Original Article

Bone Marrow Transplantation (2006) 37, 469–477. doi:10.1038/sj.bmt.1705273; published online 23 January 2006

Pediatric Transplants

Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team

Y Tsuji1, K Imai1,2, M Kajiwara1,3, Y Aoki1, T Isoda1, D Tomizawa1, M Imai1, S Ito1, H Maeda1, Y Minegishi1, H Ohkawa1, J Yata1, N Sasaki4, K Kogawa2, M Nagasawa1, T Morio1, S Nonoyama2 and S Mizutani1

  1. 1Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
  2. 2Department of Pediatrics, National Defense Medical College, Saitama, Japan
  3. 3Department of Blood Transfusion, University Hospital Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
  4. 4Department of Pediatrics, Saitama Medical School, Saitama, Japan

Correspondence: Dr Y Tsuji, Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail: ytsuji@ndmc.ac.jp

Received 8 August 2005; Revised 8 November 2005; Accepted 10 November 2005; Published online 23 January 2006.



We retrospectively analyzed our results of 30 patients with three distinctive primary immunodeficiency diseases (PIDs) – severe combined immunodeficiency (SCID, n=11), Wiskott–Aldrich syndrome (WAS, n=11) and X-linked hyper-immunoglobulin M (IgM) syndrome (XHIM, n=8) – who underwent hematopoietic SCT (HSCT) during the past 20 years. Until 1995, all donors were HLA-haploidentical relatives with T-cell depletion (TCD) (n=8). Since 1996, the donors have been HLA-matched related donors (MRD) (n=8), unrelated BM (UR-BM) (n=7) and unrelated cord blood (UR-CB) (n=7). Twenty-seven of 30 patients had various pre-existing infections with or without organ damages before HSCT. Conditioning regimen and GVHD prophylaxis were determined according to disease, donor and pretransplant status. Although one of eight patients transplanted with TCD is alive with full engraftment, the other seven died. On the other hand, 18 of 22 patients transplanted without TCD are alive and well, including six of eight transplanted from MRD, seven of seven from UR-BM and five of seven from UR-CB. All 19 survivors did not require Ig supplementation after HSCT. These results indicate that UR-CBT as well as UR-BMT provides good results for PID comparable to MRD-SCT, and that early diagnosis, HSCT at early stage, careful supportive therapy and monitoring for various pathogens are important for the successful HSCT.


primary immunodeficiency disease, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked hyper IgM syndrome, hematopoietic stem cell transplantation, cord blood transplantation



Primary immunodeficiency diseases (PIDs) are often accompanied with life-threatening infections. Hematopoietic SCT (HSCT) can be a treatment of choice to cure most of the lethal forms of immunodeficiencies, including severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome (WAS) and X-linked hyper immunoglobulin M (IgM) syndrome (XHIM). An HLA-matched related donor (MRD), the best hematopoietic stem cell source, may not always be available. T-cell depletion (TCD) of BM from HLA-haploidentical donors made this possible as another stem cell source for patients without MRD, to prevent GVHD and to lead successful transplantation.1 Methods of TCD varied among different HSCT centers and the results of HSCT also significantly varied.1, 2, 3, 4 BMT with TCD from haploidentical donor often leads to the development of opportunistic infections, such as CMV disease, or lymphoproliferative disorders owing to EBV (EBV-LPD).5 In the 1990s, HSCT using three alternative sources of stem cell developed: BM from matched unrelated donor (UR-BM),6 cord blood from unrelated donor (UR-CB)7 and positively selected CD34+ cells from HLA-mismatched related donor.8

In this study, we retrospectively analyzed the results of 31 consecutive HSCTs for 30 patients with three distinctive immunodeficiency diseases: SCID, WAS and XHIM in a single team experience over 20 years.


