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2. medicine
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Unrelated Donor Bone Marrow Transplantation for Correction of Lethal
Congenital Immunodeficiencies
By Alexandra H. Filipovich, Ralph S. Shapiro, Norma K.C. Ramsay, Tae Kim, Bruce Blazar, John Kersey,
and Philip McGlave
Unrelated donor marrow transplantation was undertaken in
eight infants with severe combined immunodeficiency (SCID)
and two children each with Wiskott-Aldrich syndrome (WAS)
and Chediak-Higashi syndrome (CHS) who did not have
histocompatible siblings. Donors for three patients were
phenotypically matched at all HLA-A, B, Dr, and Dw loci,
whereas nine donors were mismatched from the recipients at
one of the HLA-A or B loci but phenotypically identical at
evaluable D loci. All but one patient received conditioning
chemotherapy and/or radiotherapy before infusion of donor
marrow, which was not T-cell depleted. Prophylaxis for
graft-versus-host disease (GVHD) consisted of methotrexate
and prednisone combined with either cyclosporine A (six
patients), antithymocyte globulin (five patients), or anti-CD5
ricin A chain immunotoxin (one patient). All patients engrafted with donor cells, and only 4 of 12 experienced any
GVHD (1of 8 SCID, 1of 2 WAS, 2 of 2 CHS). Two children who
developed grade II and two who developed grade 111 GVHD
were successfully treated and all are now alive, off immunosuppressive therapy, with no evidence of chronic GVHD
greater than 18 months after transplant. Ten patients are
alive with excellent immunoreconstitution h l year t o 2 3
years after transplant; actuarial survival is predicted t o be
83% with a median follow-up of 2 years. Two children with
SCID succumbed t o pre-existing opportunistic infection early
posttransplant. We conclude that closely matched unrelated
donor bone marrow transplantation can correct congenital
immunodeficiencies including variants of SCID, WAS, and
CHS, with an acceptably low incidence of transplant-related
complications, principally GVHD.
0 1992b y The American Society of Hematology.
T
without malignancies; (2) it has been associated with severe
graft-versus-host disease (GVHD)12; and (3) it has an
alarming incidence of posttransplant Epstein-Barr virus
(EBV)-associated B-cell lymphoproliferative disorder (especially in WAS).13 The time course for immunoreconstitution following T-depleted haploidentical bone marrow
transplantation (BMT) in many reported cases has been
markedly prolonged9J4 and recovery of specific antibody
synthesis has not been achieved in some cases?Jo
For the rare cases of congenital immunodeficiency where
the genetic defect is known, enzyme replacement therapyI5
and/or gene therapy16has been attempted, as in the case of
SCID secondary to adenosine deaminase (ADA) deficiency. However, the long-term benefits of these approaches remain to be proven, and the genetic defects for
the majority of prematurely lethal congenital immunodeficiencies are unknown. For these reasons we initiated a
study of unrelated donor (URD) marrow transplantation to
treat children who had the types of prematurely lethal
immunodeficiencies that had been clearly demonstrated to
benefit from marrow transplantation from HLA-matched
siblings, but who lacked such histocompatible sibling donors. Twelve children who received URD transplants for
lethal immunodeficiencies are the subject of this report.
H E FIRST REPORTS of successful marrow transplantation for the correction of congenital immunodeficiencies appeared in 1968, involving patients with severe combined immunodeficiency (SCID) and Wiskott-Aldrich
syndrome
During the following 15 years marrow
transplantation from histocompatible siblings became accepted as curative treatment for children with SCID?
WAS,4s5 Chediak-Higashi syndrome (CHS),6 as well as
other congenital immunodefi~iencies.~
Unfortunately, the
percentage of infants with congenital immunodeficiencies
(eg, SCID) who have healthy histocompatible sibling donors has been estimated at approximately lo%? For some
children without matched siblings successful reconstitution
of both T- and B-lymphocyte immune function has been
achieved during the past decade through the use of T-celldepleted transplantation from haploidentical, generally
parental, family members. Immunoreconstitution has been
achieved in a significant proportion of SCID patients9-”
and less frequently in WAS.12 T-cell-depleted haploidentical transplantation has several disadvantages: (1) it often
requires intensive pretransplant conditioning therapy including the use of total body irradiation (TBI) in patients
From the Bone Marrow Transplant Program and the Department of
Pediatrics, Divisions of Immunology and BMT; the Divisions of
HematologylOncology and BMT; the Department of Medicine, Division of Hematology; the Department of Therapeutic Radiology; and
the Department of Laboratory Medicine and Pathology, University of
Minnesota Hospital and Clinic, Minneapolis.
