, a n a ut o m atic e m ail n otific ati o n will b e 
g e n er at e d t o t h e st u dy t e a m, i ncl u di n g t h e NI AI D M e dic al M o nit or. T h e sit e will t h e n e nt er t h e d et ails of 
t h e s eri o us a d v ers e e v e nt i nt o t h e D AI T C RI S I nt erc h a n g e wit hi n 7 2 h o urs of disc ov eri n g t h e e v e nt.     
F or s eri o us a d v ers e e v e nts, all r e q u est e d i nf or m ati o n o n t h e A E/ S A E  c as e r e p ort f or m will  b e pr ovi d e d.  
H o w e v er, u n a v ail a bl e d et ails of t h e e v e nt will  n ot d el ay s u b missi o n of t h e k n o w n i nf or m ati o n.  As 
a d diti o n al d et ails b ec o m e a v ail a bl e, t h e A E/ S A E c as e r e p ort f or m  will  b e u p d at e d a n d r e-s u b mitt e d.  
 R e p orti n g t o H e alt h A ut h orit y  
Aft er a n a d v ers e e v e nt r e q uiri n g 2 4 -h o ur  r e p orti n g ( p er S ecti o n 1 2. 5. 1, R ep orti n g of S eri o us A d v ers e 
E v e nts t o S p o ns or) is s u b mitt e d b y t h e sit e i nv esti g at or a n d ass ess e d b y t h e I N D s p o ns or a n d st u dy 
m e dic al m o nit or .  T h er e ar e t w o o pti o ns f or r e p orti n g t o t h e h e alt h a ut h oriti es: 
 A n n u al R e p orti n g  
NI AI D as t h e I N D S p o ns or , will i ncl u d e i n t h e a n n u al st u d y r e p ort t o h e alt h a ut h oriti es all a d v ers e e v e nts 
cl assifi e d as:  
o  S eri o us, ex p ect e d, s us p ect e d a d v ers e r e acti o ns (s e e S ecti o n 1 2 . 2. 1. 1, S us p ect e d A d v ers e R e acti o n, 
a n d S ecti o n 1 2 . 2. 2, U n ex p ect e d A d v ers e E v e nt ). 

 
C o nfi d e nti al  
P a g e 6 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
o  S eri o us a n d n ot  a s us p ect e d a dv ers e r e acti o n (s e e S ecti o n 1 2 . 2. 2, S us p ect e d A d v ers e R e acti o n ). 
o  Pr e g n a nci es.  
N ot e t h at all a d v ers e e v e nts ( n ot j ust t h os e r e q uiri n g 2 4 -h o ur r e p orti n g) will b e r e p ort e d i n t h e I N D 
A n n u al R e p ort.  
 E x p e dit e d S af et y R e p orti n g  
T his o pti o n, wit h 2 p ossi bl e c at e g ori es, a p pli es if t h e a d v ers e e v e nt is cl assifi e d as o n e of t h e f oll o wi n g:  
C at e g or y 1 :  S eri o us a n d u n e x p ect e d s us p ect e d a d v ers e r e acti o n  [S U S A R]  (s e e S ecti o n 1 2. 2. 1. 1, 
S us p ect e d A d v ers e R e acti o n a n d S ecti o n 1 2 . 2, U n ex p ect e d A d v ers e E v e nt  a n d 2 1 C F R 3 1 2. 3 2(c)( 1)i).  
T h e I N D s p o ns or s h all r e p ort a n y s us p ect e d a d v ers e r e acti o n t h at is b ot h s eri o us a n d u n ex p ect e d.  T h e 
I N D s p o ns or s h all r e p ort a n a d v ers e e v e nt as a s us p ect e d a d v ers e r e acti o n o nly if t h er e is e vi d e nc e to 
s u g g est a c a us al r el ati o ns hi p b et w e e n t h e st u dy dr u g a n d t h e a d v ers e e v e nt, s uc h as:  
1.  A si n gl e occ urr e nc e of a n e v e nt t h at is u nc o m m o n a n d k n o w n t o b e str o n gl y ass oci at e d wit h dr u g 
ex p os ur e ( e. g., a n gi o e d e m a, h e p atic i nj ury, or St e v e ns -J o h ns o n Sy n dr o m e); 
2.  O n e or m or e occ u rr e nc es of a n e v e nt t h at is n ot c o m m o nly ass oci at e d wit h dr u g ex p os ur e, b ut is 
ot h er wis e u nc o m m o n i n t h e p o p ul ati o n ex p os e d t o t h e dr u g ( e. g., t e n d o n r u pt ur e);  
3.  A n a g gr e g at e a n alysis of s p ecific e v e nts o bs erv e d i n a cli nic al tri al (s uc h as k n o w n c o ns e q u e nc es of 
t h e u n d erl yi n g dis e as e or c o n diti o n u n d er i nv esti g ati o n or ot h er e v e nts t h at c o m m o nly occ ur i n t h e 
st u dy p o p ul ati o n i n d e p e n d e nt of dr u g t h er a py) t h at i n dic at es t h os e e v e nts occ ur m or e fr e q u e ntl y i n 
t h e dr u g tr e at m e nt gr o u p t h a n i n a c onc urr e nt or hist oric al c o ntr ol gr o u p.  
 
C at e g or y 2 : A n y fi n di n gs fr o m st u di es t h at s u g g ests a si g nific a nt h u m a n ris k   
 
T h e I N D s p o ns or s h all r e p ort a n y fi n di ngs fr o m ot h er e pi d e mi ol o gic al st u di es, a n alys es of a d v ers e e v e nts  
wit hi n t h e c urr e nt st u dy or p o ol e d a n al ysis acr oss cli nic al st u di es or a ni m al or i n vitr o t esti n g ( e. g. 
m ut a g e nicit y, t er at o g e nicit y, c arci n o g e nicity) t h at s u g g est a si g nific a nt risk i n h u m a ns ex p os e d t o t h e 
dr u g t h at w o ul d r es ult i n a s af et y-r el at e d c h a ng e i n t h e pr ot oc ol, i nf or m e d c o ns e nt, i nv esti g at o r 
br oc h ur e or p ac k a g e i ns ert or ot h er a s p ects of t h e ov er all c o n d uct of t h e st u dy.   
T h e I N D s p o ns or  s h all n otify t h e F D A of ex p e dit e d S af et y R e p orts  wit hi n 1 5 c al e n d ar d a ys; u n ex p ect e d 
f at al or i m m e di at el y lif e-t hr e at e ni n g s us p ect e d a d v ers e r e acti o n(s) s h all b e r e p ort e d as s o o n as p ossi bl e 
or wit hi n 7 c al e n d ar d a ys.  
 R e p orti n g of A d v ers e E v e nts t o I R Bs/I E Cs  
T h e i nv esti g at ors  s h all r e p ort a d v ers e e v e nts, i ncl u di n g e x p e dit e d r e p orts, i n a ti m el y f as hi o n t o t h e 
r es p ecti v e I R B i n acc or d a nc e wit h a p plic a bl e re g ul ati o ns a n d g ui d eli n es.  
1 2. 6   Pr e g n a nc y R e p orti n g  
T h e  sit e i nv esti g at or s h all b e i nf or m e d i m m e di at el y of a n y pr e g n a nc y i n a st u dy s u bj ect or a p art n er of a 
st u dy s u bj ect. T h e i nv esti g at or s h all c o u ns el t h e s u bj ect a n d disc uss t h e risks of c o nti n ui n g wit h t h e 
pr e g n a nc y a n d t h e p ossi bl e eff ects o n  t h e f et us. M o nit ori n g of t h e pr e g n a nt s u bj ect s h all c o nti n u e u ntil 
t h e c o ncl usi o n of t h e p r e g n a nc y.    