Patients and methods

Patients (Table 1)

Between July 1984 and February 2005, 30 children with PID, including 11 patients with SCID, 11 with WAS and eight with XHIM, underwent 28 HSCTs at Tokyo Medical and Dental University and three HSCTs (P13, P22, P30) at the National Defense Medical College, Japan. All 30 patients were male, and the mean and median ages of these patients at HSCT were 5 years 11 months and 10 years 1 month, respectively (range 5 months to 19 years). The analysis was performed at May 2005. Pre-existing infections (Table 2) and clinical complications (Table 3) before HSCT were assessed in all patients. Detailed HSCT courses of P29, 10, 11 and P1412 were reported previously. HSCTs for the patients with XHIM (P23–29) were reported elsewhere.13 A short report of two SCID patients (P10, P11) has been published previously.14 Written informed consent for HSCT was obtained from the parents of each patient.


The diagnosis was confirmed by mutation analysis of the causative genes in all patients except for one patient (P5) whose phenotype was T-B-NK+ SCID. Mutation analysis of IL2RG in X-linked SCID (X-SCID) patients (P2–4),15 RAG1 in Omenn syndrome (OS) patient (P14),16 WASP in WAS patients (P6, P15, P16, P17, P22 in this study are P44, P18, P3, P46, P13, respectively17) and CD40L in XHIM patients (P23–29)13 were reported previously.

Conditioning regimen (Table 1)

For SCID patients (P1–5) from HLA-haploidentical related donors, no conditioning was given. Conditioning for 18 patients, including four patients with SCID (P9–12), eight patients with WAS (P6–8, P16–22) and six patients with XHIM (P24–29) consisted of BU 4 mg/kg/day for 4 days and CY 50 mg/kg/day for 4 days. In all patients transplanted since 2002, BU dosage was determined by pharmacokinetic study in which BU average steady-state plasma concentration was adjusted between 700 and 900 ng/ml.18 TBI 12 Gy and CY 60 mg/kg/day for 2 days were used for five patients (P6–8, P15, P23). AraC 2–3 g/m2 for four doses was added for four patients with WAS (P6–8, P15). Three patients (P13, P14, P30) were transplanted with reduced-intensity conditioning (RIC) regimen, including fludarabine (FLU) 25–30 mg/kg/day for 3 to 5 days and either small dose of TBI (2 Gy) (P13) or melphalan (L-PAM) 70 mg/kg/day for 2 days (P14, P30). Rabbit (P15) or equine (P14, P17–21, P30) antithymocyte globulin (ATG) was used to avoid rejection for eight patients.

GVHD prophylaxis (Table 1)

All but five patients (P1, P3, P6, P14, P23) received short-term (days 1, 3 and 6) MTX. CsA was used for all HSCT except for four patients who received tacrolimus (FK) (P13, P18, P19) or only MTX (P5). Seven patients (P2, P6, P14, P16, P19, P20, P23) received prednisolone (PSL) or methyl-PSL (1 mg/kg/day). Whole blood concentrations of CsA and FK were maintained around 200 and 10 ng/ml until day 30, respectively. These drugs were administered intravenously from day -1, until they could be taken orally. It was carefully tapered over 1 month after day 100 in the absence of GVHD.

Hematopoietic stem cell source (Tables 1 and 4)

BM was obtained from HLA-haploidentical related donor in nine, MRD in seven and UR-BM in seven transplants. Unmanipulated PBSC was used in one transplant (P23) and UR-CB was used in seven transplants.

As none of the patients transplanted before 1994 had MRD and unrelated donors were not available during this period, all donors for these patients were haploidentical relatives. Donor–recipient histocompatibility was determined by serology for HLA-A, -B and DR in transplants until 1995 and by DNA typing for HLA-DRB1 thereafter.

HLA disparities between donors and recipients in UR-BMT and UR-CBT are shown in Table 4. In seven UR-BM donors, HLA was genotypically full matched in four and genotypically one locus mismatched in three donors. In seven UR-CB donors, HLA was genotypically full matched in one, one locus mismatched in four, two loci mismatched in one and three loci mismatched in one.