Submitted November 12, 1991; accepted March 5, 1992.
Supported by National Institutes of Health Grant No. CA 21737.
Address reprint requests to A .H. Filipovich, MD, University of
Minnesota Hospital and Clinic, Box 261 Mayo, 420 Delaware St SE,
Minneapolis, MN 55455.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1992 by The American Society of Hematology.
0006-4971l92l8001-0013$3.00/0
270
MATERIALS AND METHODS
Patients. All consecutive patients with SCID, WAS, or CHS
referred to our institution for BMT between January 1987 and
March 1990 who lacked histocompatible siblings or closely matched
related donors were referred to the National Marrow Donor
Program (NMDP) for an unrelated donor search. This included 11
infants with SCID, two with WAS, and two with CHS.
Histocompatibility testing. Lymphocytes from all patients were
tested by HLA-A, B, C, and Dr typing using standard serologic
techniques.” Dw typing was performed with homozygous typing
cells.I8 Mixed lymphocyte cultures between recipients and potential donors were performed as previously reported.19 In some cases
DNA analyses using restriction fragment length polymorphisms
were used to confirm Dr identity between patients and potential
marrow donors.20
Blood, VOI 80, NO1 (July 1). 1992: pp 270-276
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UNRELATED DONOR TRANSPLANTS FOR IMMUNODEFICIENCIES
BMT, All patients were hospitalized in private HEPA filtered
rooms on the acute marrow transplant unit from the time that
pretransplant conditioning was initiated until an acceptable absolute neutrophil count was achieved posttransplant. Careful hand
washing precautions were used for all patients. Infants with SCID
were maintained in gown, glove, and mask isolation and provided
with sterile formula (when fed enterally) until relevant laboratory
assays showed evidence of donor type engraftment and functional
immuno-reconstitution (typically 2 to 3 months post grafting). All
patients received trimethoprin/sulfamethaxozole 2 days/week as
Pneumoqsfis carinii prophylaxis and weekly intravenous (IV) IgG
until day +180 (because all donors were EBV and/or cytomegalovirus [CMV] seropositive). Acyclovir 10 mg/kg t.i.d. was administered IV while patients were hospitalized. Blood products were
CMV-negative and irradiated. All blood products administered to
SCID patients were leukopoor, infused through a PALL filter.
Conditioning therapy was assigned according to the underlying
diagnosis as outlined (see the footnote to Table 3). For the patients
in this report it consisted of either: (1) no pretransplant therapy
(one SCID patient); (2) busulfan 2 mg/kg p.0. bid x 4 days
followed by cyclophosphamide 50 mg/kg/d IV X 4 days and
antithymocyte globulin 15 mg/kg bid IV on days -2 and -1 and 15
mg/kg/d IV on day +1 and +2 (nine patients: seven SCID, two
WAS); (3) cyclophosphamide 60 mg/d IV X 2 days followed by
fractionated TBI (165 cGy bid x 4 days, total 1,350 cGy [one CHS
patient]); or (4) cyclophosphamide 60 mg/d IV X 2 days on days
-7, -6, etoposide (VP-16) 500 mg/(mol/L)* IV X 3 days on days
-7 to -5, fractionated TBI (165 cGy x 4 days) and antithymocyte
globulin (ATG) 15 mg/kg bid IV on days -2 and -1 and 15
mg/kg/d IV on days +1 and +2 (one CHS patient). All patients
were infused with 3 x 108 donor bone marrow mononuclear
cells/kg recipient weight.
