Bone marrow transplantation in 26 patients with Wiskott-Aldrich syndrome from a single center

Bone marrow transplantation in 26 patients with Wiskott-Aldrich syndrome from a single center Hulya Ozsahin, MD, Fran(~oise Le Deist, MD, Malika Benkerrou, MD, Marina C a v a z z a n a - C a l v o , MD, PhD, Lina Gomez, MD, C l a u d e Griscelli, MD, S t e p h a n e Blanche, MD, a n d Alain Fischer, MD, PhD From the Department of Pediatrics, Universit~ts Kinderklinik, Zurich, Switzerland, the Department of Pediatric Immunology/Hematology, INSERM U29, H6pital des Enfants-Malades, Paris, France, and the Immunodeficiency Pediatric Unit, Institute of Immunology, Kashorskoye Shausse, Moscow, Russia We retrospectively analyzed the outcome of bone marrow transplantation (BMI) performed in 26 patients with Wiskott- Aldrich syndrome (WAS) in one center. Twenty-eight transplantation procedures were performed. Ten unselected patients received unmanipulated marrow from a donor with genetically identical human leukocyte antigen (HLA). Eight patients were cured and survive 1.5 to 16.5 years after BMT. One patient successfully received a T-cell-depleted marrow from a matched unrelated donor. Sixteen patients were selected to receive a related HLA partially incompatible BMT because of the occurrence of life-threatening complications from the WAS (i.e., refractory thrombocytopenia, autoimmunity including vasculitis and sepsis). All but one received T-cell-depleted marrow after a conditioning regimen of busulfan and cyclophosphamide. One patient had two BMTs. Engraftment occurred in 12 of 17 attempts. The addition of monoclonal antibodies to lymphocyte function-associated antigen-I and CD2 molecules appeared to improve engraftment. Six patients were long-term survivors, whereas others died of viral infections (n = 7), among which Epstein-Barr virus-induced Blymphocyte proliferative disorder was predominant. Delay in development of full T- and B-cell functions accounted for severe infectious complications. These results confirm the excellent outcome of HLA genetically identical BMT in WAS, whereas BMT from HLA partially incompatible donors should be strictly restricted to patients with severe complications of WAS. (J Pediatr 1996; 129:238-44)

Wiskott-Aldrich syndrome is an X-linked primary immunodeficiency characterized by a progressive T- and B-cell immunodeficiency associated with allergy, bleeding tenSupported by the Institut National de la Sant6 et de la Recherche Mrdicale and Association pour la Recherche sur le Cancer and Ligue National contre le Cancer. Submitted for publication Nov. 11, 1995; accepted March 30, 1996. Reprint requests: Alain Fischer, MD, PhD, INSERM 429, H6pital des Enfants-Malades, 149. rue de S~vres, 75015 Paris, France. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/21/73888

238

dency caused by thrombocytopenia, and thrombopathy.1 The gene mutation in WAS has been recently identified. It encodes the WAS P protein of yet unknown function. 2 Although the prognosis of WAS has improved considerably in the last 10 years through the availability of appropriate antiinfectious therapy and more frequent usage of splenectomy, 3 its overall outcome remains poor. Infections, hemorrhage, autoimmune manifestations, and lymphomas are the major lethal complications. Bone marrow transplantation provides cure of all manifestations of the disease provided that there is engraftment of all hematopoietic lineages. 4' 5 Human leukocyte antigen-identical BMT appears to be a

The Journal of Pediatrics Volume 129, Number 2

BMT CMV EBV EBV B-LPD GVHD HLA LFA-1 MUD WAS

Bone marrow transplantation Cytomegalovirus Epstein-Barr virus Epstein-Barr virus-associated B-lymphoproliferativedisease Graft-versus-hostdisease Human leukocyte antigen Lymphocyte function-associated antigen-1 Matched unrelated donor Wiskott-Aldrichsyndrome

safe and efficient treatment of WAS, because 80% to 90% of patients can be cured. 6-11 In the absence of HLA-identical donors, transplantation from matched unrelated donors appears potentially promising. 12' 13 In contrast, most attempts at HLA partially incompatible BMT have had poor results.6, 7, 9.10 We retrospectively analyzed the outcome of 28 BMTs performed in 26 patients with WAS at a single center during a 15-year period. Ten transplants from an HLA genetically identical donor, one from a MUD, and 17 from a related HLA partially incompatible donor were performed. Results were analyzed according to clinical status before BMT and HLA compatibility.