T-cell depletion

T cells were depleted from BMs of HLA-haploidentical related donor to avoid severe GVHD reaction. In P1, soybean lectin with E-rosetting was used as reported by others.19 In P2, monoclonal antibody, B7, which recognizes E-rosette receptor, was used with complement. In P3, P4, P6–8, monoclonal anti-CD2 and anti-CD6 antibodies were used with immunomagnetic beads. In P5, monoclonal anti-CD5 and anti-CD8 antibody coated flasks were used.

Infused cell dose (Tables 5 and 6)

In seven HSCTs with TCD using monoclonal antibody (P3–8), the mean infused nucleated cell count (NCC) was 2.4 times 107/kg body weight (range 1.0–3.5 times 107/kg), the mean removal rate of CD3+ cells was 2.4 log (2.0–2.8 log) and the mean infused CD3+ and CD34+ cells were 1.0 times 105/kg (0.35–2.6 times 105/kg) and 1.1 times 106/kg (0.2–3.2 times 106/kg), respectively (Table 5). In seven BMTs from MRD, seven UR-BMT and seven UR-CBT, the mean infused NCCs were 3.5 times 108/kg, 4.8 times 108/kg and 8.5 times 107/kg, respectively (Table 6). In one PBSCT from MRD (P23), the infused CD34+ cell count was 9.0 times 106/kg.

Supportive therapy

All patients were nursed in a room with laminar airflow until neutrophil count exceeds 1 times 109/l or more. All patients with conditioning received G-CSF from day 1 until neutrophil counts recovered to more than 1 times 109/l. Antimicrobial prophylaxis during transplantation period consisted of acyclovir 15 mg/kg/day intravenously from day –7 to day 30, cotrimoxazole until 1 year after HSCT and oral amphotericin B or fluconazole until day 100 or more. Four patients (P5, 9, 15, 19) with previous CMV infection received intravenous ganciclovir instead of acyclovir. Vancomycin and polymyxin B were used as intestinal decontamination before mid-1990s and quinolones were used thereafter. All patients received intravenous Ig (IVIG) during the transplantation period maintaining the trough IgG level over 700 mg/dl. Blood samples of all patients were screened for CMV by antigenemia (since 1993) or by PCR (since 2001), and those who tested positive were treated with intravenous ganciclovir and, if necessary, foscarnet.

Post transplantation period

Engraftment was defined as the first day on which neutrophil count exceeded 0.5 times 109/l for 3 consecutive days. Chimerism was assayed on the peripheral blood using HLA typing, XY fluorescence in situ hybridization (FISH; for sex-mismatched HSCT) or variable number of tandem repeat (VNTR) analysis (for sex-matched HSCT). In transplants with no conditioning, lineage-specific chimerism analysis by FISH, VNTR or HLA typing was used. GVHD20 and veno-occlusive disease (VOD)21 were diagnosed and classified according to the standard criteria.

Statistical analysis

The probabilities of overall survival were calculated by Kaplan–Meier analysis. Overall survival was measured from transplantation until death from any causes. The log-rank test was used to compare cumulative survival between subgroups.



Pretransplant status (Tables 1, 2 and 3)

Twenty-seven of 30 patients had pre-existing infections with or without organ damages before HSCT. Bacterial infections were observed in half (15 patients) of the patients. These include skin infections (n=9), otitis media (n=8), pneumonia (n=6) and sepsis (n=1) (Table 1). Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) was diagnosed in 12 patients (five SCID, one WAS, six XHIM patients), and was controlled by cotrimoxazole by conditioning for HSCT. CMV disease was diagnosed in six patients (three SCID, three WAS) and was treated with ganciclovir or ganciclovir in combination with foscarnet (Table 2a). Three SCID patients were vaccinated with Bacillus–Calmette–Guerin (BCG) before diagnosis; however, none experienced disseminated infection before HSCT.

Among SCID patients, five showed failure to thrive, six had intractable diarrhea and three displayed liver dysfunction (Table 3). Two patients with XHIM (P23, P30) suffered from cholangitis, liver dysfunction and prolonged diarrhea caused by Cryptosporidium parvum (C. parvum) infection. Autoimmune diseases were seen in two WAS patients (P16, P20). P16 had severe juvenile idiopathic arthritis and IgA nephropathy, which required steroid therapy. P20 had severe autoimmune cytopenia (autoimmune neutropenia, anemia and thrombocytopenia).