GVHD prophylaxis was administered according to the pilot
protocols in effect for all unrelated donor transplants conducted at
our institution during that particular time period. MCP: methotrexate 15 mg/kg IV on day +1, 10 mg/kg IV on day +3, +6, +11,
cyclosporine A 1.5 mg/kg bid IV day -1 to day +30 then 5 to 6
mg/kg bid p.0. until day 180, prednisone 5 mg/d until day 30 and
then tapered; MAP as previously published?' or MXP-"short
course" methotrexate: 15 mg/kg/d IV on day + 1 , l O mg/kg/d on d.
+3, +6, +11, anti-CD5 monoclonal antibody-ricin A chain conjugate 0.1 mg/kg IV qd. on days +1 to + 10 then q.0.d. on days +I2 to
+20 and prednisone 40 mg/(mol/L)2 qd on day + I to day +20 then
tapered over 1 week.
Engrajhent studies. Documentation and quantitation of donor
cell engraftment was performed using restriction fragment length
polymorphisms (RFLP) for discriminating DNA markersz2 on
bone marrow aspirates or blood at approximately day +28, day 100,
and later time points in the majority of patients.
Immune function studies. Evaluations of serum Ig levels, specific antibody titers, T-cell phenotypes, T-cell mitogen, and antigen
proliferation were sequentially performed by standard methods.
Statistical anaZysis. Clinical data were retrieved from the University of Minnesota Bone Marrow Transplant Database which
contains systematically and prospectively collected data on all bone
marrow transplant patients. The end points of survival, mean day
of engraftment, and acute GVHD were determined using the
Kaplan-Meier product limits methods.23
RESULTS
Patient characteristics. Characteristics of the 12 children
with SCID, WAS, or CHS who received URD BMT are
described in Table 1. Median age at BMT for SCID patients
was 8.5 months (range 3 months to 23 months). Two infants
271
Table 1. Patients With Lethal CongenitalImmunodeficiencies
Treated With Unrelated Donor BMT
UPN
Immunodeficiency
807
SClD .1B, .1 Tcells,
t NK cells
SClD .1T, hypogammaglobulinaemia
SClD Omenn's syndrome
SClD ADA deficiency
SClD .1 8, .1T cells,
t NK cells
SClD Absent CD8+ T
cells, nonfunctional
CD4+ cells
SClD Absent CD8+ T
cells, nonfunctional
CD4+ cells
7moF
SClD Absent CD8+ T
cells, nonfunctional
CD4+ cells
WAS
3moM
WAS
CHS
CHS
8moM
4yrF
8yrM
937
1024
1049
1091
1107
1265*
1289'
966
1204
818*
1118'
AgelSex
10 mo M
Significant Pretransplant
Complications
PCP, Parainfluenza
pneumonia
PCP
4moF
21 m o F
Transfusion acquired
GVHD and aplasia
PCP
Adenoviral hepatitis
23 mo F
PCP
27 mo M
Severe pulmonary
compromise (2" to
prolonged ventilator
course for PCP and
CMV pneumonia)
6moF
30 mo M
Pure red blood cell
aplasia
Accelerated phase
Accelerated phase
Abbreviation: PCP, Pneumocystiscarinii pneumonia.
*Siblings.
were identified as very high risk secondary to (1) pretransplant transfusion-acquired GVHD and aplastic anemia
with opportunistic infection in one case (unique patient
number [UPN] 1024), and (2) a prolonged pretransplant
ventilator course secondary to pneumonitis with pneumocystis carinii and cytomegalovirus resulting in chronic oxygen
dependence in another case (UPN 1265). One patient with
WAS (UPN 966) developed pure red blood cell aplasia 2
months before BMT and both children with CHS were in
the accelerated phase at the time of BMT.
Donor selection. Results of histocompatibility antigen
testing for donors and recipients are shown in Table 2.
Acceptable donors were found for 8 of 11 infants with
SCID, 2 of 2 patients with WAS, and 2 of 2 patients with
CHS. (The three infants with SCID for whom closely
matched unrelated donors could not be identified received
T-depleted BMT from parental donors.) Three patients
had phenotypically identical donors (all with SCID) while
the rest of the patients had donors mismatched at one A
(six patients) or B (three patients) locus.
BMT. Regimens of pretransplant conditioning and
GVHD prophylaxis are shown in Table 3, as are outcomes
with respect to engraftment, GVHD, and current status.