 
C o nfi d e nti al  
P a g e 6 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
T h e  sit e i nv esti g at or s h all r e p ort t o t h e D AI T/ NI AI D all pr e g n a nci es wit hi n 1 b usi n ess d ay of b ec o mi n g 
a w ar e of  t h e e v e nt usi n g t h e Pr e g n a nc y c as e r e p ort f or m .  All pr e g n a nci es i d e ntifi e d d uri n g t h e st u dy 
s h all b e f oll o w e d t o c o ncl usi o n a n d t h e o utc o m e of e ac h m ust b e r e p ort e d.  T h e Pr e g n a nc y c as e r e p ort 
f or m s h all b e u p d at e d a n d s u b mitt e d t o t h e D AI T/ NI AI D  w h e n d et ails a b o ut t h e o utc o m e ar e a v ail a bl e.  
W h e n p ossi bl e, si mil ar i nf or m ati o n s h all b e o bt ai n e d f or a  pr e g n a nc y occ urri n g i n a p art n er of a st u dy 
s u bj ect. 
I nf or m ati o n r e q u est e d a b o ut t h e d eliv ery s h all i ncl u d e: 
o  
G est ati o n al a g e at d eliv ery  
o  
Birt h w ei g ht, l e n gt h, a n d h e a d circ u mf er e nc e  
o  
G e n d er  
o  
A p p e ar a nc e, p uls e, gri m ac e, acti vit y, a n d r es pir ati o n ( A P G A R) sc or e at 1 mi n ut e, 5 mi n ut es, a n d 2 4 
h o urs aft er birt h, if a v ail a bl e  
o  
A n y a b n or m aliti es.  
All pr e g n a nc y  c o m plic ati o ns t h at r es ult i n a c o n g e nit al a b n or m alit y, birt h d ef ect,  misc arri a g e, a n d 
m e dic all y  i n dic at e d a b orti o n - a n S A E s h all b e s u b mitt e d t o  t h e D AI T/ NI AI D  usi n g t h e S A E r e p orti n g 
pr oc e d ur es d escri b e d a b ov e.  I n a d diti o n, t h e F D A will b e n otifi e d as a p pr o pri at e. 
1 2. 7  R e p orti n g of Ot h er S af et y I nf or m ati o n  
A n i n v esti g at or s h all pr o m ptl y n otify t h e sit e I R B as  w ell as t h e D AI T/ NI AI D  w h e n a n “ u n a ntici p at e d 
pr o bl e m i n v ol vi n g risks t o s u bj ects or ot h ers” is i d e ntifi e d, w hic h is n ot ot h er wis e r e p ort a bl e as a n 
a dv ers e e v e nt.  
1 2. 8  R e vi e w of S af et y I nf or m ati o n  
 M e dic al M o nit or R e vi e w  
T h e  NI AI D M e dic al M o nit or  s h all r ec ei v e m o nt hly r e p orts fr o m t h e Pri nci p al I nv esti g at or  c o m pili n g n e w 
a n d acc u m ul ati n g i nf or m ati o n o n A Es, S A Es, a n d pr e g n a nci es r ec or d e d by t h e st u dy sit e o n t h e 
a p pr o pri at e c as e r e p ort f or m.  
I n a d diti o n, t h e NI AI D  M e dic al M o nit or s h all r e vi e w a n d m a k e d ecisi o ns o n t h e dis p ositi o n of t h e S A E 
a n d pr e g n a nc y r e p orts  (S e e S ecti o ns 1 2. 5. 1, R e p orti n g of  S eri o us A d v ers e Ev e nts t o S p o ns or , a n d 1 2. 6, 
Pr e g n a ncy R e p orti n g ).   
 D S M B R e vi e w  
1 2. 8. 2. 1 Pl a n n e d D S M B R e vi e ws  
T h e NI AI D  D at a a n d S af et y M o nit ori n g B o ar d ( D S M B) s h all r e vi e w s af et y d at a at l e ast y e arl y d uri n g 
pl a n n e d D S M B D at a  R e vi e w M e eti n gs. D at a f or t h e pl a n n e d s af et y r e vi e ws will i ncl u d e, at a mi ni m u m, a 
listi n g of all r e p ort e d A Es a n d S A Es , a n d s u m m ari es of th e n u m b er a n d p erc e nt of p ati e nts r e p orti n g 
a dv ers e e v e nts f or e ac h p h as e of t h er a py ( B OL T, p ost -l u n g tr a ns pl a nt, B M T, p ost-B M T)  a n d ov er all.  
T h e D S M B will b e i nf or m e d of a n Ex p e dit e d S af et y R e p ort i n a ti m el y m a n n er. 
1 2. 8. 2. 2 A d h oc  D S M B R e vi e ws  

 
C o nfi d e nti al  
P a g e 6 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
I n a d diti o n t o t h e pr e-sc h e d ul e d dat a r e vi e ws a n d pl a n n e d s af et y m o nit ori n g, t h e D S M B m a y b e c all e d 
u p o n f or a d h oc  r e vi e ws. T h e D S M B will r e vi e w a n y e v e nt t h at p ot e nti ally i m p acts s af et y at t h e r e q u est 
of t h e pr ot oc ol c h air or D AI T/ NI AI D . I n a d diti o n, if a ny st o p pi n g r ul es ar e m et ( S ecti o n 1 1. 2) t h e D S M B 
will p erf or m a n a d h oc r e vi e w.  
Aft er r e vi e w of t h e d at a, t h e D S M B will m a k e r ec o m m e n d ati o ns r e g ar di n g st u dy c o n d uct a n d/ or 
c o nti n u ati o n. 

 
C o nfi d e nti al  
P a g e 6 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 3  St atistic al C o nsi d er ati o ns a n d A n al ytic al Pl a n  
1 3. 1  O v er vi e w  
T his is a pr os p ecti v e, si n gl e ar m ( n o n -r a n d o miz e d) st u dy e v al u ati n g t h e f e asi bilit y, s af et y a n d effic ac y of 
B OL T f oll o w e d b y B M T f or pri m ary i m m u n o d efici e nc y p ati e nts wit h p ul m o n ary f ail ur e.   
1 3. 2  E n d p oi nts  
 Pri m ar y E n d p oi nts  
 S af et y E n d p oi nt  
S af et y will b e d et er mi n e d b y c o nti n u e d e nr oll m e nt wit h o ut exc e e di n g t h e st o p pi n g r ul es as d et er mi n e d 
b y o bs ervi n g t h e c u m ul ati v e i nci d e nc e of tr a ns pl a nt r el at e d m ort alit y a n d e n gr aft m e nt f ail ur e.  
 Effic ac y  E n d p oi nts   
•  
F or all s u bj ects, ≥ 2 5 % d o n or T -c ell c hi m eris m at 1 2 m o nt hs p ost B M T.  
•  
F or s u bj ects wit h my el oi d dis or d ers ( e. g. C G D), ≥ 1 0 % my el oi d c hi m eris m is als o r e q uir e d at 1 2 
m o nt hs.  
•  
F or s u bj ect s wit h B-c ell dis or d ers, ≥ 1 0 % B-c ell c hi m eris m is als o r e q uir e d at 1 2 m o nt hs.  
 S ec o n d ary E n d p oi nts  
T h e f oll o wi n g s ec o n d ary e n d p oi nts will b e ass ess e d:  
•  
F e asi bilit y of pr oc e e di n g t o B M T wit hi n 6 m o nt hs f oll o wi n g l u n g tr a ns pl a nt ati o n.  
•  
D e v el o p m e nt of t ol er a nc e t o b ot h t h e h ost a n d p ul m o n ary gr aft. 
•  
Lo n g -t er m c o m plic ati o ns of c o m bi n e d s oli d or g a n a n d b o n e m arr o w tr a ns pl a nt . 
•  
A c ut e c ell ul ar r ej ecti o n a n d gr aft f ail ur e p ost B M T.  
•  
A c ut e a n d c hr o nic gr aft -v ers us -h ost dis e as e ( G V H D) f oll o wi n g t a n d e m l u n g a n d B M T . 
•  
Ti m e fr o m B M T t o  wit h dr a w al of i m m u n os u p pr essi o n .  
•  
Ti m e fr o m B M T t o i n d e p e n d e nc e fr o m tr e at m e nt d os e a nti micr o bi al dr u gs . 
•  
F or T c ell l y m p h o p e ni as, ac hi e vi n g a g e a dj ust e d, l o w li mit n or m al r a n g e l y m p h oc yt e c o u nt b y 1 -y e ar 
p ost -B M T.  
•  
A si g nific a nt d e v el o p m e nt i n c hr o nic l u n g all o gr aft d ysf u ncti o n ( as e vi d e nc e d b y a c h a n g e i n B O S 
st a g e, s e e p g. 1 9 f or B O S t a bl e) or all o gr aft f ail ur e at 1-y e ar a n d u p t o 2 y e ars p ost l u n g tr a ns pl a nt 
f or B OL T al o n e a n d B OL T-B M T s u bj ects.  
•  
I nci d e nc e of Gr a d e 4 or 5 a d v ers e e v e nts p ossi bl y r el at e d t o t h e us e of Rit uxi m a b pri or t o t h e st art 
of B M T c o n diti o ni n g.  
 M ec h a nistic E n d p oi nts  
•  
P ac e  of r ec o nstit uti o n of i m m u nit y . 
•  
I nci d e nc e of mix e d c hi m eris m ( > 5 % h ost c ells) at m o nt hs 1, 3, 6, 1 2 a n d 2 4  p ost -tr a ns pl a nt. 
•  
F or all s u bj ects r ec ei vi n g l u n g tr a ns pl a nt, a bs e nc e of s e v er e all o gr af t d ysf u ncti o n usi n g B O S sc ori n g 
syst e m at 1-y e ar p ost l u n g tr a ns pl a nt.  