METHODS Patients. From March 29, 1979, through March 16, 1994, 26 patients with WAS underwent BMT in the Department of Pediatric Immunology/Hematology of the H6pital Necker-Enfants Malades, Paris, France. Two patients in whom engraftment failed had two BMTs. Patient characteristics are summarized in Table I. The diagnosis of WAS was based on established clinical and laboratory criteria (i.e., recurrent infections, eczema, bleeding tendency, thrombocytopenia with reduced platelet volume, IgM deficiency in patients older than 1 year of age, and defective antibody responses to polysaccharide antigens). Age at BMT ranged from 8 months to 15 years (median 28 months, mean 41 months). The decision to perform BMT was based on the (1) the presence of an HLA genetically identical donor or (2) the severity of WAS-related complications in patients lacking a suitable HLA genetically identical donor. As shown in Table I, occurrence of life-threatening complications was observed in all recipients of HLA genetically nonidentical marrow before BMT (i.e., refractory thrombocytopenia [-< 10,000/~] after splenectomy [n = 4], vasculitis requiring aggressive immunosuppression [n = 7], autoimmune neutropenia requiring aggressive and prolonged immunosuppression, hemolytic anemia [n= 10], and life-threatening sepsis [n = 2]). Donors. In all but one patient (UPN 275), donors were related. Of the 28 BMTs performed, 10 were from an HLA-

Ozsahin et al.

239

compatible sibling, 17 were from an HLA-incompatible parent, and one was from a MUD. Of the 17 incompatible transplantationss, 8 were haploidentical, 7 had two antigen mismatches, and 2 had one antigen mismatch (Table II). The selection of donors was based primarily on the results of class I and class II HLA typing. When two potential donors were similarly compatible, the cytomegalovirus and EpsteinBarr virus status of the donor and the recipient was the decisive factor.

Conditioning regimens Human leukocyte antigen-identical transplants. Both patients who had BMT in 1979 and 1981 received total body irradiation (single dose of 8 Gy with pulmonary shielding) combined with either antithymocyte globulin or cyclophosphamide (two doses of 60 mg/kg). All other patients received busulfan (four doses of 4 mg/kg) and cyclophosphamide (four doses of 50 mg/kg). Since 1988 patients younger than 5 years of age have received four doses of busulfan, 5 mg/kg (Table II). Human leukocyte antigen-nonidentical bone marrow transplantation. All patients had the same conditioning regimen as recipients of HLA-identical BMT with busulfan and cyclophosphamide; etoposide (three doses of 300 mg/m 2) was added in one case (UPN 65). To prevent graft rejection, recipients of T-cell-depleted marrow (see below) also received antithymocyte globulin (four doses of 2.5 mg/kg) and anti-lymphocyte function-associated antigen-1 murine monoclonal antibody (five doses of 0.1 mg/kg) 14 (patients UPN 88, 91,112, and 117), anti-LFA-1 antibody (10 doses of 0.2 mg/kg) I5 (patients UPN 134, 136, 137, 138, 170, and 165), or anti-LFA- 1 and anti-CD2 antibody (0.2 mg/kg each from day - 3 or day - 2 to day +10 or +11, respectively) (patients UPN 165b, 224, 229, 247, and 258) (Table II). T-cell depletion. All but one of the HLA genetically nonidentical marrow samples were T-cell depleted. As shown in Table II, E-rosetting was used for T-cell depletion in 12 cases. A total of 2.3 × 108 nucleated cells/kg (range 4 to 7 x 108) were infused. CD3 + T cells infused were 3.6 × 105/ kg (range 1 to 7 x 105). Campath 1-M antibody plus complement 15 was used for T-cell depletion in five cases. The number of nucleated cells per kilogram infused was 4.6 × 108 (range 1.5 to 10 × 108) with estimated CD3 + T-cell numbers of 5.2 × 105/kg (range 1.5 to 9.6 × 105). Supportive care. Patients were isolated in a sterile room. They received oral preparations of nonabsorbable antibiotics for gut decontamination and, since 1980, weekly intravenous immune globulin administration until day 100. Since 1986, if either the recipient or the donor or both had anti-CMV antibody, acyclovir was given intravenously (1500 mg/m 2 per day) from day -1 to +60. Graft-versus-host disease prophylaxis. Methotrexate alone was given on clays +1, +3, +6, +11, then weekly to day