Three patients with SCID (in the group 1 diagnostic
category (footnote, Table 3) UPN 807,937, and 1049) were
initially infused with donor marrow without any preconditioning. No evidence for engraftment of donor cells was
found after 6 weeks of observation in two of three patients:
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272
FlLlPOVlCH ET AL
Table 2. Histocompatibility Typing of Unrelated Donors for BMT of Lethal Congenital Immunodeficiencies
MLC (relative response) %
Donor
UPN
Immunodeficiency
Recipient Typing
807
SClD
A2.32
87.62
937
SClD
A2,2
860,62
1024
SClD
Al,28
88.44
1049
SClD
A1.3
88,7
1051
SClD
A2,2
844.35
1107
SClD
A2.32
844.62
1265
SClD
Al,11
88
1289
SClD
Al.11
88,57
966
WAS
A1.3
87.57
1204
WAS
A26,33
817.38
A2,3
CHS
818
A1,3
CHS
1118
87,44
88.7
Dr2.4
Dw2.4
Dr4,5
Dw4.5
Dr2,4
Dw2,4
Dr2.3
Dw2.3
Dr1.6
Dw1,18
Dr2.4
Dw2.4
Dr3
Dw17
Dr3.7
Dwl7.7
Dr5,7
Dw5,7
Dr6
Dw6
Dr8
Dw18.8
Dr3,8
Dw3,8
Donor
Mismatch
RDx
DM
31yM
A3 v A32
0
0
M YF
827 v 860
0
3
47yM
Identical
1
0
50yM
Identical
2
0
29YF
A28 v A2
14
8
(SI = 1.6)
39YM
A1 vA32
1
1
53yM
Identical
0
0
36yM
817 v 857
0
0
47yF
862 v 857
0
4
36yM
A1 v A33
32
19
(SI = 14)
38YF
A1 v A 2
5
18
(SI = 2.1)
38YF
A26 v A3
5
8
(SI = 7.4)
Abbreviations: MLC, mixed lymphocyte culture; RDx, relative response of recipient cells responding against irradiated donor cells; DRx, relative
response of donor cells responding against irradiated recipient cells; SI, stimulation index of RDx/RRx.
UPN 937 and 1049. These two patients subsequently
underwent chemotherapy as outlined for group 2 diagnoses
(footnote, Table 3), and second grafts of cryopreserved
marrow from the same donor. The five remaining SCID
patients who had unusual variants (not described in the
World Health Organization classification) received chemotherapy conditioning for the first BMT. Three of the
patients (UPN 1107,1205, and 1289) had a variant form of
SCID characterized by lack of CD8+ T cells,24a unique
activation defect, and a reduced capacity to respond to
allogeneic stimuli. UPN 1024 with Omenn’s syndrome had
acquired GVHD from an unirradiated erythrocyte transfusion pretransplant.z UPN 1091 had low numbers of T cells
but demonstrated a slight degree of responsiveness to
allogeneic cells, although mitogen responses were markedly
decreased.
The two boys with WAS were treated with a conditioning
protocol patterned after Kapoor et a15 and identical to the
one that has been used successfully for transplantation of
WAS patients from histocompatible siblings at our institu-
Table 3. Unrelated BMT for Lethal Congenital Immunodeficiencies
UPN
Disease1
Phenotype
AgelSex
Pretransplant
Conditioning*
GVHD
Prophylaxis
RFLP ( O h )
807
937
1024
1049
1091
1107
1265
1289
966
1204
818
1118
SClD
SClD
SClD
SClD
SClD
SClD
SClD
SClD
WAS
WAS
CHS
CHS
7moF
10moM
6moF
4moF
21 moF
23moF
27mo M
3moM
2.5yr M
8moM
4yrF
8yrM
1
1.2
2
1.2
2
2
2
2
2
2
3
3
MCP
MCP
MCP
MCP
MAP
MAP
MXP
MAP
MCP
MAP
MCP
MAP
51-75
76-99
100
51-75
76-99
76-99
76-99
76-99
100
100
100
100
Day 28
Current
RFLP I%)
25-50
51-75
NE
51-75
100
51-75
NE
51-75
100
100
100
100
GvHD
Acute Chronic
Ill
0
NE
0
0
0
0
0
111
0
II
Ill
0
0
NE
0
0
0
0
0
0
0
0
0
Current Status
Well at home > 47 mo
Well at home > 33 mo
Died d 20 aspergillosis
Well at home > 30 mo
Well at home > 27 mo
Well at home > 25 mo
Died d 65 CNS hemorrhage
Well at home > 18 mo
Well at home > 33 mo
Well at home > 20 mo
Well at home > 23 mo
Well at home > 23 mo
Abbreviations: MCP, methotrexate, CSA, prednisone; MAP, methotrexate, ATG, prednisone; MXP, methotrexate, anti-CD5 immunotoxin
(Xoma-zyme),prednisone; MC, methotrexate, CSA; NE, not evaluable.
