Abstract 4571

Severe combined immunodeficiency (SCID) is the most severe form of the primary immunodeficiencies (PID), the most frequent type of which is X-linked SCID (X-SCID; T-B+NK-SCID). Hematopoietic stem cell transplantation (SCT) is the only curative treatment for these high-risk patients. Recently, some PID cases treated with unrelated cord blood stem cell transplantation (CBT) have been reported. To avoid severe infection during SCT and late complications, such as mental and growth retardation, reduced-intensity conditioning (RIC) regimens have been used for unrelated SCT for PID patients. However, reports of X-SCID patients receiving CBT with reduced-intensity stem cell transplantation (RIST) are quite limited. We report successful allogenic RIST from unrelated cord blood (CB) for treatment of X-SCID in our single centre. Three patients with X-SCID who had no HLA-matched sibling received unrelated CBT. Mutations in the common gamma chain gene were detected in all patients. Pre-transplantation conditioning for all patients consisted of fludarabine (FLU) (30 mg/m2/day) from day -7 to day -2 (total dose 180 mg/m2) and busulfan (BU) 4 mg/kg/day from day -3 to day -2 (total dose 8 mg/kg). All CB units were serologically matched HLA-A, B, and DR loci. Though two of the patients suffered from fungal or bacterial pneumonia before transplantation, there were no additional infectious complications during transplantation. All patients achieved engraftment with an absolute neutrophil count > 500/μ l with a mean of 22 days (range, 19–27 days), and they showed 100% donor chimerism by fluorescence in situ hybridization of their peripheral mononuclear cells using × and Y chromosome probes at one-year post transplantation. Full donor chimerism of both T and B cells was also confirmed. Only one patient (patient 2) developed grade III acute graft versus host disease (GVHD), which resolved with increased oral corticosteroid. None of the patients have developed chronic GVHD, received intravenous immunoglobulin replacements after the transplantations, or showed delayed psychomotor development during 21 to 77 months of follow-up. Only one patient (patient 3) had short stature (-2.4SD) at 21-month follow-up. The most commonly used RIC regimens worldwide have been the FLU/melphalan (LPAM) and the FLU/BU regimens. LPAM has broad stem cell toxicity to both primitive and committed stem cells, while BU may spare committed stem cells, resulting in early onset and a prolonged duration of neutropenia with the FLU/LPAM regimen. Moreover, it has been reported that the LPAM-containing conditioning regimen is a risk factor for hepatic veno-occlusive disease. Although conditioning regimens including standard-dose BU may be associated with a high rate of treatment-related complications due to organ toxicity, reduced-dose BU in combination with FLU is less myelosuppressive and less toxic than the FLU/LPAM regimen. Moreover, CBT has some advantages with regard to incidence and intensity of GVHD and availability compared with other alternative stem cell sources. Patients 1 and 2 had overcome pre-existing fungal and bacterial pneumonias, respectively, and recovered after transplantation. Thus, immediate SCT using an RIC regimen could be indicated for patients with X-SCID to reconstitute the immune system regardless of pre-existing infections. Since pre-existing infections are the principal risk factors for poor SCT outcomes, early diagnosis and transplantation before any infectious episodes is necessary for X-SCID patients. In conclusion, CBT is a suitable alternative to bone marrow transplantation for X-SCID patients requiring urgent SCT with no sibling donors. RIC consisting of FLU and BU is an effective and safe treatment for such cases.

Table 1.

Patients’ Characteristics

Patient 1Patient 2Patient 3
Age at diagnosis (months) 
Age at CBT (months) 
Common gamma chain mutation 682T>G in exon 5 9_10insA in exon 1 216G>A in exon 2 
CD34+ cell dose (×105/kg) 6.7 5.3 3.2 
Hematological recovery    
 Neutrophils>500/μ l day+19 day+22 day+27 
 Platelets>50×109/l day+28 day+43 day+31 
Chimerism (donor%) 100 100 100 
 B cell engrafted (donor% (day)) 100 (day+120) 100(day+89) 100(day+83) 
Outcome Alive +77 months Alive +69 months Alive +21 months 
 Height −0.53SD −0.49SD −2.4SD 
 Body mass index 15.0 16.1 15.6 
 Mental status normal normal normal 
Patient 1Patient 2Patient 3
Age at diagnosis (months) 
Age at CBT (months) 
Common gamma chain mutation 682T>G in exon 5 9_10insA in exon 1 216G>A in exon 2 
CD34+ cell dose (×105/kg) 6.7 5.3 3.2 
Hematological recovery    
 Neutrophils>500/μ l day+19 day+22 day+27 
 Platelets>50×109/l day+28 day+43 day+31 
Chimerism (donor%) 100 100 100 
 B cell engrafted (donor% (day)) 100 (day+120) 100(day+89) 100(day+83) 
Outcome Alive +77 months Alive +69 months Alive +21 months 
 Height −0.53SD −0.49SD −2.4SD 
 Body mass index 15.0 16.1 15.6 
 Mental status normal normal normal 

CBT, cord blood transplantation

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.