240

Table

Ozsahin et al.

The Journal of Pediatrics August 1 9 9 6

I. P a t i e n t c h a r a c t e r i s t i c s

UPN

Age at Clinical presentation before BMT diagnosis (yr) Infections* Eczemat Bleeding~ Autoimmunity

HLA-identical B M T 25 2.3 33 1.0

+++ ++

+++ ++

+ +++

51 73 78 126 191 239 285

3.0 0.3 0.7 0.7 0 0.8 0.2

++ + ++ + -=

+ ++ + + + + +

+ + + ++ +++ ++ +

170b 275

0.3 0.8

+ +

+ +

+++ +

HLA-nonidentical B M T 65 0.7 88 0.6

. A o r t a vasculitis . . .

Treatment before BMT Steroids Splenectomy Azathioprine .

.

.

.

.

.

.

.

.

.

. .

. .

Other

.

.

.

.

AHA A o r t a vasculitis AHA Neutropenia

+ + + +

+ + -

+ +

VB + C -

+ ++

-Gastrointestinal a n d skin vasculitis

+ +

+ -

+ -

-

+++ +

+ +++

Vasculitis A H A , Neut, r e f thrombocytopenia

+ +

+

+

Vasculitis, arthritis, IBD A H A , ref thrombocytopenia

+

-

-

+

+

-

-

Cy

91

0.3

++

+

+

112

0.1

++

+

+

117 128 134

0.5 0.5 0.3

++ + +

++ ++ +

+++ ++ +

AHA Arthritis, IBD Vasculitis

+ + +

+ +

+ -

-

136 137

0 0.3

+++ ++

++ +

++ +++

+ +

+

-

-

138

0.2

++

++

+

-Thrombocytopenia, ICB Vasculitis, A H A , Nent, IBD

+

-

+

-

170

0.3

--

+

+

+

+

+

-

224 165

0 0.1

++ +

+++ ++

+++ ++

AHA, thrombocytopenia A H A , neutropenia A H A , neutropenia

+ +

+ +

+ -

-

165b 229 247

0.1 0.7 0.2

+ +++ +

+ + +

++ ++ ++

AI-/A A H A , vasculitis A H A , neutropenia

+ + +

+ + +

+ + +

Anti-D

258

0.8

+

+

++

Cerebral vasculitis

+

+

-

Cy

AHA, Autoimmune hemolytic anemia; BMT, bone marrow transplantation; C, colchicine; Cy, cyclophosphamide; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; ICB, intracerebral bleeding; Neut, neutropenia; Ref, refractory; UPN,unique patient number; VB, vinblastine. *+, Upper respiratory tract infections; ++, pneumonitis, diarrhea; +++, life-threatening systemic infection. t+, Localized; ++, generalized but improvement with topical therapy; +++, generalized, needs systemic immunosuppressive therapy. :~+, Petechiae, purpurae; ++, epistaxis, mncosal bleeding, hematoma; +++, life-threatening bleeding (oral, intracrarlial, gastrointestinal).