*1, none; 2, ATG-l5mg/kg IV bid on d -2, -1,15 mg/kg/d I V o n d +1, +2, busulfan-2 mg/kg bid PO x 4d,cyclophosphamide-50mg/kg IV x 4d;
3, pre 1989 cyclophosphamide-60 mg/kg/d IV x 2 d. Fractionated TBI-165 cGy bid x 4 d. Post 1989 cyclophasphamide-60 mg/kg/d IV x 2 d.
Etoposide-500mg/m2/dIV x 3d. FractionatedTBL165cGybid x 4d.ATG-l5mg/kg/bidIVond -2, -1,15mg/kg/dIVond +1, +2.
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UNRELATED DONOR TRANSPLANTS FOR IMMUNODEFICIENCIES
273
(UPN 818, 1118). Three of six patients who developed
G W D had received prophylaxis with MCP while one of six
patients who had MAP prophylaxis developed GVHD.
These differences were not statistically significant. Grade
11, I11 GVHD were easily controlled in three of four
patients who developed this complication. Moderate dose
systemic steroids were used in two cases and antLCD5 ricin
A chain immunotoxin (Xoma-zyme) infusion in UPN 807
(who was eligible for a multi-institutional pilot protocol28of
this agent as primary therapy of GVHD at the time she
developed this complication). UPN 1118 with CHS, the
oldest child in this series, developed an acutelchronic
GVHD overlap syndrome along with severe pancreatitis
while on prednisone therapy. He subsequently received a
course of ATG and was maintained on cyclosporine A for 9
months. He is currently off all immunosuppressive therapy
greater than 20 months post-BMT with no evidence of
chronic GVHD, normal Ig levels, and normal T-cell responses to mitogens (Table 4). Kaplan-Meier estimate of
survival for this patient series is 83% with a median
follow-up of 2 years (Fig 1).
Reconstitution of hematologic and immune function. The
11 patients who received conditioning therapy achieved 3
consecutive days of white blood count of greater than
l,000/mm3 by a median of 24 days. All patients have
recovered normal blood counts post BMT including persistently normal platelet counts in two of two patients with
WAS and absence of Chediak-Higashi granules in peripheral blood lymphocytes and bone marrow in two of two
tion. Patients with CHS in accelerated phase received doses
of cyclophosphamide and fractionated TBI standardly administered for BMT of leukemias at our center.26UPN 1118
also received VP16 because this agent has been reported to
be effective in the transplantation of hemophagocytic syndromes*’ and had been added along with ATG to the
protocol for transplantation of patients with CHS (with
matched related or unrelated donors) at our institution
during the intervening period (footnote, Table 3).
GVHD prophylaxis was assigned sequentially according
to the protocol that was being used at our institution for all
unrelated donor BMT during a given period of time. Thus,
the first six patients were treated with the combination of
MCP: methotrexate, cyclosporine A, prednisone; the next
four with MAP: methotrexate, ATG, prednisone; the subsequent patient (UPN 1265) with MXP: methotrexate, antiCD5 ricin A chain immunotoxin (Xoma-zyme), and prednisone. The most recent patient (UPN 1289) again received
MAP secondary to parental refusal of the MXP protocol.