 
C o nfi d e nti al  
P a g e 6 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
•  
I m prov e m e nt i n i m m u n ol o gic m ark er(s) u ni q u e f or t h e u n d erl yi n g PI D sy n dr o m e b y o n e -y e ar p ost 
B M T (s e e A p p e n dix 5).  
  M e as ur es t o Mi ni miz e Bi as   
T his is a si n gl e -ar m  st u dy wit h o ut  r a n d o miz ati o n or bli n di n g.  S a m pl es will b e i d e ntifi e d b y st u dy I D 
r at h er t h a n p ati e nt n a m e w h e n f e asi bl e, f or pri v ac y a n d f or o bj ecti vit y of l a b or at ory st aff.  
1 3. 3  A n al ysis Pl a n  
 A n al ysis of S af et y a n d Effic ac y  
A n al ysis of s af et y d at a:  All r e p ort e d a d v ers e e v e nts  ( d efi n e d i n 1 2. 3. 1) will b e c o d e d usi n g t h e N CI 
c o m m o n toxicit y crit eri a  (v ersi o n 4. 0).  T h e n u m b er a n d p erc e nt of p ati e nts r e p orti n g a d v ers e e v e nts 
will b e q u a ntifi e d f or e ac h p h as e of t h er a py ( B OL T, p ost -l u n g tr a ns pl a nt, B M T, p ost-B M T)  a n d ov er all .  
Wit hi n e ac h p h as e of t h er a py, a n d s e p ar at el y f or e ac h p ati e nt ov er all p h as es of t h er a py, s u m m ari es will 
i ncl u d e o nly t h e hi g h est gr a d e  ex p eri e nc e d b y e ac h p ati e nt f or e ac h a dv ers e e v e nt.   T h e r at e of 
r e p ort e d s eri o us a d v ers e e v e nts ( d efi n e d i n s ecti o n 1 2. 2. 4) will b e r e p ort e d s e p ar at ely.  
Effic ac y will b e a n alyz e d as a c as e s eri es, wit h r at es f or k e y effic ac y crit eri a r e p ort e d wit h 9 0 % Wils o n 
(sc or e) c o nfi d e nc e i nt erv als.  D e at hs will b e c o u nt e d as tr e at m e nt f ail ur es. F or ex a m pl e, if 6 p ati e nts 
r ec ei vi n g B OL T + B M T h av e my el oi d n o n T c el l dis or d ers, 1 di es wit hi n 1 2 m o nt hs of B M T, a n d 3  dis pl a y  
≥1 0 % m y el oi d c hi m eris m at 1 2 m o nt hs p ost -B M T , t h e effic ac y r at e f or t his gr o u p  w o ul d b e r e p ort e d as 
3/ 6 = 0. 5 0  ( 90 % CI 0. 2 2  –  0. 7 8 ).  
 St o p pi n g r ul es f or s af et y:   
 T e m p or ary S us p e nsi o n of E nr oll m e nt a n d B M T  
Pri or t o a n d f oll o wi n g l u n g tr a ns pl a nt, a s af et y -r el at e d s us p e nsi o n of e nr oll m e nt will occ ur p e n di n g 
n otific ati o n t o t h e I R B a n d a n ex p e dit e d r e vi e w of all p erti n e nt d at a b y NI AI D M e dic al M o nit or  a n d t h e 
NI AI D D S M B  if s p ecific cli nic al ev e nts occ ur as o utli n e d i n S ecti o n 1 1. 5 of t h e pr ot oc ol.  
 
T h e st u dy r e gi m e n will b e d e e m e d i n eff ecti v e or t o o t oxic if a n ex act o n e -si d e d 8 0 % c o nfi d e nc e i nt erv al 
f or t h e tr u e r at e of e v e nts excl u d es v al u es of 0. 3 0 or l o w er.  T h e pr o b a bilit y of c o ncl u di n g t h at t h e 
t h er a py is t o o t oxic is 0. 1 0 if t h e tr u e r at e of u n acc e pt a bl e t oxicit y is 2 0 %, a n d 0. 6 9 if t h e tr u e r at e is 
5 0 %.   
 
D o n or b o n e m arr o w e n gr aft m e nt will b e ass ess e d b y m e as uri n g, w h e n f e asi bl e , c hi m eris m as d et er mi n e d 
i n w h ol e bl o o d a n d C D 3 + T-c ell fr acti o n as p erf or m e d b y st a n d ar d, cli nic al S T R ass a y at t h e U niv ersit y of 
Pitts b ur g h M e dic al C e nt er’s HL A -L a b or at ory. F or t h os e e nr oll e d s u bj ects w h os e u n d erl yi n g i m m u n e 
d efici e nc y aff ects p h a g oc yt e f u ncti o n or n u m b ers, t y pic all y t h os e wit h c hr o nic gr a n ul o m at o us dis e as e 
( C G D) or s e v er e c o n g e nit al n e utr o p e ni a ( S C N), w h ol e bl o o d c hi m eris m will b e t h e o utc o m e m e as ur e. F or 
all ot h ers, w h os e i m m u n e d ef ect aff ects T -c ell f u ncti o n or T-c ell n u m b ers, d et er mi ni n g t h e p erc e nt a g e of 
d o n or C D 3 + T -c ell c o ntri b uti o n (c hi m eris m) will b e t h e o utc o m e m e as ur e.  N e v ert h el ess, f or all p ati e nts 
b ot h w h ol e bl o o d a n d C D 3 + T -c ell c hi m eris m will b e d et er mi n e d.  
 A n al ysis P o p ul ati o ns  