Engraftment (Table 6, Figure 1)

In nine BMTs transplanted with TCD, two (P4, P6–1) resulted in primary graft failure. P4 was scheduled to receive second BMT from unrelated donor but died from sepsis during the conditioning for second BMT. P6 underwent a second transplant from the same donor and resulted in full engraftment (P6–2). Consequently, seven patients transplanted with TCD experienced sustained engraftment; however, mixed chimerism was induced in all but one (P6) patient. These patients showed poor T-cell function after HSCT. T-cell numbers after HSCT in six of these eight patients with TCD are displayed in Figure 1. All the patients whose T-cell number did not reach 1 times 109/l until 6 months after HSCT died within 5 years. We lost all seven patients with SCID (P1–5) and WAS (P7, P8) with T-cell dysfunction. Long-term full engraftment was maintained in only one patient (P6), in whom T-cell number reached 1 times 109/l until 6 months after HSCT with TCD. The patient is currently alive and well with normal platelet count, normal T/B-cell function and IVIG is not required for 14 years.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

T-cell recovery of the patients transplanted with TCD. Numbers of CD3+ cells after HSCT in six patients transplanted with TCD are represented. P2 received thymus transplantation 5 months after SCT. Crosses indicate the death of each patient.

Full figure and legend (15K)

On the other hand, sustained engraftment was achieved in 21 out of 22 patients transplanted without TCD. Among 18 patients successfully transplanted without TCD, two (P13, P15) resulted in mixed chimerism. In P13, who received RIC, most neutrophils are of recipient origin, and T cells and most B cells are of donor origin. P15 achieved stable mixed chimerism in which 90% of neutrophils are of recipient origin, most lymphocytes are of donor origin and platelet count is around 50 times 109/l without transfusion. None of these 18 long-term survivors, including two patients with mixed chimerism, require IVIG.

GVHD and other toxicity (Table 6)

Grade 2–4 acute GVHD developed in nine out of 27 evaluable patients. Three patients with grade 4 acute GVHD (P1, P20, P25) died. The other six patients with grade 2 acute GVHD were successfully treated with mPSL pulse therapy followed by PSL. Chronic GVHD occurred in six out of 24 evaluable patients, and resolved in all but one (P20) of these six patients.

Hepatic VOD occurred in four patients and one patient (P9) died of this complication. Thrombotic microangiopathy (TMA) occurred in four patients and one patient (P20) died of it.

Post transplant infections (Table 2 and 6)

Bacterial infections during the early post transplant period could be treated by systemic antibiotics, but the infections with prolonged use of immunosuppressive drugs for GVHD or with poor immunological reconstitution were difficult to treat and were fatal in some patients (P4, P5, P23).

Mycobacterium infection occurred in three SCID patients, including one tuberculosis (P2),22 one BCG infection (P11) and one Mycobacterium avium complex infection (P14).12 In all three patients, these infections were difficult to overcome, but finally resolved with long-term medication of multiple drug and with immunological reconstitution after HSCT.

No fungal or protozoal infections were seen in SCID and WAS patients. However, these infections were common in XHIM patients. In eight XHIM patients, three (P26–28) had PCP, two (P25, P27) had candidiasis, one (P25) had fatal aspergillosis and two (P23, P30) had disseminated C. parvum infection after HSCT. Although C. parvum was effectively eradicated by high-dose azithromycin in P30, it was not overcome in P23.

CMV disease was diagnosed in six patients and two (P2, P7) of these died of CMV disease despite the treatment with ganciclovir and foscarnet. EBV-LPD occurred in two patients (P3, P8), both of whom were transplanted with TCD and these two patients died of this complication.