Ten patients demonstrated donor engraftment within the
first month after their initial transplant. As previously
mentioned, two SCID patients did not show evidence of
donor cells for 6 weeks after marrow infusion without prior
conditioning, but engrafted rapidly after a second transplant following chemotherapy (Table 4). GVHD was clinically apparent in four patients: one 7-month-old infant with
SCID (UPN 807, the only child who did not receive
pretransplant conditioning) and the three oldest patients
(ages 2.5 to 8 years) with either WAS (UPN 966) or CHS
Table 4. Immunologic and Hematologic Reconstitution After Unrelated Donor BMT for Lethal CongenitalImmunodeficiencies
Mitogen Responses* 1%)
LymphocyteSubsets ( O h )
Igs
ID
Pre/Post
ALC
G
A
M
E
CD3
CD4
CD8
CD19
CD16
PHA
ConA
PWM
807
SClD
1091
SClD
SClD
SClD
1289
SClD
966
WAS
1204
WAS
818
CHS
1118
CHS
9
31
33
36
55
4
29
7
37
65
35
65
18
55
30
8
47
49
41
49
37
37
35
18
34
70
27
21
8
30
30
40
0
34
10
24
8
35
28
39
15
39
25
49
19
51
46
24
7
4
16
13
23
58
8
1
8
8
14
7
10
47
7
17
3
3
4
19
4
97
8
0
99
7
102
0
88
0
ND
0
119
68
113
82
45
27
74
53
95
118
3
0
127
7
152
1
132
1265
62
60
36*
68
59
6
65
9
75
64
90
66
36
55
65
20
85
59
78
72
84
58
87
0
34
39
25
4
12
2
10
19
1107
12
99
<2
<2
126
8
<2
<2
7
ND
8
53
ND
4
24
27
32
23
<2
3
2
223
4
15
68
SClD
SClD
50
206
26
209
7
34
37
168
54
95
91
173
ND
14
65
77
49
27
54
86
103
89
84
22
112
1024
1049
20
99
<7
72
14
<7
23
114
11
119
39
160
ND
<7
28
129
47
83
52
68
47
231
46
6
109
SClD
6,000
1,400
500
2,560
4,800
200
1,290
1,540
1,584
5,610
1,008
5,760
400
4,440
2,100
2,490
2,565
2,200
3,480
5,000
2,205
3,500
1,650
226
540
937
Pre
24 mo post
Pre
12 mo post
Pre
Pre
12 mo post
Pre
12 mo post
Pre
6 mo post
Pre
2mopost
Pre
12 mo post
Pre
12 mo post
Pre
12 mo post
Pre
12 mo post
Pre
12 mo post
66
1
0
43
11
99
1
66
3
ND
0
91
30
51
85
29
15
39
58
101
UPN
948
366
633
505
1,000
1,580
858
601
1,870
ND
781
991t
5,800
1,140
625
1,410
804t
719
1,040
938
Abbreviation: ND, not done.
*Percent normal control responses.
tReceived IvlgG.
*Only 8% of lymphocytes expressed a PTCR.
20
19
24
5
41
12
23
13
17
17
24
17
20
2
1
ND
0
89
39
105
131
43
16
72
76
114
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274
FlLlPOVlCH ET AL
12= - L
0.8
0
1
2
3
3.8
Survival (years)
Fig 1. Actuarial immunodeficiency free survival for 12 children
undergoing unrelated donor BMT for lethal immunodeficiencies.
CHS patients. Both patients with WAS and both patients
with CHS continue to demonstrate 100%donor cell engraftment.
A summary of immune function studies performed at
most recent time points post-BMT are shown in Table 4.
Total absolute lymphocyte counts, Igs M, A, E, and phytohemagglutinin (PHA) blastogenesis are normal in all patients. Although mixed chimerism has been apparent in five
of six SCID patients who received BMT more than 1 year
ago (Table 3) all children show persistent and improving
immunocompetence. UPN 1049 has had normal white
blood cell ADA levels since first measured at day 27 post
BMT. The three children with SCID with the absence of
CD8+ T cells and a T-cell activation defect have demonstrated CD8+ CD3+ T cells postgrafting and normal proliferation to PHA in two of two surviving patients (Table 4).