100 to the first two patients. Cyclosporine venously

was given intra-

for 60 days then orally until day +180 to HLA-

identical marrow

recipients up to 1987. After 1987 a short

course of methotrexate

(day +1, +3, +6 and +11) was added

to the cyclosporine regimen.The pleted marrow

recipients of E + rosette-de-

received cyclosporine

f o r 6 0 d a y s (3 m g / k g

per day intravenously),

whereas

1-M--depleted

did not receive any further GVHD

marrow

p r o p h y l a x i s 16 ( T a b l e II).

the recipients of Campath

Graft-versus-host

disease was classified according

criteria of Glucksberg

Immunologic s t u d i e s . immunofiuorescence Lymphocyte viously

d e s c r i b e d . 18 were

toxoid,

assays

Serum measured

1980, and thereafter to tetanus

T and B cells were identified by

with specific monoclonal

proliferation

concentrations

to the

e t al. 17

were

immunoglobulin

as preisotype

by immunodiffusion

by nephelometry.

diphtheria

antibodies.18

performed

toxoid,

Serum polio

until

antibodies

viruses,

and

The Journal of Pediatrics Volume 129, Number 2

Ozsahin et al.

241

Table II. Bone marrow transplantation characteristics

UPN

Year of BMT

HLA-identical BMT 25 1979 33 1981 51 1983 73 1984 78 1984 126 1987 191 1989 239 1991 285 1993 170b 1994 275 1992 HLA-nonidentical BMT 65 1984 88 1985 91 1985 112 1986 117 1987 128 1987 134 1987 136 1987 137 1987 138 1987 170 1988 224 1990 165 1989 165b 1990 229 1990 247 1991 258 1991

Age at BMT (yr) 2.5 15.0 4.3 1.3 0.8 1.8 10.0 0.7 1.3 7.0 3.0 4.3 2.3 2.0 1.1 5.0 5.5 2.0 2.3 1.8 2.6 1.6 4.5 1.6 3.5 5.0 0.7 1.8

HLA compatibility

Donor

Conditioning regimen

GVHD prophylaxis

BMT depletion method

Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible

Sister Sister Sister Sister Sister Father Sister Brother Sister Sister MUD

ATG + TBI Cy + TBI BuCy BuCy BuCy BuCy BuCy BuCy BuCy BuCy BuCy + anti-FA-1-CD2

Mtx Mtx Cs Cs Cs Cs + Mtx Cs + Mtx Cs + Mtx Cs + Mtx Cs +Mtx --

----------C-1M

Haploidentical Haploidentical Haploidentical 4/6 identical (A, B) 4/6 identical (A, B) 5/6 identical (DR) 4/6 identical (A, B) 5/6 identical (B) 4/6 identical(B, DR) Haploidentical Haploidentical Haploidentical 4/6 identical (B, DR) 4/6 identical (B, DR) 4/5 identical (B, DR) Haploidentical Haploidentical

Mother Mother Father Brother Sister Sister Father Father Father Mother Father Mother Father Father Mother Father Father

BuCy + VP16 BuCy + ATG + anti-LFA-1 BuCy + ATG + anti-LFA-1 BuCy + ATG + anti-LFA-1 BuCy + ATG + anti-LFA-1 BuCy BuCy + anti-LFA-1 BuCy + anti-LFA-1 BuCy + anti-LFA-1 BuCy + anti-LFA-1 BuCy + anti-LFA-1 BuCy + anti-(LFA-1-CD2) BuCy + anti-LFA-1 BuCy + anti-(LFA-1-CD2) BuCy + anti-(LFA-1-CD2) BuCy + anti-(LFA-1-CD2) BuCy + anti-(LFA-1-CD2)