 
C o nfi d e nti al  
P a g e 6 6  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
T h e st u dy s a m pl e f or s af et y a n d f e asi bilit y will b e p ati e nts w h o r ec ei v e B OL T, i ncl u di n g t h os e w h o d o 
n ot pr oc e e d t o B M T. M ost effic ac y a n alys es o nly c o nsi d er p ati e nts w h o r ec ei v e b ot h B OL T a n d B M T.  
A d diti o n al p ati e nts w h o ar e e nr oll e d b ut d o n ot pr oc e e d t o B OL T or B M T will b e d escri b e d i n st u dy 
r e ports, b ut n ot i ncl u d e d i n st u dy a n alys es.  
 A n al ys es of S ec o n d ar y a n d Ot h er E n d p oi nt (s)/ O utc o m e(s) 
Effic ac y e n d p oi nts will b e d escri b e d as a c as e s eri es a n d s u m m ariz e d f or all pati e nts b as e d o n st u dy 
st at us. F or ex a m pl e, abs e nc e of s e v er e all o gr aft d ysf u nct i o n will b e s u m m ariz e d f or all p ati e nts r ec ei vi n g 
B OL T; B M T e n d p oi nts will b e s u m m ariz e d f or t h os e r ec ei vi n g B M T as w ell as B OL T.  
R at e of  i m pr ov e m e nt i n i m m u n ol o gic al m ark ers, s p ecific t o t h e u n d erl yi n g PI D, will b e a n alyz e d b y 
d escri pti v e st atistics. Si nc e s e v er al dis e as es will li k el y b e ass ess e d, e ac h p ati e nt will s erv e as t h eir o w n 
c o ntr ol, c o m p ari n g p ost -B M T m e as ur es t o v al u es pr e -B OL T a n d pr e -B M T (s e e A p p e n dix  5 ).  A d diti o n ally, 
acc o u nti n g f or u ni q u e PI D dis e as es, i m m u n e o utc o m es o n o ur p ati e nts wit h s p ecific PI D sy n dr o m es ( e. g.  
C G D, S CI D)  will b e c o m p ar e d t o o utc o m es r e p ort e d i n t h e lit er at ur e f or p e di atric l u n g tr a ns pl a nt 
p ati e nts , a n d f or p ati e nts wit h o ut l u n g f ail ur e w h o u n d er g o  B M T al o n e f or t h e i d e ntic al PI D sy n dr o m es.  
T h e pri m ary effic ac y  e n d p oi nt is t h e a bs e nc e of s e v er e all o gr aft d ysf u ncti o n ( B O S gr a d es 2 or 3), usi n g 
t h e B O S sc ori n g syst e m, at 1 -y e ar p ost l u n g tr a ns pl a nt. H o w e v er, it is a ntici p at e d t h at p ati e nts 
u n d er g oi n g B OL T b ef or e t h e e n d of y e ar 3 will h a v e 2 y e ars of f oll o w -u p t o ass ess f or B O S, f or w hic h t h e 
r e p ort e d i nci d e nc e of d ysf u ncti o n is 3 0 % [ 3 1].  
A d diti o n al s ec o n d ary effic ac y  e n d p oi nts i ncl u d e w h et h er or n ot w e a ni n g of i m m u n os u p pr essi o n h as 
b e e n i niti at e d b y 1 y e ar f oll o wi n g B M T, t h e ti mi n g of p ost -B M T i niti ati o n of w e a ni n g fr o m  
i m m u n os u p pr essi o n, a n d t h e ti mi n g of p ost-B M T i n d e p e n d e nc e fr o m tr e at m e nt d os e a nti micr o bi al 
dr u gs.  As a n ot h er s ec o n d ary e n d p oi nt r e g ar di n g l u n g all o gr aft o utc o m es, ac ut e c ell ul ar r ej ecti o n ( A C R) 
e pis o d es will b e ass ess e d, a n d t h e b ur d e n of A C R will b e d escri b e d usi n g t h e c u m ul ati v e r ej ecti o n 
sc ori n g syst e m ( C R S S). H er e a g ai n, r o u g h c o m p aris o ns a m o n g l u n g tr a ns pl a nt r eci pi e nts ar e a v ail a bl e 
wit h a p pr oxi m at el y 5 0 % of p ati e nts h a vi n g at l e ast o n e e pis o d e of A C R i n t h e first-y e ar p ost -l u n g 
tr a ns pl a nt [ 3 2].  
I n a d diti o n t o o n g oi n g r e vi e w of cli nic al r ec or ds b y r es e arc h st aff, t h es e effic ac y o utc o m es will b e 
q u eri e d s p ecific all y e v ery 3 m o nt hs ( w h e n c hi m eris m is ass ess e d).  F or ex a m pl e, if i m m u n os u p pr essi o n 
w e a ni n g h as n ot b e e n i niti at e d, t h e tr e ati n g p hysici a n s will b e ask e d w hic h of t h e 3 w e a ni n g crit eri a 
h av e n ot b e e n m et ( > 5 % d o n or T -c ell c hi m eris m; l ac k of gr a d e 2 + G V H D f or 3 m o nt hs; n o l u n g r ej ecti o n 
f or 3 m o nt hs).   
 A n al ys es of M ec h a nistic E n d p oi nts  
C hi m eris m will b e ass ess e d usi n g P C R b as e d S T R ass a y fr o m w h ol e bl o o d, C D 3 3 + e nric h e d my el oi d c ells, 
a n d C D 3 + T -c ells i n t h e cli nic al HL A l a b at m o nt hs pr e -B OL T a n d 3 m o nt hs p ost B OL T. Aft er B M T it will b e 
t est e d m o nt hs 1, 3, 6, 1 2 t h e n y e arl y.  T h es e v al u es will b e s u m m ariz e d gr a p hic all y a n d i nt er pr et e d i n 
t h e c o nt ext of ot h er cli nic al a n d l a b or at ory r es ults.  
S p uri o us c orr el ati o ns ar e a c o nc er n w h e n m ulti pl e ass a ys ar e e v al u at e d f or a s m all n u m b er of p ati e nts 
or ti m e p oi nts. Si nc e a c o m pr e h e nsi v e al p h a s p e n di n g str at e g y is i nf e asi bl e t o a p pl y i n a w a y t h at w o ul d 
yi el d e q ui v al e nt st a n d ar ds f or t esti n g e ac h p ati e nt’s i m m u n e f u ncti o ni n g, t h e e m p h asis will b e o n 

 
C o nfi d e nti al  
P a g e 6 7  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
w h et h er r es ults fr o m m ulti pl e ass a ys ar e c o nsist e nt wit h t h e h y p ot h esiz e d m ec h a nis m.  F or ex a m pl e,  if 
t h er e is a d et ect a bl e r es p o ns e b y i d e ntifyi n g circ ul ati n g t etr a m er p ositi v e c ells i n a S CI D or CI D p ati e nt 
wit h p ast C M V or a d e n ovir us ex p os ur e w h o h a d n o s uc h c ells d et ect e d pri or t o B M T, o n e c a n ex p ect i n 
p ar all el eit h er n or m aliz ati o n of C D 4 + a n d C D 8 + T c ell c o u nts or at l e ast a si g nific a nt i m pr ov e m e nt 
c o m par e d t o pr e -B M T v al u es. Cli nic al r es p o ns es s uc h as r es ol uti o n of vir e mi a, a n d or a bilit y t o r e d uc e or 
st o p a nti vir al m e dic ati o ns ar e ex p ect e d t o c orr el at e b ut lik el y wit h n ot a bl e ti m e d el a y as cli nic al 
d ecisi o ns ar e n ot t o b e i nfl u e nc e d b y t h e pr o p os e d m ec h a nistic st u dy d at a. Ex p eri m e nt al fi n di n gs i n t h e 
l u n g m uc os a will b e q u alit ati v el y c o m p ar e d t o ass a ys p erf or m e d o n P B M Cs, as h as b e e n pr e vi o usl y d o n e 
b y Dr. Mc D y er’s gr o u p [ 3 3, 3 4, 3 5]. L o n git u di n al cli nic al a n d r es e arc h l a b or at ory ass a y r es ults will b e 
d is pl a y e d gr a p hic all y, wit h n or m al f u ncti o ni n g l e v els i n dic at e d w h e n k n o w n. 
St atistic al a n al ysis will b e p erf or mi n g usi n g Gr a p h P a d Pris m, S AS/ S T A T ( S AS I nstit ut e, I nc., C ary, N C) a n d 
R ( R F o u n d ati o n f or St atistic al C o m p uti n g, Vi e n n a, A ustri a) s oft w ar e. A t w o -t ail e d p-v al u e of l ess t h a n 
0. 0 5 will b e c o nsi d er e d st atistic all y si g nific a nt.  As n o ass u m pti o n will b e m a d e r e g ar di n g t h e G a ussi a n 
distri b uti o n of m e as ur e d v ari a bl es, t h e n o n -p ar a m etric t ests of Wilc ox o n si g n e d -r a nk, M a n n-W hit n e y -
Wilc ox o n, a n d S p e ar m a n ’s r a nk c orr el ati o n will b e pri m arily us e d f or c o m p ari n g distri b uti o ns of p air e d 
m e as ur es a n d i n d e p e n d e nt gr o u ps (s uc h as s a m pl es fr o m B OL T/ B M T r eci pi e nts vs. r e p osit ory s a m pl es 
or i n vitr o T ol er a nc e ass a y c o n diti o ns wit h or wit h o ut Tr e g d e pl eti o n, IL -1 0 R  bl oc k a d e, etc). F or m a n y 
ass a ys, c o ntr ol d at a fr o m eit h er n or m al d o n ors or ot h er a g e -m atc h e d l u n g tr a ns pl a nt c o ntr ol p ati e nts 
(s uc h as p ati e nts u n d er g oi n g l u n g tr a ns pl a nt f or c ystic fi br osis) will b e a v ail a bl e f or c o m p aris o n. W h e n 
a p pr o pri at e, li n e ar mix e d -eff ects m o d els will b e fitt e d t o l o n git u di n al d at a.  
 D escri pti v e A n al ys es  
B as eli n e d e m o gr a p hic, dis e as e, a n d pri or tr e at m e nt c h ar act eristics of e ac h p artici p a nt will b e r e p ort e d 
a n d  s u m m ariz e d f or t h e s af et y a n d effic ac y a n alysis p o p ul ati o ns.  M e as ur es of c e ntr al t e n d e nc y ( e. g., 
m e a ns, m e di a ns) a n d v ari ati o n (r a n g e, st a n d ar d d e vi ati o n) will b e pr es e nt e d f or c o nti n u o us v ari a bl es 
a n d p erc e nt a g es will b e r e p ort e d f or discr et e v ari a bl es. T h e d escri pti v e st atistics m a y als o  b e str atifi e d 
b y u n d erl yi n g pri m ary i m m u n o d efici e nc y , if p ossi bl e.   
1 3. 4  I nt eri m A n al ys es  
 I nt eri m A n al ysis of Effic ac y D at a 
T h er e is n o pl a n n e d i nt eri m a n al ysis of effic ac y d at a.  
 I nt eri m A n al ysis of S af et y D at a 
I nt eri m a n al ys es of s af et y d at a will b e pr e p ar e d f or a n d r e vi e w e d b y t h e D S M B a n n u ally, a n d as n e e d e d 
( d escri b e d i n s ecti o n 1 2 . 8. 2). 
 F utilit y A n al ysis  
T h e st o p pi n g r ul es disc uss e d i n s ecti o n 1 1. 5 c o nstit ut e a f utilit y a n alysis.  
 St atistic al  H y p ot h es es  
1)  T h e B OL T + B M T a p pr o ac h will b e c o nsi d er e d f e asi bl e if at l e ast h alf of p ati e nts e nr oll e d c o m pl et e 
b ot h B OL T a n d B M T pr oc e d ur es ( alt h o u g h e nr oll m e nt will n ot b e c a p p e d at 1 6 ) 
2)  T h e B OL T + B M T a p pr o ac h will b e s af e e n o u g h n ot t o tri g g er t h e st o p pi n g r ul es i n s ecti o n 1 1. 5  