Nine patients have been immunized at 1 year with a
single dose of the pediatric diphtheria Tetanus vaccine. The
six patients tested post-immunization all showed evidence
of immune response to one or both antigens: 2 of 6 made
antibody to diphtheria, 5 of 6 made antibody to tetanus, 5 of
5 developed a proliferative response to tetanus in vitro, and
3 of 3 showed positive delayed type hypersensitivity reactions (3 of 3 tetanus, 2 of 3 diphtheria). UPN 807, the first
patient to undergo unrelated donor BMT in this series,
showed an increase in antibody titers to parainfluenza type
3 within 5 weeks post BMT. This virus had been the cause
of recurrent pneumonitis before transplantation. UPN 807
experienced an uneventful primary infection with varicella
zoster at 24 months post BMT. Over the past 3 years, she
has been immunized with a pediatric diptheria Tetanus
booster x 2, injectable polio x 2 and the measles, mumps,
rubella (MMR) vaccines. She now demonstrates protective
antibodies to all these agents as well as positive delayedtype hypersensitivity skin tests to diphtheria, tetanus,
mumps, candida, and streptococcus.
All surviving patients are well at home and do not receive
IVIgG infusions. There is no evidence for acquisition of
CMV infection associated with BMT in any of the children,
although two patients were CMV seropositive pre-BMT.
To date no patient has developed symptoms suggestive of
EBV-associated B-cell Iymphoproliferative disease.
DISCUSSION
Opportunistic infections and malignancies, respectively,
are the major causes of death in children with premature,
lethal congenital immunodeficienciesincluding SCID, WAS,
and CHS. Successful immuno-reconstitution with marrow
transplantation effectively reduces the long-term risks of
both of these complication^.^^ In the present era transplantation of SCID and WAS with whole marrow from histocompatible sibling donors is associated with disease-free survival rates of greater than 90% and 85%, r e ~ p e c t i v e l y . ~ ~ J ~
Unfortunately, the great majority of children with prematurely lethal immunodeficiencies lack histocompatible sibling donors. O’Reilly et aI3O undertook the first unrelated
bone marrow transplant for SCID in 1977. Partial engraftment was finally achieved after six attempts with the
subsequent development of extensive chronic GVHD contributing to death from squamous cell carcinoma 5 years
later. In the early 1980s, with the development of a physical
method of marrow T-cell depletion involving soybean lectin
agglutination and sheep erythrocyte rosetting,3I children
with leukemia and SCID began to receive marrow transplants from haploidentical parental donors. Initial reports
indicated that nearly half of SCID patients experienced
improvement in T-cell immunity because of partial engraftment of parental cells, such that they could be removed
from strict protective isolation, but continued to require Ig
replacement indefinitely. More recently, with the use of
pretransplant combinations of busulfan, cyclophosphamide, and/or cytosine arabinoside and ATG the rate of
successful engraftment of T-depleted marrow in classical
forms of SCID has increased to 86%.11 However, recovery
of T- and B-cell function remain variably delayed and the
reconstitution of SCID variants such as Omenn’s synd r ~ m ise still
~ ~problematic. It has been even more difficult
to achieve hematolymphopoetic engraftment in WAS with
T-depleted haploidentical donors with some exceptions,12
and the rate of posttransplant EBV-associated B-cell lymphoproliferative disorder (BLPD) is prohibitively high
(nearly 50%).13
In early attempts at our institution to use T-depleted
haploidentical transplantation, we encountered several discouraging consequences including EBV-associated BLPD,33
transfusion-acquired CMV infection, and engraftment failure in non-SCID immunodeficiencies despite the use of
TBI.34For those reasons, we initiated a pilot study of URD
BMT for patients with lethal immunodeficiencies who
lacked histocompatible siblings or closely matched related
donors.
With the exception of two children with SCID (one with
no laboratory evidence of allogeneic reaction who accepted
a third-party skin graft [UPN 9371 and the other with ADA
deficiency [UPN 10491) who did not engraft after marrow
infusion alone, all other conditioning protocols used for this
series of patients resulted in acceptable engraftment and
reconstitution of all previously deficient immunologic and
hematologic functions. These results were achieved with
doses and regimens of chemotherapy and radiation therapy
that are commonly used in children undergoing histocompatible sibling transplantation, and were not associated
with any unacceptable toxicities. Graft rejection has been
documented in phenotypically identicaP5 and HLAmismatched36 unrelated donor transplants in conjunction
with T-cell depletion. While our series of patients is
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
275
UNRELATED DONOR TRANSPLANTS FOR IMMUNODEFICIENCIES
relatively small, our experience suggests that stable engraftment can be achieved despite mismatching at class I
antigens if T-replete grafts are used.