Cs Cs Cs Cs Cs Cs +Mtx Cs ----Cs Cs Cs Cs Cs Cs

E rosette E rosette E rosette E rosette E rosette -E rosette C-1M C-1M C-1M C-1M E rosette E rosette E rosette E rosette E rosette E rosette

ATG, antithymocyteglobulin;BMT, bone marrowtransplantation;Bu, busulfan; C-1M, Campath 1M; Cs, cyclosporine;Cy, cyclophosphamide;LFA-1, lymphocyte function-associatedantigen-l; Mtx, methotrexate;MUD, matchedunrelateddonor; TBI, total body irradiation; UPN, unique patient number; VP16, etoposide.

C M V were measured by enzyme-linked immunosorbent

No manifestations o f W A S have recurred after B M T in these

assay.

nine patients. Sequelae from BMT developed in one patient (UPN 25),

RESULTS

who had short stature at the age of 18 years, probably because

Human leukocyte antigen-identical bone m a r r o w transplantation. Engraftment occurred in the 10 recipients

of total body irradiation. He also had bilateral cataracts. The

of genetically identical marrow and the recipient of a matched unrelated marrow (Table III). Full chimerism was

Human leukocyte antigen-nonidentical bone marrow transplantation. Engraftment occurred in 12 of 16 cases;

detected in all but two patients. Acute G V H D (->II) occurred

two patients (UPN 165 and 170) required two transplants.

in four cases, and it was fatal in one. Severe but resolutive

Chimefism was full in seven patients (Table HI). The influ-

chronic G V H D occurred in one case. Two patients died af-

ence o f the degree of incompatibility could not be observed

ter BMT, one o f grade IV GVHD, the second of viral encephalitis. In both these cases B M T was performed in

other patients are well with normal school attendance.

among this small group, because engraftment occurred in

1983 or earlier. All the other patients are alive and well with

both recipients of a one H L A antigen-mismatched BMT (not T-cell~iepleted in one case), in four o f six recipients of a two

normal platelet cell counts and normal immune functions

H L A antigen-mismatched B M T (including a second trans-

including antigen-specific T-cell proliferation assays in vitro

plant), and in five of eight recipients of haploidentical BMT. Engraftment of E rosette-T-pleted marrow in 2 o f 4 cases

and skin tests in vivo and B-cell antibody responses in vivo.

242

Ozsahin et al.

Table Ill.

Outcome

The Journal of Pediatrics August 1 9 9 6

of bone-marrow

transplantation

Time of immunologic reconstitution (mo) UPN 25

Chimerism

Correction of

GVHD

Cellular

Humoral

Thrombocytopenia

Autoimmunity

Eczema

Acute (grade)

Chronic

6

6

+

+

+

IlI

+

2 -5.5 6 10 4 9 +* ? +* --

--6 6 10 -12 +* ? +* --

. -+ + + + + +t + + .

IV ---IL -I -1I

-

-II

-

Full

33 51 73 78 126 191 239 285 170b 275 65

Full Full Mixed Full Full Full Full Mixed Full Full

88 91

Full Mixed

7 --

48 --

+ --

112

--

--

--

. --+t

--+

--+

II III --

-

-+

-+

+ +

---

-

I III

+

lII

+

--

-

117

Full

--

--

128 134

Mixed Mixed

-7

-+x

136 137

Full Mixed

5

138 170 224 165 165b 229 247 258

m

.

.

.

-+ + + + + + + + .

.

+ -.

--Full -Full Full

--7 ---11

--18 --11

. -+ . . +

.

Mixed Full

-4

-9

.

.

.

.

.

.

-+ . .

. + --

.

. -+

. .

. .

+

+

. . +

.