 
C o nfi d e nti al  
P a g e 6 8  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
F or e ac h effic ac y e n d p oi nt, at l e ast h alf of p ati e nts tr e at e d will h a v e a f a v or a bl e o utc o m e, f or w hic h a  
9 0 % Wils o n c o nfi d e nc e i nt erv al will i ncl u d e a 7 0 % s ucc ess r at e. 
1 3. 5  S a m pl e Siz e C o nsi d er ati o ns  
Wit h e nr oll m e nt  a n d f oll o w -u p ov er a 5 -y e ar p eri o d , w e  ex p ect a s a m pl e siz e of 8 p ati e nts t o r ec ei v e 
b ot h B OL T a n d B M T.  T his s a m pl e siz e, wit h a d diti o n al s af et y a n d f e asi bilit y d at a fr o m p ati e nts w h o d o 
n ot r ec ei v e B M T, s h o ul d b e a d e q u at e f or d et ecti n g a hi g h  r at e of B M T f ail ur e (s e e st o p pi n g r ul es, 
S ecti o n 1 1. 5 ), wit h a 6 9 % pr o b a bilit y of tri g g eri n g t h e st o p pi n g r ul e if t h e u n d erl yi n g r at e of B M T f ail ur e 
is 5 0 %.   F or bi n ary effic ac y v ari a bl es, p oi nt esti m at es of t h e r at e of tr e at m e nt s ucc ess will b e pr ovi d e d 
wit h 9 0 % Wils o n c o nfi d e nc e i nt erv als of wi dt h < 5 0  p erc e nt a g e p oi nts (s e e S ecti o n 1 3. 3. 1 ). 

 
C o nfi d e nti al  
P a g e 6 9  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 4  I d e ntific ati o n a n d Acc ess t o S o urc e D at a 
1 4. 1  S o urc e D at a  
S o urc e d oc u m e nts a n d s o urc e d at a ar e c o nsi d er e d t o b e t h e ori gi n al d oc u m e nt ati o n w h er e s u bj ect 
i nf or m ati o n, visits c o ns ult ati o ns, ex a min ati o ns a n d ot h er i nf or m ati o n  ar e r ec or d e d .   D oc u m e nt ati o n of 
s o urc e d ata is n ec ess ary f or t h e r ec o nstr ucti o n, e v al u ati o n a n d v ali d ati o n of cli nic al fi n di n gs, 
o bs erv ati o ns a n d ot h er acti viti es d uri n g a cli nic al tri al.  
1 4. 2  Acc ess t o S o urc e D at a  
T h e sit e i nv esti g at ors a n d sit e st aff will m a k e all s o urc e d at a a v ail a bl e t o t h e D AI T/ N I AI D, as w ell as t o 
t h e r el e v a nt h e alt h a ut h oriti es e. g. F o o d a n d Dr u g A d mi nistr ati o n (F D A) .  A ut h oriz e d r e pr es e nt ati v es as 
n ot e d a b ov e ar e b o u n d t o m ai nt ai n t h e strict c o nfi d e nti alit y of m e dic al a n d r es e arc h i nf or m ati o n t h at 
m a y b e li n k e d t o i d e ntifi e d i n divi d u als.  

 
C o nfi d e nti al  
P a g e 7 0  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 5  Pr ot oc ol D e vi ati o ns  
1 5. 1  Pr ot oc ol D e vi ati o n  D efi niti o ns  
Pr ot oc ol D e vi ati o n  –  T h e i nv esti g at ors a n d sit e st aff will c o n d uct t h e st u dy i n acc or d a nc e t o  t h e 
pr ot oc ol; n o d e vi ati o ns fr o m t h e pr ot oc ol ar e p er mitt e d .  A n y c h a n g e, div er g e nc e, or d e p art ur e fr o m t h e 
st u dy d esi g n or pr oc e d ur es c o nstit ut es a pr ot oc ol d e vi ati o n .  As a r es ult of a ny d e vi ati o n, c orr ecti v e 
acti o ns will b e d e v el o p e d by t h e sit e a n d i m pl e m e nt e d pr o m ptl y.  
 
M aj or Pr ot oc ol D e vi ati o n ( Pr ot oc ol Vi ol ati o n) - A P r ot oc ol V i ol ati o n is a d e vi ati o n fr o m t h e I R B 
a p pr ov e d pr ot oc ol t h at m ay aff ect t h e s u bj ect's ri g hts, s af et y, or w ell -b ei n g a n d/ or t h e c o m pl et e n ess, 
acc ur ac y a n d r eli a bilit y of t h e st u d y d at a .  I n a d diti o n, pr ot oc ol vi ol ati o ns i ncl u d e willf ul or k n o wi n g 
br e ac h es  of h u m a n s u bj ect pr ot ecti o n r e g ul ati o ns, or p olici es, a n y acti o n t h at is i nc o nsist e nt wit h t h e 
NI H H u m a n R es e arc h Pr ot ecti o n Pr o gr a m’s r es e arc h, m e dic al, a n d et hic al pri nci pl es , a n d a s eri o us or 
c o nti n ui n g n o nc o m pli a nc e wit h f e d er al, st at e, l oc al or i nstit uti o n al h u m a n s u bj ect pr ot ecti o n 
r e g ul ati o ns, p olici es, or pr oc e d ur es.  
 
N o n -M aj or  Pr ot oc ol D e vi ati o n  - A n o n -m aj or  pr ot oc ol d e vi ati o n is a n y c h a n g e, div er g e nc e, or d e p art ur e 
fr o m t h e st u dy d esi g n or pr oc e d ur es of a r es e arc h pr ot oc ol t h at d o es n ot  h av e a m aj or i m p act o n t h e 
s u bj ect's ri g hts, s af et y or w ell-b ei n g, or t h e c o m pl et e n ess, acc ur ac y a n d r eli a bilit y of t h e st u dy d at a.  
1 5. 2  R e p orti n g a n d M a n a gi n g Pr ot oc ol D e vi ati o ns  
T h e st u dy sit e pri nci p al i nv esti g at or  h as t h e r es p o nsi bilit y t o i d e ntify, d oc u m e nt a n d r e p ort pr ot oc ol 
d e vi ati o ns  as dir ect e d b y t h e st u dy S p o ns or .  H o w e v er, pr ot oc ol d e vi ati o ns m ay als o b e i d e ntifi e d d uri n g 
sit e m o nit ori n g visits or d uri n g ot h er f or ms of st u dy c o n d uct r e vi e w.  