In contrast to the eight of eight patients with SCID who
engrafted after unrelated donor bone marrow transplant,
two of three children with SCID variants who underwent
T-depleted haploidentical BMT during the same time
period with the same conditioning protocol used for URD
BMT did not engraft with donor cells and ultimately died
(A.H.F., unpublished data). One of these children went on
to develop EBV-associated B-cell lymphoproliferative disease.
The rate of GVHD in this series was lowest for infants
with SCID (one of eight patients), comparable to that
expected with histocompatible transplantation and T-depleted parental graft^.^,^ While three older children developed grade I1 to I11 GVHD, all symptoms of GVHD were
successfully reversed with conventional doses of prednisone
used for treatment of GVHD. This rate of 2 grade I1
GVHD (actuarial rate = 35%, 95% confidence limits c 28%) is significantly lower than that reported from
series of adults treated with URD BMT with and without
T-cell depletion3’ and the experience at our institution
(actuarial GVHD rate for patients > 18 years old = 73%,
95% confidence limits, f 15%.) Because the methods of
GVHD prophylaxis for URD BMT were the same for
children and adults at our institution, we can speculate that
young recipient age, and possibly the SClD background,
contributed to lowering the risk of GVHD in URD BMT as
it does in histocompatible BMT.38Because GVHD prophylaxis was administered in several sequential protocols to
small numbers of patients, no clear conclusion can be
reached regarding the most effective regimen. However,
nephrotoxicity and hypertension requiring medical intervention was observed in two of six children who received
cyclosporine A as part of their prophylaxis, and the rate of
GVHD was not lower than that observed with the combination of methotrexate, ATG, and prednisone.
The recovery of nonspecific and specific immune function has been monitored sequentially in all patients. Be-
cause of donor seropositivity for CMV and EBV all patients
received IVIgG infusions weekly until at least 6 months
post BMT, and those who were still receiving immunosuppression for GVHD, for longer periods of time. All but one
patient have now discontinued IVIgG therapy and demonstrate efficient endogeneous synthesis of Igs as well as
specific antibody formation (partial data shown in Table 4
and described in the Results section).
In summary, marrow transplantation using phenotypically identical or one HLA A or B antigen mismatched
unrelated donors was undertaken without the use of T-cell
depletion or unusually intensive pretransplant conditioning
protocols in a group of 12 children with lethal immunodeficiencies. Ten children are well at home, and have documented T- and B-cell immunoreconstitution with a median
follow-up of 2 years posttransplant. More detailed analysis
of the tempo of immune recovery and comparison with
results achieved with T-depleted haploidentical BMT will
be necessary to identify the potential advantages of the
transfer of unmanipulated marrow with immunocompetent
T cells from unrelated donors as treatment of lethal
immunodeficiencies.
NOTE ADDED IN PROOF
A third patient with WAS was treated with URD BMT after
completion of this report. UPN 1463 was an 8-year-old boy who
had suffered from refractory thrombocytopenia after splenectomy.
He had been treated with daily steroids for most of 7 ?hyears and
developed liver dysfunction 8 months before BMT. Pretransplant
evaluation showed oligoclonal EBV-associated BLPD apparently
confined to the liver. This was treated with surgical resection and
a-interferon for 3 weeks. The early posttransplant course was
unremarkable and complete donor engraftment was documented
before day 28. Unfortunately, UPN 1463 developed severe venoqcclusive disease of the liver and died of disseminated aspergillosis 55
days post BMT. At autopsy there was no evidence of GvHD or
BLPD. This case illustrates the need for ongoing careful1 evaluation of the role of marrow transplantation with nonsibling donors
in WAS and better definition of pretransplant criteria warranting
referral for nonsibling BMT.
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1992 80: 270-276
Unrelated donor bone marrow transplantation for correction of lethal
congenital immunodeficiencies
AH Filipovich, RS Shapiro, NK Ramsay, T Kim, B Blazar, J Kersey and P McGlave
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