A W 16.5 yr+ g r o w t h retardation Died (encephalitis) 0.2 yr Died G V H D day: 0.3 yr A W 11.3 yr+ A W 6.4 yr+ A W 8.7 yr+ A W 6.0 yr+ A W 3.5 yr+ A W 2.7 yr+ A W 1.5 yr+ A W 3.0 yr+ Died (thymus E B V l y m p h o m a ) 0.7 yr A W 10.2 y r + Died (EBV B-LPD, C M V ) 0.2 yr Died (thrombocytopenia) 0.5 yr Died (EBV B-LPD) 0.2 yr Died (EBV B-LPD) 1.3 yr Alive with neurologic sequelae 6 yr+ Died (adenovirus) 0.5 yr A W (dependent on IV Ig) 8.5 yr+ Died (CMV) 0.1 yr 2nd B M T A W 5.1 yr+ 2nd B M T Died (EBV B-LPD) 0.2 yr Alive with frontal lobe syndrome 4.8 yr+ Died (CMV) 0.2 yr Alive with neurologic sequelae (pre-BMT cerebral vasculitis) 3.8 yr+

. -+ + + + + + + +

.

Status at last follow-up

.

+

. +

AW, Alive and well; BMT, bone marrow transplantation; C, cutaneous; CMV, cytomegalovirus; EBV, Epstein-Barr virus; EBV B-LPD, EPV-induced B-lymphoproliferative disease; g, gastrointestinal; GVHD, graft-versus-host disease; h, hepatic;/V Ig, intravenous immune globulin. *Immune recovery occurred; time undetermined. ]'Corrected after splenectomy (after BMT).

(50%). Anti-LFA- 1 monoclonal in engraftment LFA-1

plus

antibody treatment resulted

of 6 of 10 marrows, anfi-CD2

with engraftment

antibody

whereas combined

treatment

was

anti-

associated

liferative disease in three cases. Severe chronic GVHD

Severe viral infections were observed in this group of patients. One patient (UPN

in 5 of 5 cases (p <0.01). ( - - - g r a d e II) o c c u r r e d

in 5 of 12 patients.

ovirus

infection,

One of them received an unmanipu!ated

marrow. Graft-ver-

(UPN

91), and

Acute GVHD

sus-host disease resolved immunosuppressive

in all cases, although

treatment

patients to the occurrence

it r e q u i r e d

that could have predisposed

of EBV'associated

B-lymphopro-

oc-

curred in two cases but resolved.

one one

136) died of overwhelming

patient

died

of CMV

of CMV-associated

138). A major complication

vasculitis

(UPN

was EBV B-LPD. It occurred in

7 of 16 recipients of HLA-nonidentical versus no occurrences

aden-

pneumonitis

among

BMT

(8 e p i s o d e s )

11 r e c i p i e n t s o f H L A - i d e n t i -

The Journal of Pediatrics Volume 129, Number 2

cal BMT. It was fatal in four patients (UPN 91, 117, 128, and 165b), and resolved in four patients (UPN 88, 165, 224, and 229) after treatment with monoclonal anti-B-cell antibodies} 8 Three of these four patients are long-term survivors. The EBV B-LPD was observed 2 to 4 months after BMT. It relapsed several times during 1 year in one patient (UPN 20) after failure of engraftment of the first transplant, but was sensitive to treatment by B-cell-specific anti-CD21 and CD24 monoclonal antibodies. Sepsis occurred in 3 of 12 patients soon after BMT. Meningitis that led to neurologic sequela developed 1 year after BMT in one patient who had had splenectomy. Development of T- and B-cell functions was delayed in the group of patients who had splenectomy compared with recipients of HLA-identical BMT, because it occurred after 4 to 11 months for T-cell functions and 9 to 48 months for B-cell functions (antibody production); one patient still requires intravenous immune globulin substitution (UPN 137). Persisting immunodeficiency was associated with autoimmune hemolytic anemia for 5 years after BMT in one case (UPN 88). No manifestations attributable to WAS have been observed in the six long-term survivors. However, one patient requires intravenous immune globulin substitution, and three others have neurologic sequelae: one has cerebral vasculitis that occurred before BMT, one has sequelae resulting from meningitis, and one presumably after cerebral venous thrombosis as a result of B-lymphoproliferative disease. Complete recovery was not clearly correlated with HLA incompatibility in this small series, because there were no successful transplantations in either of two recipients who received marrow with one HLA antigen mismatch, in three of six recipients of marrow with two HLA antigen incompatibility, and in three of eight recipients of haploidentical marrow. DISCUSSION