 
C o nfi d e nti al  
P a g e 7 1  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 6  Et hic al C o nsi d er ati o ns a n d C o m pli a nc e wit h G o o d Cli nic al Pr actic e  
1 6. 1  St at e m e nt of C o m pli a nc e  
T his cli nic al st u dy will b e c o n d uct e d usi n g g o o d cli nic al pr actic e ( G C P), as d eli n e at e d i n G ui d a nc e f or 
I n d ustry: E 6 G o o d Cli nic al Pr actic e C o ns oli d at e d G ui d a nc e, a n d acc or di n g t o t h e crit eri a s p ecifi e d i n t his 
st u dy pr ot oc ol.  B ef or e st u dy i niti ati o n, t h e pr ot oc ol a n d t h e i nf or m e d c o ns e nt d oc u m e nts will b e 
r e vi e w e d a n d a p pr ov e d by t he l oc al i nstit uti o n al R e vi e w B o ar d (I R B). A n y a m e n d m e nts t o t h e pr ot oc ol 
or t o t h e c o ns e nt m at eri als will  als o b e a p pr ov e d b y t h e  I R B b ef or e t h e y ar e i m pl e m e nt e d.  
1 6. 2  I nf or m e d C o nse nt Pr oc ess  
T h e c o ns e nt pr oc ess will pr ovi d e i nf or m ati o n a b o ut t h e st u dy t o a pr os p ecti v e p artici p a nt a n d will all o w 
a d e q u at e ti m e f or r e vi e w a n d disc ussi o n pri or t o his/ h er  d ecisi o n.  T h e pri nci p al i n v esti g at or or d esi g n e e 
list e d o n t h e F D A f or m 1 5 7 2 will  r e vi e w t h e c o ns e nt a n d a ns w er q u esti o ns. T h e pr os p ecti v e p artici p a nt 
will b e t ol d t h at b ei n g i n t h e tri al is v ol u nt ary a n d t h at h e or s h e m ay wit h dr a w fr o m t h e st u dy at a n y 
ti m e, f or a n y r e as o n.  All p artici p a nts ( or t h eir l e g all y acc e pt a bl e r e pr es e nt ati ve) will  r e a d, si g n, a n d d at e 
a c o ns e nt f or m b ef or e u n d er g oi n g a n y st u dy pr oc e d ur es.  C o ns e nt m at eri als will  b e pr es e nt e d i n 
p artici p a nts’ pri m ary l a n g u a g e. A c o p y of t h e si g n e d c o ns e nt f or m will  b e gi v e n t o t h e p artici p a nt.  
T h e c o ns e nt f or m will  b e r e vis e d w h e n i m p ort a nt n e w s af et y i nf or m ati o n is a v ail a bl e, t h e pr ot oc ol is 
a m e n d e d, a n d/ or n e w i nf or m ati o n b ec o m es  a v ail a bl e t h at m ay aff ect p artici p ati o n i n t h e st u dy.  
1 6. 3  Pri v ac y a n d C o nfi d e nti alit y  
A p artici p a nt’s pri v ac y a n d c o nfi d e nti alit y will b e r es p ect e d t hr o u g h o ut t h e st u dy.  E ac h p artici p a nt will 
b e assi g n e d a u ni q u e i d e ntific ati o n n u m b er a n d t h es e n u m b ers r at h er t h a n n a m es will b e us e d t o 
c oll ect, st or e, a n d r e p ort p artici p a nt i nf or m ati o n.  Sit e p ers o n n el will  n ot tr a ns mit d oc u m e nts c o nt ai ni n g 
p ers o n al h e alt h i d e ntifi ers ( P HI) t o t h e st u dy s p o ns or or t h eir r e pr es e nt ati v es.  

 
C o nfi d e nti al  
P a g e 7 2  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 7  P u blic ati o n P olic y  
T h e p u blic ati o n g ui d eli n es a n d p olici es sti p ul at e d i n t h e gr a nt will a p pl y t o t his pr ot oc ol.  

 
C o nfi d e nti al  
P a g e 7 3  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
1 8  R ef er e nc es  
1.  
Griffit h L M, C o w a n MJ, N ot ar a n g el o L D, et al. I m pr ovi n g c ell ul ar t h er a py f or pri m ary i m m u n e 
d efici e nc y dis e as es: r ec o g niti o n, di a g n osis, a n d m a n a g e m e nt. T h e J o ur n al of  all er g y a n d cli nic al 
i m m u n ol o g y 2 0 0 9; 1 2 4: 1 1 5 2-6 0 e 1 2.  
2.  
Sz a b olcs P, C a v azz a n a -C alv o M, Fisc h er A, V e ys P. B o n e m arr o w tr a ns pl a nt ati o n f or pri m ary 
i m m u n o d efici e nc y dis e as es. P e di atric cli nics of N ort h A m eric a 2 0 1 0; 5 7: 2 0 7-3 7.  
3.  
S at w a ni P, C o o p er N, R a o K,  V e ys P, A mr oli a P. R e d uc e d i nt e nsit y c o n diti o ni n g a n d all o g e n eic 
st e m c ell tr a ns pl a nt ati o n i n c hil d h o o d m ali g n a nt a n d n o n m ali g n a nt dis e as es. B o n e M arr o w 
Tr a ns pl a nt 2 0 0 8; 4 1: 1 7 3 -8 2.  
4.  
R a o K, A mr oli a PJ, J o n es A, et al. I m pr ov e d s urvi v al aft er u nr el at e d d o n or b o n e m arr o w 
tr a ns pl a nt ati o n i n c hil dr e n wit h pri m ary i m m u n o d efici e nc y usi n g a r e d uc e d-i nt e nsit y 
c o n diti o ni n g r e gi m e n. Bl o o d 2 0 0 5; 1 0 5: 8 7 9 -8 5.  
5.  
M ori o T, Ats ut a Y, T o miz a w a D, et al. O utc o m e of u nr el at e d u m bilic al c or d bl o o d tr a ns pl a nt ati o n 
i n 8 8 p ati e nts wit h pri m ary i m m u n o d efici e nc y i n J a p a n. Br J H a e m at ol 2 0 1 1; 1 5 4: 3 6 3 -7 2.  
6.  
N ot ar a n g el o L D, Pl e b a ni A, M azz ol ari E, S or esi n a A, B o n di o ni M P. G e n etic c a us es of 
br o nc hi ect asis: pri m ary i m m u n e d efici e nci es a n d t h e l u n g. R es pir ati o n 2 0 0 7; 7 4: 2 6 4 -7 5.  
7.  
E ast h a m K M, F all AJ, Mitc h ell L, S p e nc er D A. T h e n e e d t o r e d efi n e n o n -c ystic fi br osis 
br o nc hi ect asis i n c hil d h o o d. T h or a x 2 0 0 4; 5 9: 3 2 4 -7.  
8.  
Li A M, S o n n a p p a S, L ex C, et al. N o n-C F br o nc hi ect asis: d o es k n o wi n g t h e a eti ol o g y l e a d t o 
c h a n g es i n m a n a g e m e nt ? E ur R es pir J 2 0 0 5; 2 6: 8-1 4.  
9.  
P ari k h S, Sz a b olcs P. R e d uc e d -i nt e nsit y c o n diti o ni n g ( RI C) i n c hil dr e n wit h n o n m ali g n a nt 
dis or d ers ( N M D) u n d er g oi n g u nr el at e d d o n or u m bilic al c or d bl o o d tr a ns pl a nt ati o n ( U C B T). 
Bi ol o g y of bl o o d a n d m arr o w tr a ns pl a nt ati o n : j o ur n al of t h e A m eric a n S oci et y f or Bl o o d a n d 
M arr o w Tr a ns pl a nt ati o n 2 0 1 2; 1 8: S 5 3 -5.  
1 0.  
V e ys P. R e d uc e d i nt e nsit y tr a ns pl a nt ati o n f or pri m ary i m m u n o d efici e nc y dis or d ers. I m m u n ol 
All er g y Cli n N ort h A m 2 0 1 0; 3 0: 1 0 3 -2 4.  
1 1.  
A n dr e a ni M, N esci S, L uc ar elli G, et al. L o n g -t erm s urvi v al of ex -t h al ass e mic p ati e nts wit h 
p ersist e nt mix e d c hi m eris m aft er b o n e m arr o w tr a ns pl a nt ati o n. B o n e m arr o w tr a ns pl a nt ati o n 
2 0 0 0; 2 5: 4 0 1 -4.  
1 2.  
W alt ers M C, P ati e nc e M, L eis e nri n g W, et al. St a bl e mix e d h e m at o p oi etic c hi m eris m aft er b o n e 
m arr o w tr a n s pl a nt ati o n f or sic kl e c ell a n e mi a. Bi ol o g y of bl o o d a n d m arr o w tr a ns pl a nt ati o n : 
j o ur n al of t h e A m eric a n S oci et y f or Bl o o d a n d M arr o w Tr a ns pl a nt ati o n 2 0 0 1; 7: 6 6 5-7 3.  
1 3.  
Av ers a F. H a pl oi d e ntic al h a e m at o p oi etic st e m c ell tr a ns pl a nt ati o n f or ac ut e l e u k a e mi a i n a d ults: 
ex p eri e nc e i n E ur o p e a n d t h e U nit e d St at es. B o n e M arr o w Tr a ns pl a nt 2 0 0 8; 4 1: 4 7 3 -8 1.  
1 4.  
Av ers a F, T er e nzi A, T a bili o A, et al. F ull h a pl ot y p e -mis m atc h e d h e m at o p oi etic st e m -c ell 
tr a ns pl a nt ati o n: a p h as e II st u dy i n p ati e nts wit h ac ut e l e u k e mi a at hi g h risk of r el a ps e. J Cli n 
O nc ol 2 0 0 5; 2 3: 3 4 4 7 -5 4.  
1 5.  
F e d er m a n n B, B or n h a us er M, M eis n er C, et al. H a pl oi d e ntic al all o g e n eic h e m at o p oi etic c ell 
tr a ns pl a nt ati o n i n a d ults usi n g C D 3/ C D 1 9 d e pl eti o n a n d r e d uc e d i nt e nsit y c o n diti o ni n g: a p h as e 
II st u dy. H a e m at ol o gic a 2 0 1 2. 
1 6.  
C h e n X, H al e G A, B arfi el d R, et al. R a pi d i m m u n e r ec o nstit uti o n aft er a r e d uc e d -i nt e nsit y 
c o n diti o ni n g r e gi m e n a n d a C D 3-d e pl et e d h a pl oi d e ntic al st e m c ell gr aft f or p a e di atric r efr act ory 
h a e m at ol o gic al m ali g n a nci es. Britis h j o ur n al of h a e m at ol o g y 2 0 0 6; 1 3 5: 5 2 4 -3 2.  
1 7.  
E a p e n M, Kl ei n J P, S a nz G F, et al. Eff ect of d o n or -r eci pi e nt HL A m atc hi n g at HL A A, B, C, a n d 
D R B 1 o n o utc o m es aft er u m bilic al -c or d bl o o d tr a ns pl a nt ati o n f or l e u k a e mi a a n d 
my el o d ys pl astic sy n dr o m e: a r etr os p ecti v e a n alysis. L a nc et O nc ol 2 0 1 1; 1 2 : 1 2 1 4-2 1.  
1 8.  
Sc a n dli n g J D, B us q u e S, D ej b ak hs h -J o n es S, et al. T ol er a nc e a n d Wit h dr a w al of 
I m m u n os u p pr essi v e Dr u gs i n P ati e nts Gi v e n Ki d n e y a n d H e m at o p oi etic C ell Tr a ns pl a nts. 