Outcome (Table 6, Figure 2)

The mean and median follow-up periods of survivors were 51.6 and 85.6 months, respectively (range 3.3–168.0 months). Survival curves according to year of transplant and donor source are shown in Figure 2a and b, respectively. In Figure 2a, all transplants during 1984–1995 and those during 1996–2005 were performed with TCD and without TCD, respectively. In patients transplanted with TCD, only one (P6) of eight patients (12.5%) is alive. Five-year overall survival rate (plusminus1 s.d.) of these patients is 25.0 (plusminus15.3)% (Figure 2b). The causes of death were GVHD (P1), extensive CMV disease (P2, P7), EBV-LPD (P3, P8) and sepsis (P4, P5) (Table 6).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Survival curves according to year of transplant (a) and to donor source (b). All HSCTs during 1984–1995 were undergone with TCD and those during 1996–2005 were without TCD. In (a), 5-year overall survival rate during 1996–2005 (80.4plusminus8.9%) was significantly higher than that during 1984–1995 (25.0plusminus15.3%) (P=0.017).

Full figure and legend (23K)

On the other hand, overall survival rate during 1996–2005 significantly improved. Eighteen out of 22 patients (81.8%) transplanted without TCD during 1996–2005 are alive. The 5-year overall survival rate of these patients is 80.4 (plusminus8.9)% (Figure 2a, P=0.017 compared with HSCT during 1984–1995, which is identical to HSCT with TCD). Of these, seven of seven transplanted from UR-BM (100%), five of seven from UR-CB (71.4%) and six of eight from MRD (75.0%) are alive and well (Figure 2b), and none of these survivors requires IVIG replacement therapy. VOD (P12) and TMA (P20) were the causes of death in two UR-CB patients. Two XHIM patients (P23, P25) transplanted from MRD died of infection. All of these four deceased patients had severe pretransplant complications.

Autoimmune diseases in two WAS patients resolved after HSCT. Although one (P20) was deceased by TMA, pre-existing severe arthritis in another (P16) resolved after HSCT and no medication is required. IgA nephropathy of this patient is stable and only microscopic hematuria exists after HSCT with no medication.

The mean and median days of post-HSCT in-patient hospitalization in 19 survivors were 172 and 248 days, respectively (range 63–429 days).



In this study, we retrospectively analyzed the results of 31 HSCTs for 30 patients with PID, especially with three distinctive disorders: SCID, WAS and XHIM.


Until 1995, unrelated donor stem cell transplant was not available in Japan; thus, we performed HSCT with TCD from HLA-haploidentical relatives for patients without MRD. We used soybean lectin with E-rosetting in the first HSCT, but the patient (P1) had fatal GVHD in spite of using CsA. The other SCTs with TCD for seven patients (four SCID and three WAS) were undertaken using monoclonal antibodies and resulted in no or transient (grade 0 or 1) acute GVHD (Table 6). The reason for this minimal GVHD may be owing to the low dose of infused CD3+ cells. Although the initial transplant courses were uneventful, all of these seven patients failed to develop durable T-cell function. One WAS patient was treated by the second BMT from the same donor and full T-cell reconstitution was achieved. However, the other six patients suffered from prolonged and fatal infections after 100 days, including two extensive CMV diseases, two EBV-LPD and two sepsis. As shown in Figure 1, the initial increase of T-cell number after HSCT may predict the following durable T-cell engraftment and function. One reason for these results may be the insufficient number of infused CD34+ cells as suggested by others23 (Table 5).

Although TCD-BMT was one of the commonly used transplantation modalities, our result on BMT with TCD was far from satisfactory, which led us to use unrelated donor stem cells that became available in 1990s.


Our result of 22 HSCTs without TCD with conditioning including 14 unrelated donor transplants was encouraging (5-year overall survival: 80.4%). All 18 survivors are alive and well with complete chimerism except for two patients (P13, P15). All 18 survivors, including two patients with RIC, are free of IVIG.