We report a single-center experience of allogeneic BMT as treatment of WAS. Long-term outcome of HLA-identical BMT was excellent except in two patients treated in the early 1980s, one of whom had advanced disease including aortic coarctation probably resulting from vasculitis. These excellent results are similar to the 90% to 100% success rates reported by several other studies for HLA-identical BMT. 7-9 Although our results are based on a small group of patients, the outcome of BMT from MUD in WAS appears satisfactory except in a single case. Filipovich et al. H reported Success in two of two cases, and Lenarsky et al. 12 in four of four cases. As already reported in most studies, the outcome of HLAnonidentical BMT in patients with WAS is poor. One of 6 patients described by Brochstein et al.7 and 3 of 13 described by O'Reilly et al.6 survived. Mullen et al.9 mentioned that 1

Ozsahin et al.

243

in 4 recipients of haploidentical BMT survived, whereas in the multicenter study recently reported by Sullivan et al., l° only 3 of 11 recipients of HLA-nonidentical BMT survived. However, Rumelhart et a1.19reported three successes among four recipients of hapioidentical BMT. In our series, HLAmismatched BMT was successful in 6 of 16 patients. One other patient (UPN 170), in whom engraftment failed after HLA-nonidentical BMT, was cured with HLA identical BMT 5~ years later. Although graft failure seems to have been efficiently prevented with use of the last protocol, 10ng-term immtmodeficiency status after BMT remains the major problem, because it favors the occurrence of EBV BLPD.20, 21 Epstein-Barr virus-associated B-lymphoproliferative disease is particularly frequent after BMT in patients with WAS presumably because of pretransplant EBV positivity with inefficient control of EBV replication after transplant. 22 Nevertheless, the comparison of the outcome of HLA-identical and nonidentical BMT in patients with WAS as in our study is in part an oversimplification. Indeed, recipients of HLA-nonidentical BMT were selected because of the occurrence of severe life-threatening complications of WAS that often required very aggressive immunosuppression. In contrast, recipients of HLA-identical BMT had transplantation regardless of the severity of the disease. This parameter alone may therefore be a poor prognostic factor. However, in our study, four of five recipients of HLA-identical BMT who had severe complications before BMT have been cured. In the future, increasing availability of MUD may help in successful BMT in poor-risk patients. In this setting, although EBV B-LPD may occur after transplantation with Tcell-depleted marrow, treatment with peripheral T cells from the donor seems to be efficient in controlling EBV B-LPD in most cases. 23 Haploidentical BMT should certainly be restricted to those who have life-threatening complications, because the long-term prognosis of patients with WAS, in the absence of BMT, is seemingly good provided that they have had splenectomy. The median survival is now 25 years in such patients. 9 We are grateful for the dedicated work of the nursing and medical staff who cared for these patients. REFERENCES

1. Remold-O'Donnell E, Rosen FS. Sialophorin (CD43) and the Wiskott-Aldrich syndrome. In: Rosen FS, Seligmann M editots. Imrnunodeficiencies. Chur, Switzerland: Harwood Academic Publishers, 1993:225-42. 2. Derry JMJ, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 1994;78:635-44. 3. Lum LG, Tubergen DG, Corash L, Blaese RM. Splenectomy in the management of the thrombocytopenia of the WiskottAldrich syndrome. N Engl J Med 1980;302:892-6. 4. Bach FH, Albertini RJ, Anderson JL, Joo P, Brotin MM. Bone

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The Journal of Pediatrics August 1996

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