 
C o nfi d e nti al  
P a g e 7 4  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
A m eric a n j o ur n al of tr a ns pl a nt ati o n : offici al j o ur n al of t h e A m eric a n S oci et y of Tr a ns pl a nt ati o n 
a n d t h e A m eric a n S oci et y of Tr a ns pl a nt S ur g e o ns 2 0 1 2; 1 2: 1 1 3 3 -4 5.  
1 9.  
L e v e nt h al J, A b ec assis M, Mill er J, et al. C hi m eris m a n d t ol er a nc e wit h o ut G V H D or e n gr aft m e nt 
sy n dr o m e i n HL A-mis m atc h e d c o m bi n e d ki d n e y a n d h e m at o p oi etic st e m c ell tr a ns pl a nt ati o n. Sci 
Tr a nsl M e d 2 0 1 2; 4: 1 2 4r a 2 8.  
2 0.  
L e v e nt h al J, A b ec assis M, Mill er J, et al. T ol er a nc e i n d ucti o n i n HL A dis p ar at e livi n g d o n or ki d n e y 
tr a ns pl a nt ati o n by d o n or st e m c ell i nf usi o n: d ur a bl e c hi m eris m pr e dicts o utc o m e. 
Tr a ns pl a nt ati o n 2 0 1 3; 9 5: 1 6 9 -7 6.  
2 1.  
L e v e nt h al J, L evitsk y J, A b ec assis M M, et al. S p o nt a n e o us o p er ati o n al t ol er a nc e i n ki d n e y 
tr a ns pl a nt r eci pi e nts. A m J Tr a ns pl a nt 2 0 1 2; 1 2: 1 3 5 0; a ut h or r e ply 1-2.  
2 2.  
O e v er m a n n L, L a n g P, F e uc hti n g er T, et al. I m m u n e r ec o nstit uti o n a n d str at e gi es f or r e b uil di n g 
t h e i m m u n e syst e m aft er h a pl oi d e ntic al st e m c ell tr a ns pl a nt ati o n. A n n als of t h e N e w Y ork 
Ac a d e m y of Sci e nc es 2 0 1 2; 1 2 6 6: 1 6 1 -7 0.  
2 3.  
C h e n X, H al e G A, B arfi el d R, et al. R a pi d i m m u n e r ec o nstit uti o n aft er a r e d uc e d -i nt e nsit y 
c o n diti o ni n g r e gi m e n a n d a C D 3 -d e pl et e d h a pl oi d e ntic al st e m c ell gr aft f or p a e di atric r efr act ory 
h a e m at ol o gic al m ali g n a nci es. Br J H a e m at ol 2 0 0 6; 1 3 5: 5 2 4 -3 2.  
2 4.  
D o n n e n b er g A D, G or a ntl a V S, Sc h n e e b er g er S, et al. Cli nic al i m pl e m e nt ati o n of a pr oc e d ur e t o 
pr e p ar e b o n e m arr o w c e lls fr o m c a d a v eric v ert e br al b o di es. R e g e n M e d 2 0 1 1; 6: 7 0 1-6.  
2 5.  
G or a ntl a V S, Sc h n e e b er g er S, M o or e L R, et al. D e v el o p m e nt a n d v ali d ati o n of a pr oc e d ur e t o 
is ol at e vi a bl e b o n e m arr o w c ells fr o m t h e v ert e br a e of c a d a v eric or g a n d o n ors f or c o m p osit e 
or g a n gr afti n g. C yt ot h er a py 2 0 1 2; 1 4: 1 0 4 -1 3.  
2 6.  
M ac h ali nski B, P aczk o wski M, K a w a M, P aczk o wsk a E, Ostr o wski M. A n o pti miz ati o n of is ol ati o n 
of e arl y h e m at o p oi etic c ells fr o m h e p ari niz e d c a d a v eric or g a n d o n ors. Tr a ns pl a nt Pr oc 
2 0 0 3; 3 5: 3 0 9 6 -1 0 0.  
2 7.  
L a n g P, T eltschik H -M, F e uc hti n g er T et al.,  Tr a ns pl a nt ati o n of C D 3/ C D 1 9 d e pl et e d all o gr afts 
fr o m h a pl oi d e ntic al f a mily d o n ors i n p a e di atric  l e u k a e mi a.  Britis h J o ur n al of H a e m at ol o g y 
2 0 1 4; 1 6 5: 6 8 8 -9 8.  
2 8.  
B a d er P, S o er e ns e n J, J aris h A et al.,  R a pi d i m m u n e r ec ov ery a n d l o w T R M i n h a pl oi d e ntic al st e m 
c ell tr a ns pl a nt ati o n i n c hil dr e n a n d a d ol esc e nc e usi n g C D 3/ C D 1 9 -d e pl et e d st e m c ells.  B est 
Pr actic e & R es e arc h Cli nic al H a e m at ol o g y 2 0 1 1; 2 4: 3 3 1 -3 7.  
2 9.  
K o h K -N, I m HJ, Ki m B E et al.,  H a pl oi d e ntic al h a e m at o p oi etic st e m c ell tr a ns pl a nt ati o n usi n g C D 3 
or C D 3/ C D 1 9 d e pl eti o n a n d c o n diti o ni n g wit h fl u d ar a bi n e, c ycl o p h os p h a mi d e, a n d 
a ntit h y m oc yt e gl o b uli n f or ac q uir e d s e v er e a pl astic a n a e mi a.  Britis h J o ur n al of H a e m at ol o g y 
2 0 1 2; 1 5 7: 1 3 9 -4 1.  
3 0.  
B et h g e W A, F a ul C, B or n h a us er M et al., H a pl oi d e ntic al all o g e n eic h e m at o p oi etic c ell 
tr a ns pl a nt ati o n i n a d ults usi n g C D 3/ C D 1 9 d e pl eti o n a n d r e d uc e d i nt e nsit y c o n diti o ni n g: a n 
u p d at e.  Bl o o d C ells, M ol ec ul es, a n d Dis e as es 2 0 0 8; 4 0: 1 3 -1 9.  
3 1.  
W ei gt S S, W all ac e W D, D er h ov a n essi a n A, et a l. C hr o nic all o gr aft r ej ecti o n: e pi d e mi ol o g y, 
di a g n osis, p at h o g e n esis, a n d tr e at m e nt. S e mi n ars i n r es pir at ory a n d critic al c ar e m e dici n e 
2 0 1 0; 3 1: 1 8 9 -2 0 7.  
3 2.  
M arti n u T, H o w ell D N, P al m er S M. Ac ut e c ell ul ar r ej ecti o n a n d h u m or al s e nsitiz ati o n i n l u n g 
tr a nspl a nt r eci pi e nts. S e mi n ars i n r es pir at ory a n d critic al c ar e m e dici n e 2 0 1 0; 3 1: 1 7 9 -8 8.  
3 3.  
Pi p eli n g M R, W est E E, Os b or n e C M, et al. Diff er e nti al C M V -s p ecific C D 8 + eff ect or T c ell 
r es p o ns es i n t h e l u n g all o gr aft pr e d o mi n at e ov er t h e bl o o d d uri n g h u m a n pri m ary i nf ecti o n. J 
I m m u n ol 2 0 0 8; 1 8 1: 5 4 6-5 6.  
3 4.  
Ak uli a n J A, Pi p eli n g M R, J o h n E R, Or e ns J B, L ec htzi n N, Mc D y er J F. Hi g h -q u alit y C M V -s p ecific 
C D 4 + m e m ory is e nric h e d i n t h e l u n g all o gr aft a n d is ass oci at e d wit h m uc os al vir al c o ntr ol. 
A m eric a n j o ur n al of tr a ns p l a nt ati o n : offici al j o ur n al of t h e A m eric a n S oci et y of Tr a ns pl a nt ati o n 
a n d t h e A m eric a n S oci et y of Tr a ns pl a nt S ur g e o ns 2 0 1 3; 1 3: 1 4 6 -5 6.  