Severe (grade 3–4) acute GVHD was rare (two out of 22). In two patients with grade 4 GVHD, one was transplanted from MRD (P25) and the other was from HLA one locus-mismatched UR-CB (P20). In all the other HLA genotypically mismatched HSCT from UR-BM (n=3) and UR-CB (n=5), severe GVHD did not occur. Thus, HLA disparity seemed not to be correlated with severe GVHD.


In SCID, myeloablative conditioning (MAC) was not tolerated by one patient (P12) because of severe pre-existing organ dysfunctions. Most patients with SCID carry infections or organ dysfunctions at the time of HSCT; thus, RIC seems to be suitable as pointed out by others.24 In our latest two patients with SCID (P13, P14), we performed HSCT with RIC. The clinical course of P13 was uneventful; T cells were fully engrafted and IVIG is not required. P14 experienced M. avium complex infection, which required prolonged multidrug antimycobacterial therapy, but finally resolved.

In XHIM, MAC was tolerated in five patients without organ dysfunction (P24, P26–29), but not in two patients with severe organ dysfunction (P23, P25). According to these results and to other reported results,24, 25 RIC seems to be feasible for patients with organ dysfunction. We underwent HSCT with RIC for an XHIM patient who had liver dysfunction and hepatic encephalopathy at the time of HSCT (P30). P30 did not experience hepatic failure, but suffered from severe involuntary movement associated with EBV reactivation, which gradually resolved with immunological reconstitution.

In WAS, the conditioning regimen consisted of BU+CY for HSCT from MRD (P16, P22) and adding ATG for HSCT from unrelated donor26 (P17–19, P21) seemed to be tolerable and to be feasible for full engraftment. On the other hand, one UR-BMT with TBI, CY and AraC (P15) resulted in mixed chimera with relatively low platelet and prolonged need of IVIG. The role of ATG should be determined by prospective studies with much higher numbers of patients. RIC regimen remains to be assessed in WAS patients.

Cord blood transplantation

Four of five patients with SCID and one of two patients with WAS transplanted with UR-CB are alive and well with fast and durable engraftment with no need for IVIG. This result is encouraging, and thus if MRD is not available, we plan to continue to perform UR-CBT for SCID patients because of the availability when urgently required. In WAS patients without MRD, UR-BMT has been preferred27 rather than haploidentical BMT with TCD, but successful UR-CBT was also reported recently.28 Thus, UR-CBT may be a treatment of choice for patients with WAS, if urgent HSCT is necessary or if the patient lack a suitable UR-BM donor.

Pretransplant condition

In our results, pretransplant condition in PID was important and seemed to be correlated with the outcome. In HSCT without TCD, all four deceased patients (P12, P20, P23, P25) had severe pretransplant complications. Transplant at an early age seems to be important and may alter the outcome. In our three patients with SCID, BCG vaccination had already been performed before the diagnosis of SCID and BCG infection became overt and difficult to control after HSCT in one patient (P11). As BCG vaccination is performed before 6 months of age in Japan, early diagnosis by neonatal screening29 and early HSCT seem to be important and necessary, especially in SCID patients.30 Recurrence of PCP was observed in three XHIM patients in spite of the prophylactic use of cotrimoxazole, but it was controllable in all three cases. However, one of the recurrences of C. parvum infection in two XHIM patients was difficult to control, indicating the requirement of early HSCT for XHIM as pointed out by others.25



In summary, our results for HSCT with TCD for patients with PID were disappointing, but the result of HSCT without TCD including unrelated donors was excellent and promising. Early diagnosis and early HSCT may alter the outcome and may allow us to conduct a multicenter study because many various pre-existing problems in each patient limited us in using the same conditioning regimen. In patients with no suitable donor including cord blood, and in patients in whom urgent HSCT is necessary, HSCT from HLA-haploidentical relative by CD34+ selection may be a treatment of choice. Multicenter studies are needed to determine the best procedures in HSCT for patients with these rare disorders.



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This study is in part supported by a grant from Ministry of Health, Labour and Welfare, Japan Defense Agency, Japan Intractable Diseases Research Foundation, and Kawano Masanori Foundation for Promotion of Pediatrics.