 
C o nfi d e nti al  
P a g e 7 5  of 8 4  
B OL T -B M T  
V ersi o n 8. 0 /J a n u ar y 15 , 2 0 2 1 
3 5.  
P o p esc u I, Dr u m m o n d M B, G a m a L, et al. Acti v ati o n -i n d uc e d c ell d e at h dri v es pr of o u n d l u n g 
C D 4( +) T -c ell d e pl eti o n in HI V -ass oci at e d c hr o nic o bstr ucti v e p ul m o n ary dis e as e. A m eric a n 
j o ur n al of r es pir at ory a n d critic al c ar e m e dici n e 2 0 1 4; 1 9 0: 7 4 4-5 5.  
3 6 .  
C ar p e nt er P A, Kit k o CL, El a d S, Fl o w ers M E, G e a -B a n acl oc h e J C, H alt er J P, H o o di n F, J o h nst o n L, 
L a witsc h k a A, Mc D o n al d G B, O pi p ari A W, S a v a ni B N, Sc h ultz K R, S mit h S R, Syrj al a KL, Tr eist er N, 
V o g els a n g G B, Willi a ms K M, P a vl etic S Z, M arti n PJ, L e e SJ, C o uri el D R.  N ati o n al I nstit ut es of  
H e alt h C o ns e ns us D e v el o p m e nt Pr oj ect o n Crit eri a f or Cli nic al Tri als i n C h r o nic Gr aft-v ers us-H ost 
Dis e as e I. T h e 2 0 1 4 Di a g n osis a n d St a gi n g  W orki n g  Gr o u p R e p ort . Bi ol  Bl o o d M arr o w Tr a ns pl a nt. 
2 0 1 5 J ul ; 2 1( 7): 1 1 6 7-8 7 .  
3 7.  
Ti k k a n e n J M , Si n g er L G, Ki m SJ , Li Y, Bi n ni e M , C h a p arr o C, C h o w C W , M arti n u T , Az a d S , 
K es h avj e e S , Ti nc k a m K . D e N ov o D Q D o n or -S p ecific A nti b o di es Ar e Ass oci at e d wit h C hr o nic 
L u n g All o gr aft D ysf u ncti o n aft er L u n g Tr a ns pl a nt ati o n . A m J R es pir Crit C ar e M e d.  2 0 1 6 S e p 
1; 1 9 4( 5): 5 9 6 -6 0 6 . 
3 8.  
M arti n u  T , C h e n D, P al m er  S. Ac ut e R ej ecti o n a n d H u m or al S e nsitiz ati o n i n L u n g  
T r a ns pl a nt R eci pi e nts. Pr oc A m T h or ac S oc. 2 0 0 9 J a n 1 5; 6( 1): 5 4 – 6 5.  
3 9.  
D M B ur ns, S R a n a, E M arti n, S N a gr a, J W ar d, H Os m a n, AI B ell, P M oss, N H R uss ell, C F Cr a d d oc k, 
C P F ox a n d S C h a g a nti. Gr e atl y r e d uc e d risk of E B V r e activ ati o n i n  rit uxi m a b-ex p eri e nc e d 
r eci pi e nts of al e mt uz u m a b-c o n diti o n e d all o g e n eic HS C T . B o n e M arr o w Tr a ns pl a nt ati o n . 2 0 1 6 
F e b 2 2; 5 1 :8 2 5 – 8 3 2 . 
4 0.  
Ci ur e a S O , T h all P F, W a n g X, W a n g S A, H u Y, C a n o P, A u n g F, R o n d o n G, M oll dr e m JJ, K or bli n g M, 
S h p all  EJ, d e Li m a M, C h a m pli n R E, F er n a n d ez -Vi n a M.  D o n or -s p ecific a nti-HL A A bs a n d gr aft 
f ail ur e i n m atc h e d u nr el at e d d o n or h e m at o p oi etic st e m c ell tr a ns pl a nt ati o n. Bl o o d. 2 0 1 1 N ov 
2 4; 1 1 8( 2 2): 5 9 5 7 -6 4 . 
4 1.  
St e w art S, Fis h b ei n M C, S n ell GI, et al. R e visi o n of t h e 1 9 9 6 w orki n g f or m ul ati o n f or t h e 
st a n d ar diz ati o n of n o m e ncl at ur e i n t h e di a g n osis of l u n g r ej ecti o n. T h e J o ur n al of h e art a n d l u n g 
tr a ns pl a nt ati o n : t h e offici al p u blic ati o n of t h e I nt er n ati o n al S oci et y f or H e art Tr a ns pl a nt ati o n 
2 0 0 7; 2 6: 1 2 2 9 -4 2.  
 
 
 

 
C o nfi d e nti al  
P a g e 7 8  of 8 4  
B OL T -B M T  
V ersi o n  8. 0 /J a n u ar y 15 , 2 0 2 1 
 
 
 
9D S A m ay b e r e p e at e d as cli nic ally i n dic at e d a n d r es ults will b e c oll ect e d as a p art of t h e st u d y.    
1 0T h es e c e ntr al l a b or at or y ass ess m e nts m ay b e c oll ect e d at f or c a us e visits at t h e discr eti o n of t h e I n v esti g at or.  
1 1C oll ect e d if t h e ex pl a nt e d l u n g is pr oc ess e d.  
1 2A n yti m e pri or t o tr a ns pl a nt.  
 
 
 

 
C o nfi d e nti al  
P a g e 8 1  of 8 4  
B OL T -B M T  
V ersi o n  8. 0 /J a n u ar y 15 , 2 0 2 1 
 
 
 
 
 
 
1 0 S a m pl es t o b e c oll ect e d 1) s u bj ect is off I VI G f or at l e ast 3 m o nt hs a n d n ot y et v acci n at e d a n d 2) v acci n at e d wit h at l e ast t w o a d mi nistr ati o ns   
1 1If h ost T-c ells ar e 1 0 % a n d i ncl u d es a nti -d o n or T C R V B i m m u n os e q u e nci n g, a nti -d o n or pr olif er ati o n, a nti -d o n or cyt o ki n e pr ofil e a n d a nti -d o n or cyt ot oxicit y .  
1 2E B V, C M V a n d A d e n o vir us t esti n g is p erf or m e d acc or di n g t o U P M C g ui d eli n es a n d as cli nic ally i n dic at e d . 
1 3  F oll o wi n g B M T, d at a will b e c oll ect e d f or a n y cli nic ally i n dic at e d b o n e m arr o w as pir at es.  
1 4C D 3 +, C D 3 +/ C D 4 +, C D 3 +/ C D 4 5 R A +, C D 4 +/ C D 4 5 R A +/ C D 6 2L.  
1 5T -c ells ( C D 3), H el p er c ells ( C D 4), S u p pr ess or c ells ( C D 8), B -c ells ( C D 1 9), N K c ells ( C D 1 6/ C D 5 6), H el p er/ S u p pr ess or R ati o.  
1 6T h es e c e ntr al l a b s p eci m e ns m ay b e r e p e at e d d uri n g a n y s ur v eill a nc e or f or c a us e visit ( at t h e discr eti o n of t h e I n v esti g at or) pr o v i d e d t h e sit e d o es n ot exc e e d t h e l oc al 
i nstit uti o n al bl o o d v ol u m e g ui d eli n es.  
1 7T h es e s a m pl es s h o ul d b e c oll ect e d pri or t o t h e i niti ati o n of i m m u n os u p pr essi o n wit h dr a w al ( esti m at e d b et w e e n 9 -1 2 m o nt hs p ost B M T) a n d > 2 m o nt hs aft er c o m pl eti o n of 
i m m u n os up pr essi o n t a p er ( esti m at e d b et w e e n 1 4 -2 4 m o nt hs p ost B M T).